1991 — 1993 |
Dewhurst, Stephen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Characterization of Siv Ltr @ University of Rochester
DESCRIPTION: (Adapted from applicant's abstract) The proposed studies will attempt to elucidate the contribution of the human immunodeficiency virus (HIV) LTR to pathogenesis using SIV as a model system. The investigator will attempt to assess whether LTR mutations between phenotypically distinct viruses lead to "genetic" and/or "cell-type/species-specific" differences in viral gene expression by measuring relative levels of LTR-driven expression of an indicator gene (CAT/SEAP). The applicant will attempt to correlate such differences with other parameters, including LTR-binding by cellular proteins and viral pathobiology. Site-directed mutagenesis will be used to assign significance to individual mutations between LTRs. Data correlation will be facilitated by using the same panel of cells for all studies, that is, peripheral blood mononuclear cells (PBMC), lymphoid cell lines, enteric macrophages and lymphocytes from several primate species, as well as human cell lines of various lineage. Finally, the applicant proposes to investigate whether LTR changes are associated with pathogenesis of other SIV isolates. LTRs will be cloned from necropsied tissues and /or "post-disease onset" PBMC specimens from animals that succumbed to fatal SIVsmm infection, as well as serial blood samples (harvested before and after onset of disease). Comparative sequence analysis will then be performed.
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1 |
1994 |
Dewhurst, Stephen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Siv Ltr @ University of Rochester
DESCRIPTION: (Adapted from applicant's abstract) The proposed studies will attempt to elucidate the contribution of the human immunodeficiency virus (HIV) LTR to pathogenesis using SIV as a model system. The investigator will attempt to assess whether LTR mutations between phenotypically distinct viruses lead to "genetic" and/or "cell-type/species-specific" differences in viral gene expression by measuring relative levels of LTR-driven expression of an indicator gene (CAT/SEAP). The applicant will attempt to correlate such differences with other parameters, including LTR-binding by cellular proteins and viral pathobiology. Site-directed mutagenesis will be used to assign significance to individual mutations between LTRs. Data correlation will be facilitated by using the same panel of cells for all studies, that is, peripheral blood mononuclear cells (PBMC), lymphoid cell lines, enteric macrophages and lymphocytes from several primate species, as well as human cell lines of various lineage. Finally, the applicant proposes to investigate whether LTR changes are associated with pathogenesis of other SIV isolates. LTRs will be cloned from necropsied tissues and /or "post-disease onset" PBMC specimens from animals that succumbed to fatal SIVsmm infection, as well as serial blood samples (harvested before and after onset of disease). Comparative sequence analysis will then be performed.
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1 |
1994 — 1998 |
Dewhurst, Stephen |
K04Activity Code Description: Undocumented code - click on the grant title for more information. |
Pathogenesis and Therapy For Lentiviruses @ University of Rochester
The pathogenesis of AIDS will be studied using a molecularly cloned, acutely pathogenic, simian immunodeficiency virus, SIVsmmPBj14. A collaboration with a highly-regarded primatologist at the University of Alabama at Birmingham (Dr. P. Fultz) has been established and experiments are proposed to determine the pathobiologic significance of mutations in cis-acting sequences which regulates viral transcription. Other studies focus on improving gene therapeutic approaches to HIV treatment. These experiments involve the characterization and analysis of cis-acting DNA elements which regulate the DNA replication of a ubiquitous human virus, human herpesvirus 6 (HHV-6). Ultimately, these studies are expected to result in the development of gene delivery vectors or artificial mini- chromosomes" based on this T-lymphotropic herpesvirus.
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1 |
1994 — 1997 |
Dewhurst, Stephen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Hhv-6 Vectors For Aids Therapy @ University of Rochester
Human immunodeficiency virus type 1 (HIV-1) is the cause of acquired immunodeficiency syndrome (AIDS) and is estimated to infect roughly one million Americans. Currently available therapies for HIV-infected individuals are inadequate. We propose to develop a novel gene delivery system, which would allow for "intracellular immunization" against HIV in vivo. Human herpesvirus 6 (HHV-6) is a ubiquitous virus with minimal known pathogenicity, and a host cell range very similar to that of HIV-1 (it infects CD4+ T-cells and monocyte/macrophages). This proposal sets forth experiments that are designed to characterize cis-acting sequences which regulate DNA replication of HHV-6 with a view towards developing HHV-6 based vectors. By analogy to other herpesviruses, it is expected that two DNA elements will be required for HHV-6 replication. These comprise an origin of replication and a packaging site. Using a transient replication-complementation assay it has been shown that plasmid constructs containing cloned fragments of HHV-6 DNA were replicated in human T-cells when trans-acting factors were provided by HHV-6 infection. Thus, a lytic-phase origin of HHV-6 DNA replication has been identified. A viral packaging site will identified by a similar approach and both of these elements will be molecularly characterized via-site-directed mutagenesis. These DNA elements will then be combined into a single plasmid, or "amplicon", together with a beta-galactosidase indicator gene. The ability of this construct to mediate gene transfer into various cells will be assessed, using wild-type helper virus. Studies will also be carried out to assess the feasibility of constructing HHV-6 based human artificial chromosomes. The genomic status of HHV-6 DNA during viral latency will be determined, and the functional significance of telomere-like structures within the HHV-6 genome will be studied. 2D-gels and stable replication assays will then be used to determine whether a distinct viral origin, analogous to EBV oriP, is used during latent-phase HHV-6 DNA replication. These studies are expected to contribute to the development of a novel gene delivery system for intracellular immunization against HIV-1.
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1 |
1996 — 1998 |
Dewhurst, Stephen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Immunopathology of Acute Siv Infection @ University of Rochester
DESCRIPTION (Adapted from investigator's abstract): This application will examine the primary infection of macaques with the SIV strain, SIVsmmPBj14. SIVsmmPBj14 induces severe acute disease, with viremia and high circulating levels of the cytokines tumor necrosis factor alpha (TNFa) and interleukin-6 (IL-6). Experiments proposed will test the hypothesis that immune activation is crucial in the pathogenesis of acute lentiviral disease, through effects on cytokine production, virus replication and apoptosis. In vitro studies will characterize SIVsmmPBj14-induced cellular proliferation. Experiments will test whether cellular proliferation is dependent on endogenous pro- inflammatory cytokines (TNFa, IL-6) or an T cell activation. Studies will also be conducted to assess whether virally-induced T-cell proliferation is dependent on TCR-mediated signaling and/or on specific T-cell costimulatory pathways. In addition, studies will be performed to determine whether SIVsmmPBj14 Nef is required for induction of cellular proliferation and whether sro-homology domains contained within the protein are required for this effect. In vivo experiments will be conducted to directly test whether T cell activation or pro-inflammatory cytokines contribute to acute SIV disease. Finally, the contribution of T-cell activation to the subsequent progression of SIV-induced immunodeficiency will be analyzed directly, using SIVsmmFGB. SIVsmmFGB is closely related to SIVsmmPBj14, but is not acutely lethal--rather, it induces fatal immunodeficiency within 4-6 months. Studies will be conducted to assess the effect that treatment of macaques with cyclosporin-A during the acute-phase of SIVsmmFGB infection has on clinical, immunologic and virologic parameters.
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1 |
1997 — 2000 |
Dewhurst, Stephen |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Nfkb and Oxidative Stress in Neuro-Aids @ Children's Memorial Hospital (Chicago)
This Project will test the hypothesis that activation of NFkB in microglia, and in cells that constitute the blood-brain barrier (BBB), may contribute to the neuropathogenesis of AIDS, and the blockade of NFkB may have therapeutic potential in this setting. The following Specific Aims are proposed. (1) Examine whether persistent NFkB activation is correlated with the release of neurotoxins from, or HIV-1 replication in, microglia. Experiments will also be conducted to test directly whether NFkB activation leads to production of neurotoxins by microglia, and whether specific blockade of NFkB leads to inhibition of the release of neurotoxins from, or HIV-1 replication 1, microglia. (2) Employ cell culture models for the BBB (brain microvascular endothelial cells [BMVECs] and astrocytes) to test the hypothesis that activation of NFkB in cells that comprise the BBB may result in damage to the integrity of this barrier. Experiments will determine whether NFkB activation leads to increased expression of adhesion molecules or metallo-proteases by MBVECs and astrocytes, and studies will also be conducted to test whether induction of these proteins by TNF-alpha is prevented by specific blockade of NFkB. In addition, analogous experiments will be conducted using in vitro assays for BBB integrity. Specifically, the integrity of MMVEC and BMVEC/astrocyte monolayers will be assessed by measuring their permeability to macromolecules and by quantitating trans-monolayer migration by monocytes. (3) Test broadly-based anti-oxidant and anti- inflammatory drugs for their ability to block NFkB activation in microglia and in BMVECs. Data from these studies will be correlated with effects on neurotoxin release (microglia) and adhesion molecule and metalloprotease expression (BMVECs). Taken together, these experiments are expected to result in the identification of novel therapeutic strategies for the treatment of HIV-1 dementia.
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1 |
1998 — 1999 |
Dewhurst, Stephen |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Targeted Dna Delivery For Hiv Vaccine Development @ University of Rochester
DESCRIPTION (Adapted from the applicant's abstract): This application is focused on the enhancement of immune responses to HIV envelope proteins, and seeks to develop a new method to facilitate targeted expression of native immunogens in vivo, with the aim of advancing HIV vaccine design. The experiments proposed will examine whether candidate DNA accines can be targeted more efficiently to APCs, with special emphasis on blood-derived DCs, by conjugating them to an adenovirus protein (penton base) that binds to specific cellular integrins and participates in endosome lysis, or by linking them to Type 1 HIV (HIV-1) Tat-derived peptide, which undergoes efficient cellular import. In Aim 1, the applicants will test whether adenovirus penton base protein (ADPB), which contains RGD and LDV motifs found in Ad7 and Ad11, can be used to facilitate DNA delivery to cultured blood DCs. In Aim 2, modifications will be introduced into ADPB to selectively alter its ability to interact with cellular integrins. Known integrin-binding motifs will be substituted into ADPB, including the HIV-1 Tat RGD motif, and a high-affinity RGD motif selected by phage display. The ability of these modified ADPBs to target cultured DCs will be examined. In Aim 3, the investigators will examine whether a bifunctional peptide, containing the basic domain of HIV-1 Tat plus a poly-lysine tract, can be used to deliver exogenous DNA molecules to DCs. In vivo studies will be conducted in Aims 4 and 5. In Aim 4, experiments will be conducted to determine whether native ADPBs (Aim 1), mutant ADPBs (Aim 2) or Tat-derived peptides (Aim 3), when conjugated to a reporter plasmid (E. coli beta-galactosidase (b-Gal), or green fluorescent protein (GFP)), can produce more efficient expression of a reporter gene and enhanced targeting to DCs in mice. These reporter genes show improved expression after intradermal injection or gene gun delivery. The optimal delivery agents then will be conjugated to HIV-1 DNA vaccine encoding gp120. Finally, the optimal ADPB derivative (from Aims 1-4) will be conjugated to a candidate HIV-1 DNA vaccine, and its ability to engender anti-HIV-1 immune responses in vivo (mice) will be compared to that of the same DNA construct, when delivered by conventional means.
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1 |
1998 |
Dewhurst, Stephen |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Hhv6 and Hhv7 Vectors For Aids Therapy @ University of Rochester
DESCRIPTION: Human herpesvirus 7 (HHV-7) was shown to infect T cells and uses the CD4 receptor, and it has also been found to inhibit HIV-1 infection. This study proposes to characterize two viral glycoproteins that may play an important role in infection and immune modulation. The first glycoprotein is a homologue of the HHV-6 gp105 which is a target for virus-neutralizing antibodies, and the second is the M85 ORF which is a homologue of the T cells co-stimulating ligand (OX-2). Four specific aims were proposed. The first three focused on the gp105 homologue and the last on the U85 ORF. Specific aim 1 proposes to characterize the HHV-7 gp105 homologue cDNA and its protein. Specific aim 2 proposes to functionally characterize the gp105 homologue and determine whether it plays a role in viral infection and entry. The third aim proposes to construct and characterize an HHV-7 mutant lacking gp105. The last aim proposes to characterize the HHV-7 OX-2 homologue to determine whether it possesses any co-stimulatory activities. These studies should shed light on fundamental aspects of the biology and replication of HHV-7, and may contribute to the development of HHV-7 as vector for gene transfer into CD4+ T cells.
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1 |
1999 — 2000 |
Dewhurst, Stephen |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Cytomegalovirus Vectors For Hiv Vaccine Development @ University of Rochester
humoral immunity; laboratory mouse; transfection /expression vector
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1 |
2000 — 2001 |
Dewhurst, Stephen |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Novel Systems For Cns Gene Therapy @ University of Rochester
transcytosis; transfection /expression vector; biotechnology; blood brain barrier; membrane permeability; gene therapy; membrane model; peptide chemical synthesis; differential display technique; embryo /fetus tissue /cell culture; hollow fiber separation technique; human fetus tissue; laboratory mouse; protein sequence; peptide library; serial analysis of gene expression;
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1 |
2000 — 2007 |
Dewhurst, Stephen Sia, Elaine (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Reu Site Program in Cellular and Molecular Biology At Rochester @ University of Rochester
This REU Site Program is designed to organize the resources, environment and experience of a major research University so as to provide enhanced research opportunities in Cellular and Molecular Biology to promising undergraduate students. The Program builds upon major strengths in the University of Rochester's programs in the Biological Sciences and it is intended not only to provide outstanding research experiences, but also to encourage participating undergraduates to pursue career paths in the biological sciences. Students will be recruited principally from four-year colleges, including minority-serving institutions with which the Program Director has developed linkages. The central research experience will take place during a 10-week, full-time work period each summer. At this time, each REU student will pursue an independent research project under the supervision of a specific faculty mentor, and with the hands-on guidance of a "bench advisor" such as a graduate student or postdoctoral fellow, who will provide assistance with laboratory methods and new techniques. The summer experience will be enriched through seminars on a range of research topics and career-development issues (including a roundtable discussion of careers in science). In addition, a GRE prep course will be offered for interested students, and all participating students will be encouraged to get to know each other through scheduled social activities. All students who do not live in the Rochester area will also be offered no-cost housing for the summer in a single on-campus dorm, located within 5-minutes walk of the laboratories in which they will conduct their research. All students will be given the opportunity to enhance their communication skills by presenting posters on their research at the end of the summer, at a mini-symposium that will be attended by other trainees and faculty members. Finally, all students will be strongly encouraged to present their research at national and local scientific meetings, and to continue part-time research work during the academic year. The major goal of this program is to help to support the progression of promising undergraduates into Ph.D. programs in the Biological Sciences.
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1 |
2000 — 2003 |
Dewhurst, Stephen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Disregulation of Neuronal Gsk-3beta by Paf @ University of Rochester
DESCRIPTION (adapted from applicant's abstract): Platelet activating factor (PAF) is a bioactive phospholipid which plays a variety of roles in the central nervous system (CNS). A number of pathologic events, including seizures, ischemia and inflammatory reactions lead to the synaptic accumulation of PAF. In this setting, PAF can act as a mediator of neuronal injury. Excessive levels of PAF may also interfere with the normal development of the CNS, by inhibiting neuronal migration (for example, in the context of Miller-Dieker lissencephaly). Our preliminary studies have shown that PAF can upregulate the activity of glycogen synthase kinase 3-beta (GSK-3b) in primary neurons. This may be relevant to PAF's effects on neuronal survival and neuronal migration because GSK-3b has been implicated in axonal remodeling and in the regulation of the neuronal cytoskeleton, and also because activation (over expression) of GSK-3b has been demonstrated to lead to apoptosis of PC12 cells. We therefore hypothesize that PAF's effects on GSK-3b may contribute both to its neurotoxic activity and to its ability to disrupt neuronal migration. The studies proposed in this application are intended to experimentally test this hypothesis. First, the molecular mechanisms, which contribute to PAF-mediated activation of neuronal GSK-3b, will be delineated (Aim 1). Second, experiments will be conducted; to test the hypothesis that GSK-3b activation is required for PAF-mediated neurotoxicity (Aim 2). Finally, studies will be performed to determine whether GSK-3b activation is also required for PAF-mediated disruption of neuronal migration (Aim 3). Taken together, these experiments are expected to provide new insights into the regulation of GSK-3b activity in neurons, and into the role that GSK-3b may play in mediating PAF's effects on neuronal survival and neuronal migration.
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1 |
2001 — 2005 |
Dewhurst, Stephen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Adaptations of Human Herpesvirus-7 to Salivary Glands @ University of Rochester
Human herpesvirus (HHV)-7 infection is associated with persistence of viral genomes in salivary gland (SG) tissues, and chronic expression of viral antigens in these sites. The virus is generally thought to be spread by a salivary route, and there is lifelong shedding of large amounts of infectious virions in saliva. These observations suggest the following hypothesis: that HHV-7 has evolved specific mechanisms to gain entry to SG cells and to evade host immune responses in SG tissues. In this proposal, we will examine the role of specific viral proteins in virus attachment and entry to SG epithelial cells. In the first two specific aims, the unique viral glycoprotein, gp65, will be studied. Gp65 is a component of the virus particle, and polyclonal antisera directed against gp65 neutralize virus infectivity; HHV-7 gp65 also binds to heparan sulfate proteoglycans (HSPGs). These data strongly suggest that gp65 plays a role in cellular attachment and entry by HHV-7; this hypothesis will be tested experimentally. First, we will examine the interaction of purified recombinant HHV-7 gp65 with cell surface HSPGs found on cultured human SG cells. Second, a gp65- deleted recombinant virus will be constructed, and its ability to attach to and enter cultured SG cells will be examined. Third, the molecular architecture of gp65, and its interaction with host macromolecules will be studied. In the third aim, we will study two putative 7-transmembrane (7- tm) receptors encoded by HHV-7, U12 and U51. Homologous genes encoded by rat and mouse cytomegalovirus (CMV) are essential for efficient viral replication in salivary glands, and a related gene in human CMV has been shown to contribute to membrane fusion events that may be involved in virus entry or spread. Experiments will therefore be conducted, to determine whether HHV-7 U12 and U51 can enhance membrane fusion events mediated by different viral proteins in cultured SG cells. It is expected that a greater understanding of the molecular pathways exploited by HHV-7 will contribute to the future design of enhanced gene delivery vehicles for SG gene therapy; such vector systems may incorporate components of HHV-7.
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1 |
2001 — 2004 |
Dewhurst, Stephen |
P51Activity Code Description: To support centers which include a multidisciplinary and multi-categorical core research program using primate animals and to maintain a large and varied primate colony which is available to affiliated, collaborative, and visiting investigators for basic and applied biomedical research and training. R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Lentivirus Attenuation Through High Fidelity Replication @ University of Rochester
Human Immunodeficiency Virus type-1 (HIV-1) reverse transcriptase (RT) is a highly error-prone enzyme that is thought to be responsible for the generation of viral genetic diversity. This in turn has been suggested to be essential to the virus' ability to evade host immune responses, and to establish a state of persistent, productive infection in the host. Our hypothesis is that viruses with enhanced replicational fidelity will generate fewer mutants than wild-type viruses, and that such "high- fidelity" viruses may be incapable of escaping from host immune pressure, due to their inability to spawn highly diverse quasispecies. If correct, this hypothesis could have important implications for the design of live-attenuated HIV vaccines. This application represents a proof-of-concept study that is designed to test whether a "high fidelity" primate lentivirus is indeed attenuated in terms of the generation of new mutants and escape from immune pressure within a nonhuman primate host. The Simian Immunodeficiency Virus (SIV)/macaque model system will be used for these experiments. In earlier studies, we have created HIV-1 and SIV RT mutants with increased replicational fidelity (approx. 10-fold greater than wild-type). Similar methods will be used to create several high-fidelity mutants of SIVmac239 RT. After biochemical characterization, these RT mutants will be substituted into an intact SIVmac239 molecular clone, and virus stocks will be generated (SIVmac239-hifi). The replicational fitness and fidelity of these viruses will be tested in vitro, and a clone with wild-type replicational fitness but enhanced replicational fidelity will then be selected for in vivo studies. This virus will be inoculated into rhesus macaques (both Mamu-A*01 positive and Mamu-A*01 negative animals), and the development of virus-specific, Mamu-A*01 restricted CTL responses will be examined using MHC:peptide tetramers. Plasma virus load will be measured at selected time points following infection, and viral genetic diversity will be analyzed at several loci, including a Mamu-A*01 restricted Tat CTL epitope that has previously been to shown to undergo very rapid replacement in SIVmac239-infected, Mamu-A*01 positive rhesus macaques, but not in infected Mamu-A*01 negative animals. These experiments are expected to provide insight as to the potential utility of using high fidelity RT mutants to improve the safety of live-attenuated HIV vaccines.
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1 |
2001 — 2002 |
Dewhurst, Stephen |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Role of Gsk-3beta in Hiv 1 Induced Neuronal Damage @ University of Rochester
DESCRIPTION: (Provided by applicant): A significant proportion of individuals infected with human immunodeficiency virus type-1 (HIV-1) will develop HIV-associated dementia (HAD). Neuronal injury and cell death are thought to contribute to the pathogenesis of this disorder, and these events are believed to occur in response to the production and release of both viral and cellular gene products; collectively, these molecules are referred to as candidate HIV neurotoxins. We have evidence that two well-characterized candidate HIV-1 neurotoxins (HIV-1 Tat and platelet activating factor, or PAF) up-regulate the activity of glycogen synthase kinase 3-beta (GSK-3beta) in neurons. Furthermore, the toxic effects of Tat and PAF can be eliminated by inhibition of GSK-3beta. These findings suggest the following hypothesis: that activation of GSK-3beta may contribute to neuronal death and damage in the context of HAD. This hypothesis will be tested experimentally through the studies set forth in this proposal. Specifically, the contribution of GSK-3beta activation to the activity of candidate HIV neurotoxins will be examined, using intracellular molecular inhibitors of GSK-3beta (Frat and a dominant-negative GSK-3beta mutant). Analysis of the mechanism(s) involved in GSK-3beta mediated neuronal apoptosis and neuronal damage will then be examined, with emphasis on beta-catenin, protein tau, and the antiapoptotic transcription factor, NFKB. Finally, experiments will be conducted to identify novel peptides capable of disrupting the interaction between GSK-3beta and the scaffolding protein, Axin. This interaction is known to be necessary for phosphorylation of many key substrate molecules of GSK-3beta, and is therefore expected to represent an important and useful therapeutic target that may lead to new insights into the design of neuroprotective molecules for use in HAD and other neurodegenerative disorders.
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1 |
2001 — 2010 |
Dewhurst, Stephen |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Training in Hiv Replication and Pathogenesis @ University of Rochester
DESCRIPTION (provided by applicant): The overall goal of the proposed predoctoral training program is to contribute highly creative, productive and well trained HIV/AIDS researchers to meet national health and research priorities. This goal will be achieved by having a cadre of predoctoral students train in the well-established interdepartmental graduate training milieu of the University of Rochester School of Medicine and Dentistry (URMSD), under the supervision of experienced and caring mentors. This highly interactive core environment will be fostered by: a faculty dedicated to excellence in teaching and research and committed to training in HIV/AIDS research;outstanding HIV/AIDS research programs of the program faculty;lecture courses and structured seminars in various aspects of HIV/AIDS research;journal clubs;well-designed enrichment activities and workshops;and a catalytic number of trainees. Research opportunities in a wide variety of relevant problems within the purview of HIV/AIDS research will be offered to trainees by experienced mentors with strong extramural funding and an established history of collaboration. Specific objectives of the program are as follows: 1. To develop an interactive, productive and exciting interdisciplinary environment in which predoctoral trainees obtain an outstanding education in the area of HIV/AIDS research. This will be achieved by integrating faculty from several different departments and disciplines. 2. To provide an enriched training and learning environment for students, with skills workshops, structured seminar programs and journal clubs, distinguished extramural speakers, career development activities, enhanced training in the responsible conduct of research, and opportunities for training in mentoring. Students will also be trained to evaluate and write both manuscripts and grant applications. 3. To foster communication among trainees and faculty through the programs outlined above. This will exploit the intimate environment provided at the URSMD, where all the participating faculty and trainees work together in the same physical space, under a single roof. 4. To support training efforts in three major emphasis areas: (i) viral replication and reverse transcription, (ii) viral immunology and vaccine biology, and (iii) viral pathogenesis, with special emphasis on neuroAIDS and host factors that control virus replication.
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1 |
2002 — 2006 |
Dewhurst, Stephen |
R25Activity Code Description: For support to develop and/or implement a program as it relates to a category in one or more of the areas of education, information, training, technical assistance, coordination, or evaluation. |
Research and Education in Microbiology and Immunology @ University of Rochester
DESCRIPTION (provided by applicant): The long-term goal of this proposal is to prepare trainees from underrepresented minority groups for careers as outstanding research scientists and leaders in the biomedical community. This training program will provide research and education opportunities in microbiology and immunology, that are of direct relevance to many of the health problems that disproportionately affect minorities and medically underserved groups (e.g., arthritis, cancer, cardiovascular disease, diabetes, HIV and other STDs, and respiratory diseases). This program has three specific objectives. First, a supportive, productive, and exciting environment will be created, in which trainees will conduct outstanding research in microbiology and immunology, while working as full-time laboratory technicians under the supervision of a program faculty member. This will be achieved by bringing together a highly interactive and experienced group of well-funded faculty concerned with the advancement of underrepresented minority trainees, whose research interests span a diverse range of topics, and whose laboratories use a wide array of experimental approaches. The second aim of the program is to provide high quality educational opportunities that will prepare trainees for future doctoral studies. To this end, each trainee will perform an independent research project under the supervision of a faculty mentor. In addition, an individual plan of study will be developed for each PREP participant, tailored specifically to meet the individual needs of that trainee. This will include a small number of carefully selected courses, designed to allow trainees to (a) receive necessary instruction in specific skills/areas, (b) demonstrate their academic preparedness for doctoral studies, and (c) to gain academic credit towards the Ph.D. at the University of Rochester. The third aim of the program is to provide a highly enriched learning environment, with strong peer support. Enrichment activities will include instruction in scientific communication skills, attendance at national scientific meetings, internship opportunities, participation in an annual retreat/symposium, participation in extramural workshops and seminars (including intensive hands-on training in sophisticated scientific methodologies, as well as in-depth instruction in grant writing), and the opportunity to select, invite and meet with extramural seminar speakers. Finally the trainees will be provided with opportunities for social interaction and networking with one another, and they will have access to peer mentors for collegiality, collaborations and, if needed, personal tutoring.
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1 |
2003 |
Dewhurst, Stephen |
U09Activity Code Description: To provide the chairman of an initial review group funds for operation of the review group. |
Acquired Immunodeficiency Syndrome Review @ U.S. Phs Public Advisory Groups |
0.903 |
2005 — 2006 |
Dewhurst, Stephen |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Bacteriophage Gene Transfer For Hiv Vaccine Delivery @ University of Rochester
[unreadable] DESCRIPTION (provided by applicant): Several mammalian virus vectors are in human clinical trial to evaluate their potential as HIV vaccine delivery platforms, but these vectors also have significant drawbacks that include safety concerns, high production and purification costs, and a host cell tropism that is often very broad. In contrast,bacteriophage vectors are cheap to manufacture and purify, and can be selectively targeted to mammalian cells through engineered modifications of the phage coat proteins. The central hypothesis of this Innovation grant application is therefore as follows: (i) that bacteriophage vectors can be retargeted so as to allow efficient transduction of dendritic cells (DC), and (ii) that these modified bacteriophage vectors can be used to elicit specific and potent immune responses to an encoded (HIV-1) antigen. This hypothesis will be tested experimentally, in a proof-of-principle study, through three specific aims. In the first aim, modified bacteriophage vectors capable of transducing DC will be generated, using multiple complementary approaches. To do this, a mammalian GFP reporter cassette will be inserted into our phage vectors, and these GFP-phage will then be subjected to specific coat protein modifications intended to enhance phage uptake into DC; a series of complementary approaches that will be evaluated in parallel in order to determine the optimum approach. In the second specific aim, an HIV-1 gene insert will be introduced into the genomes of the DC-targeted phage vectors, and their ability to express HIV-1 antigens in DC will be evaluated. Finally, in Aim 3, the most promising HIV-1 antigen-encoding phage vectors will be inoculated into BALB/c mice and into guinea pigs, together with relevant control phage, and their ability to elicit HIV-1-specific cellular and humoral immune responses will be examined. These experiments will also include studies to determine the effectiveness of multiple immunizations with phage vectors (i.e., to test whether anti-phage antibodies induced after an initial immunization have an impact upon subsequent boosting with the same phage, or different/modified phage). [unreadable] [unreadable]
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1 |
2007 — 2008 |
Dewhurst, Stephen |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Overcoming Low Hiv-1 Envelope Spike Immunogenicity by High Density Display @ University of Rochester
[unreadable] DESCRIPTION (provided by applicant): The display of proteins in dense, repetitive arrays in known to result in strong humoral immune responses, as exemplified by the virus-like particle (VLP) vaccine for human papillomavirus. This concept has relevance to HIV-1 vaccine development, because recent structural studies of HIV-1 virions have shown that the envelope spikes on the virus surface are sparse and irregularly distributed. This may contribute to low spike immunogenicity, and complicate the generation of broadly neutralizing antibodies. [unreadable] [unreadable] This proposal will test the hypothesis that the immunogenicity of HIV-1 envelope spikes is limited, in part, as a result of their sparse and irregular distribution on the virion surface. To do this, HIV-1 envelope spikes will be displayed at high density on a repetitively ordered scaffold (provided by the bacteriophage lambda capsid). Env display will be acheived using a simple in vitro complementation system, to "decorate" phage particles with soluble Env oligomers, produced in mammalian cells. In the R21 (feasibility) phase of this proposal, experiments will be conducted to generate lambda phage particles that display well-characterized, oligomeric envelope spikes on their surface at both high and low density. The immunogenicity of these phage particles will then be assessed in a small animal model, to determine if ordered, high density display of envelope spikes results in a measurable increase in the magnitude or quality of Env-specific antibody responses (including virus-neutralizing antibodies). [unreadable] [unreadable] If quantifiable milestones are met, the project will progress to the R33 (development) phase. This phase focus on the evaluation of methods intended to further improve the quality and magnitude of the humoral immune response elicited by lambda phage particles displaying HIV-1 Env. The focus will be on the evaluation of practical, translationally-relevant strategies that can be readily applied to enhance humoral immune responses to the phage-displayed envelope spikes. The studies will culminate in a proof-of- concept immunogenicity study in non-human primates, in which the immune response to phage-displayed envelope spikes will compared to that elicited by a soluble oligomeric envelope preparation. [unreadable] [unreadable] Collectively, these experiments are expected to provide a comprehensive proof-of-concept evaluation of our hypothesis that ordered, dense display of HIV-1 envelope spikes on the lambda phage scaffold will allow for the generation of improved antibody responses to HIV-1 Env. [unreadable] [unreadable] [unreadable]
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1 |
2007 — 2009 |
Dewhurst, Stephen |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Lambda Phage as a Scaffold For Influenza Immunization @ University of Rochester
[unreadable] DESCRIPTION (provided by applicant): Effective influenza A vaccines represent a major public health need, both to combat annual virus outbreaks in at-risk populations, and also to protect against possible pandemic infection by new strains, including highly pathogenic avian influenza A (H5N1) strains. Human clinical trials have shown that baculovirus-expressed recombinant hemagglutinins (rHA) can elicit serum antibody responses in both healthy and elderly adults. However, because the HA is administered as a soluble protein without adjuvant, relatively high doses have been required to achieve protective immunity; this has been a particular problem for the H5 rHA as well as for egg-derived H5 vaccines in humans. Moreover, recent work has suggested that alum, the most widely available adjuvant for vaccines in humans, will not have a significant dose-sparing effect for H5 vaccines in man. As a result, alternative approaches are urgently needed to increase the immunogenicity of H5 vaccines, and decrease the dose needed to achieve protective immunity. Display of proteins or peptides in an ordered, repetitive array can lead to greatly increased immune responses, compared to immunization with soluble protein antigens. Bacteriophage particles are well- recognized for their ability to permit the display of short, exogenous peptides at high copy number in a quasicrystalline array that facilitates antibody production through cross-linking of surface immunoglobulins. The central hypothesis of this proposal is that influenza A virus vaccine approaches can be improved, by using lambda phage as a scaffold to display viral antigens in a highly immunogenic context. We propose to achieve this by using a simple in vitro complementation system to "decorate" phage particles with baculovirus-produced H5 rHA. Proof-of-principle experiments will be conducted to explore the effectiveness of this novel approach. In the first aim, H5 rHA will be displayed on the lambda phage capsid. This will be achieved by expressing translational fusions between the major lambda phage coat protein, gpD, and the H5 hemagglutinin (HA) in insect cells, and then using this material to decorate preformed, gpD-deficient phage capsids. In the second aim, a mouse model system will be used to assess the immunogenicity of lambda phage particles displaying H5 rHA. These experiments will assess humoral immune responses to H5 HA, and will compare results to those elicited by purified, recombinant H5 rHA alone. Finally, live virus challenge studies will be conducted, in order to test the protective effectiveness of the elicited immune responses. Collectively, these experiments are expected to provide proof-of-concept data in support of our hypothesis that the lambda phage scaffold will allow for the generation of strong antibody responses to influenza virus antigens, such as H5 HA. This application is aimed at developing a new and improved method to develop vaccines for influenza viruses, including the highly pathogenic avian influenza viruses that are a major domestic and global health concern. The approach we are proposing has the potential to both increase the immunogenicity as well as decrease the dose of these vaccines, and at the same time utilizes an inexpensive and relatively simple technology that could easily be adapted for use on a large scale. [unreadable] [unreadable] [unreadable]
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1 |
2008 — 2012 |
Dewhurst, Stephen |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
University of Rochester Developmental Center For Aids Research @ University of Rochester
[unreadable] DESCRIPTION (provided by applicant): The primary mission of the University of Rochester (UR) Developmental Center For AIDS Research (D-CFAR) is to raise the overall quality and quantity of HIV/AIDS research at the UR. This objective will be achieved by the establishment of four interconnected core facilities, and by leveraging the infrastructure created for the UR's Clinical and Translational Science Institute (CTSI). The Administrative Core (Core A) will oversee the progress of the entire D-CFAR and facilitate functions necessary for the day-to-day function of the D-CFAR through organizational and fiscal oversight, support of program communications and program evaluation, and creation of a Bioinformatics resource that will support the entire D-CFAR program. The Developmental Core (Core B) will catalyze new multidisciplinary research on HIV/AIDS by funding pilot awards that support new collaborative efforts in strategically selected "areas of opportunity". Support will also be provided for Traveling Fellowships and Mentored Investigator Awards patterned on the K08 mechanism; this will complemented by the creation of a structured mentoring program for young faculty and a grant facilitation service. New scientific seminar programs will also be supported, as well as pilot collaborations with international partners in South Africa. The Clinical Science Core (Core C) will be structured around the concept of a "Protocol Team Service", that draws on the 20-year experience of the major UR HIV/AIDS clinical research programs. This will provide an 'investigator-centered' service that addresses the most pressing needs that clinical researchers face as they design, implement and conduct their studies, including support for Biostatistics, Data Management and Biomathematical Modeling. Core C will also support research collaborations with partners in South Africa. Finally, the Basic Research Core (Core D) will provide a full range of virology and immunology assays, as well as access to institutional core facilities. New services will include the creation of a Recombinant Protein Expression service, in response to faculty needs that were identified during the strategic planning process. Additional services will be provided through Molecular Virology and Flow Cytometry services, and will include availability of lentiviral vectors; a centralized Sample Repository will be also created, to facilitate access to, and storage of, clinical specimens. The success of the D-CFAR mission will be ensured by oversight from Internal and External Advisory Boards, a formal outcomes assessment program, and an active, effective strategic planning process. [unreadable] [unreadable] [unreadable] CORE A: ADMINISTRATIVE CORE (Dewhurst, S) [unreadable] [unreadable] CORE A DESCRIPTION (provided by applicant): The Administrative Core has been organized to exploit institutional research strengths at the University of Rochester (UR), and to leverage the UR's Clinical and Translational Science Institute (CTSI). The primary mission of Administrative Core will be to support the research programs of participating D-CFAR members, and to facilitate new research interactions and projects. The Administrative Core will fulfill its mission by: overseeing the entire D-CFAR and the establishment of new programs; supporting the functions necessary for the day-to-day function of the D-CFAR (through organizational and fiscal oversight); providing a comprehensive D-CFAR strategic planning process; and interacting with internal and external advisory boards that will provide crucial guidance and advice. The Administrative core will also provide support for program evaluation and communications (including a dedicated web site, as well as scientific seminars and meetings), and it will create a shared Bioinformatics resource, designed to serve all D-CFAR members. This resource will coordinate and integrate existing clinical databases and data files into a shared virtual data repository; it will also adapt systems and standards for general communication and data collection; develop tools that enhance subject recruitment; implement strategies for delivery of behavioral interventions; facilitate collaboration with investigators in South Africa; and provide analytical tools and software to support laboratory-based studies. A process of regular internal and external review, combined with a comprehensive plan for measurement of specific objectives and outcomes, will ensure that each of the D-CFAR initiatives makes desired progress. Overall, the Administrative Core will provide the "glue" required to successfully integrate the various components of this D-CFAR with key institutional centers and programs, and to make sure that it achieves a level of progress necessary for successful conversion to a full CFAR award. [unreadable] [unreadable] [unreadable]
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1 |
2008 — 2018 |
Dewhurst, Stephen |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Developmental Core @ University of Rochester
AIDS Virus; AIDS neuropathy; AIDS prevention; AIDS/HIV; AIDS/HIV prevention; AIDS/HIV problem; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; African; Applications Grants; Area; Award; Behavior; Biometrics; Biometry; Biometry and Biostatistics; Biostatistics; Class; Clinical; Clinical Research; Clinical Study; Clinical Trials; Clinical Trials Design; Clinical Trials, Unspecified; Collaborations; Complement; Complement Proteins; Data; Data Set; Dataset; Development; Discipline; EXTMR; Educational workshop; Ensure; Environment; Epidemiology; Extramural; Extramural Activities; Faculty; Feedback; Fellowship; Funding; Future; Gene Products, RNA; Generations; Goals; Grant; Grant Proposals; Grants, Applications; HIV; HIV Prevention; HIV vaccine; HIV/AIDS; HIV/AIDS Vaccines; HIV/AIDS prevention; HIV/AIDS problem; HTLV-III; Human; Human Immunodeficiency Viruses; Human Resources; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human, General; Immune response; Immunology; Immunology (Including BRMP); Immunology (NCI Program); Industry Collaboration; Institutes; Institution; Instruction; Interdisciplinary Research; Interdisciplinary Study; International; Interpersonal Violence; Investigation; Investigators; Investments; LAV-HTLV-III; Laboratories; Lymphadenopathy-Associated Virus; Man (Taxonomy); Man, Modern; Manpower; Math Models; Medical center; Mentors; Minority; Mission; Modeling; Multidisciplinary Collaboration; Multidisciplinary Research; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nature; Numbers; Opportunistic Infections; Optics; Outcome; P. carinii; P.carinii; Pattern; Pilot Projects; Pneumocystis carini; Pneumocystis carinii; Prevention; Prevention Research; Process; Program Development; Programs (PT); Programs [Publication Type]; Public Health; RNA; RNA, Non-Polyadenylated; Recruitment Activity; Relative; Relative (related person); Republic of South Africa; Research; Research Design; Research Personnel; Research Resources; Researchers; Resources; Ribonucleic Acid; Science of Virology; Scientist; Services; Site; South Africa; Staging; Strategic Planning; Structure; Study Type; Study, Interdisciplinary; Substance abuse problem; Training; Training Activity; Translational Research; Translational Research Enterprise; Translational Science; Travel; Union of South Africa; United States National Institutes of Health; Universities; Vaccine Research; Virology; Virus; Virus-HIV; Viruses, General; Work; Workshop; Writing; abuse of substances; antiretroviral therapy; base; career; clinical investigation; cohort; concept; experience; fitness; host response; human immunodeficiency virus vaccine; immunoresponse; interest; mathematical model; mathematical modeling; nano medicine; nanomedicine; neuroAIDS; novel; peer; personnel; pilot study; pre-clinical; preclinical; programs; public health medicine (field); recruit; statistics/biometry; study design; substance abuse; success; translation research enterprise; vaccine development; virology
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1 |
2008 — 2009 |
Dewhurst, Stephen Ovitt, Catherine |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Radioprotection by Targeted Sirna Delivery to Salivary Gland @ University of Rochester
[unreadable] DESCRIPTION (provided by applicant): Salivary gland (SG) hypofunction is a predictable and highly debilitating consequence of the use of ionizing radiation in the treatment of head and neck cancers, which results from irreversible damage to salivary acinar cells. Clinically, the currently accepted treatment for radioprotection of salivary glands involves the use of amifostine to protect normal salivary tissue against radiation and cytotoxic damage. This is associated with significant side effects and is of uncertain effectiveness in combination radio/chemotherapy regimens. Amifostine is thought to exert its radioprotective effects through the activation of the survival- promoting transcription factor, nuclear factor ?B (NF?B), which regulates anti-oxidant genes, and also opposes the action of pro-apoptotic mediators. The central hypothesis of this proposal is that targeted delivery to salivary gland cells of selected siRNAs that either engage cell survival pathways known to play a role in radioprotection, or block the action of mediators of irradiation-induced cell death, will result in the protection of these cells from irradiation-induced damage. We propose two Specific Aims: 1) to develop efficient, nanoparticle-based methods to deliver siRNA to SG cells. We will use well-characterized peptide ligands to target siRNA-containing nanoparticles to SG cells, including (i) cell-permeabilizing peptides (CPP) and (ii) peptide ligands for apical integrins. These in vitro experiments will use cultured SG cells and a panel of different siRNA-containing nanoparticle formulations. Successful siRNA delivery will be assessed using fluorescently labeled siRNA molecules and also by measuring knockdown of a reporter gene (GFP); and 2) to determine whether siRNA-mediated gene knockdown can protect against irradiation-induced SG damage. Two classes of siRNA molecules will be tested for their ability to protect salivary gland tissue against irradiation-induced damage: (i) siRNAs that will transiently activate the survival promoting factor, NF?B (mimicking the action of amifostine); and (ii) siRNAs that will transiently inhibit the expression of pro-apoptotic mediators that are induced following radiation treatment (PKC4, Bax and p53). Following in vitro characterization of siRNA function, experiments will be conducted in vivo to determine the effect of siRNA-mediated gene knockdown on irradiation-induced cell damage using two radiation models: (a) acute induction of SG cell apoptosis following exposure of mice to a low dose of irradiation, and (b) chronic induction of xerostomia and acinar depletion following exposure of mice to a large radiation dose. It is expected that these experiments will provide proof-of-principle support for our hypothesis that siRNA-mediated gene knockdown can protect against irradiation-induced damage to salivary gland tissue. Project Narrative: Salivary gland tissue is highly sensitive to ionizing radiation, and can become permanently damaged as a result of cancer radiotherapy. The resultant loss of saliva production leads to a permanent and profound reduction in quality of life, with severe oral complications. The present proposal seeks to develop a new and more effective approach to the treatment of this predictable and important consequence of cancer therapy. [unreadable] [unreadable] [unreadable]
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1 |
2008 — 2018 |
Dewhurst, Stephen |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Administrative Core @ University of Rochester
AIDS/HIV; AIDS/HIV problem; Activities, Educational; Administrative Coordination; Advisory Committees; Award; Behavior Conditioning Therapy; Behavior Modification; Behavior Therapy; Behavior Treatment; Behavior or Life Style Modifications; Behavioral Conditioning Therapy; Behavioral Modification; Behavioral Therapy; Behavioral Treatment; Bio-Informatics; Bioinformatics; Bioinformatics Shared Resource; Budgets; Clinical; Collaborations; Communication; Communities; Computer Software Tools; Conditioning Therapy; Data Banks; Data Bases; Data Collection; Data Files; Databank, Electronic; Databanks; Database, Electronic; Databases; Development; Educational Activities; Ensure; Files, Data; Financial Management; Generations; Glues; HIV/AIDS; HIV/AIDS problem; Institutes; International; Internet; Investigators; Laboratories; Lectures; Lectures (PT); Lectures [Publication Type]; Life Style Modification; Measurement; Mentors; Mission; NIH; National Institutes of Health; National Institutes of Health (U.S.); Occupational activity of managing finances; Outcome; Policies; Process; Program Evaluation; Programs (PT); Programs [Publication Type]; Regulation; Reporting; Republic of South Africa; Research; Research Personnel; Research Resources; Researchers; Resource Allocation; Resources; Services; Site; Software Tools; South Africa; Standards; Standards of Weights and Measures; Strategic Planning; Structure; Support of Research; System; System, LOINC Axis 4; Task Forces; Tools, Software; Training; Translational Research; Translational Research Enterprise; Translational Science; Union of South Africa; United States National Institutes of Health; Universities; WWW; analytical tool; base; behavior intervention; behavioral intervention; clinical data repository; clinical data warehouse; conference; data repository; day; design; designing; desire; lectures; member; programs; relational database; symposium; tool; translation research enterprise; virtual; web; world wide web
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1 |
2008 — 2012 |
Dewhurst, Stephen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cerebrovascular Mechanisms in Methamphetamine-Mediated Exacerbation of Neuroaids @ University of Rochester
[unreadable] DESCRIPTION (provided by applicant): Methamphetamine (MA) use is associated with accelerated progression of HIV-associated neurocognitive disorders (HAND), through poorly understood mechanisms. In addition to its well studied ability to induce oxidative stress and glial activation, MA abuse also has pronounced neurovascular effects that are reflected by an increased risk of stroke, persistent white matter hyperintensities and reductions in cerebral blood flow (CBF) in MA abusers. Consistent with this, our preliminary data show that acute MA exposure results in a significant decline in CBF in wild-type mice, as measured by laser doppler flowmetry. Thus, our central hypothesis is that: MA disrupts cerebral blood flow and elicits cerebrovascular changes that exacerbate the progression of HIV-induced neurologic disease. This hypothesis will be tested through three aims. In Aim 1, we will analyze MA's effects on cerebral blood flow. We will first test whether the effects of acute MA exposure on CBF are exacerbated in animals with underlying HIV-induced neuroinflammatory disease (using gp120 and Tat transgenic mice). We will then probe the underlying mechanism by testing whether MA-induced hypoperfusion is due to the induction of specific vasoactive eicosanoids, and in Aim 1C, we will determine whether chronic MA exposure elicits a sustained reduction in CBF in wild-type mice or in animals with underlying HIV-induced neuroinflammatory disease. Aim 2 will analyze MA's effects, alone and in combination with HIV virotoxins, on tissue microcirculation and oxygenation, and neuronal metabolism. In Aim 2A, we will test whether MA's effects on CBF are accompanied by impairment of regional microcirculation, as measured by radiotracer imaging, and by induction of hypoxic gene expression signatures (Aim 2B). In Aim 2C, we will determine whether MA exposure results in impairment of local tissue oxygenation, or changes in local neuronal oxidative metabolism, by using a highly innovative approach (in vivo two-photon nicotinamide adenine dinucleotide [NADH] imaging). Finally, in Aim 3, we will analyze MA's effects on the blood-brain barrier (BBB). HIV virotoxins and acute high-dose MA exposures have been shown to independently damage the BBB, and we will therefore test whether acute exposure to MA results in exacerbated damage to the BBB and induction of microhemorrhages in mice with underlying HIV-induced neuroinflammatory disease, as compared to wild- type mice. This will be assessed by measuring the entry of plasma proteins into the CNS and by the induction of inflammatory vascular changes. Analogous experiments will also be performed in mice with chronic exposure to MA, to determine if this results in prolonged disruption of the BBB. Results from all three aims will be correlated, to determine whether BBB disruption and microhemorrhages are associated with sustained hypoperfusion and reductions in microcirculation. Collectively, these experiments will provide new insight into the mechanisms by which MA accelerates the progression of HAND. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Methamphetamine (MA) abuse has been linked to a worsening of neurologic disease in persons infected with the Human Immunodeficiency Virus type-1 (HIV-1). This proposal seeks to determine whether exposure to MA causes impairment of normal blood flow to the brain, including the development of microhemorrhages ("mini-strokes"), and whether this is exacerbated in the context of underlying brain inflammation due to HIV. The long-term goal is to understand better how MA exposure worsens neuroAIDS, and to define new targets for therapeutic intervention. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]
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1 |
2009 — 2010 |
Dewhurst, Stephen Rose, Robert C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Transmission-Blocking Vaccine For Hiv-1 @ University of Rochester
Semen contains cationic amyloid fibrils derived from proteolytic cleavage fragments of prostatic acid phosphatase (PAP) that efficiently capture HIV-1 particles. These fibrils have been termed semen-derived enhancer of viral infection (SEVI) and enhance HIV-1 infectivity by several orders of magnitude. It is expected HIV-1 virions in semen will efficiently form complexes with SEVI, and that the transmitted form of HIV-1 in semen may therefore correspond to virus-SEVI complexes. We hypothesize that virus-SEVI complexes will present novel antigenic structures, different from those present on free virions or conventional recombinant antigens, and that the virus-SEVI complex can be targeted to derive an innovative vaccine capable of protecting against HIV transmission via semen. By targeting the complex between a host protein and the virus, we expect to elicit an immune response that recognizes the authentic form of HIV-1, as it is found in semen, and - potentially - to circumvent the problem of viral antigenic variation. Two aims are proposed. In aim one, we will test whether antibodies can block SEVI-mediated enhancement of HIV-1 infection. To do this, we will first identify PAP residues essential for enhancement of HIV-1 infectivity by SEVI. This will be achieved by testing whether fibrils formed by mutated derivatives of the amyloidogenic PAP peptide can enhance the efficiency of HIV-1 infection. Since other amyloid fibrils (Ass) have adjuvant-like immunostimulatory properties, we will also test whether these mutated fibrils elicit the production of inflammatory cytokines. We will then immunize guinea pigs with SEVI, or with short linear peptides derived from the virus-binding surface of SEVI, and test whether the elicited antibodies prevent SEVImediated enhancement of HIV-1 infectivity and/or SEVI-mediated immune activation. In aim two, we will evaluate whether virus-SEVI complexes, or mimics thereof, can elicit protective, virusneutralizing antibodies. To do this, we will assemble complexes between SEVI and virus particles, and also between SEVI and oligomeric gp140 (as a surrogate for the virus-SEVI complex). We will then evaluate the antigenicity of these complexes using competitive antibody-binding ELISA assays and compare results to those obtained with free gp140 oligomers or virus particles. In Aim 2B, we will immunize guinea pigs with gp140-SEVI (or virus-SEVI) complexes and assess the strength and quality of the elicited humoral immune response (including neutralizing antibodies);results will be compared to animals receiving gp140 or SEVI alone. Finally, in Aim 2C, we will test whether a SEVI-based vaccine is immunogenic in rhesus macaques and whether it can protect against vaginal transmission of SIV. Collectively, these studies will provide a conclusive proof-of-principle test for our proposed approach.
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1 |
2010 — 2011 |
Dewhurst, Stephen |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Use of Discontinuous Peptide Display For Generation of Hiv Antigen Mimics @ University of Rochester
DESCRIPTION (provided by applicant): A major roadblock in HIV vaccine development is our inability to elicit broadly neutralizing antibodies (BNA) that recognize the HIV-1 envelope. This reflects, in part, the sequestration of key neutralizing epitopes on HIV-1 Env. One way of solving this problem is to develop antigenic mimics of these sequestered, conformational epitopes, which can then be used as immunogens to elicit BNA. Previous efforts to produce such mimics have been unsuccessful, largely because the linear mimotopes that were selected using conventional phage display technology failed to recapitulate the structure of discontinuous, virus-neutralizing epitopes on Env. We propose an innovative solution to this problem, by exploiting a unique molecular scaffold that can be diversified in three discontinuous, but interacting, surface exposed loops. Our hypothesis is that it is necessary to use a diverse, discontinuous molecular library to identify antigenic mimics of conformational gp120 epitopes such as the broadly neutralizing epitope recognized by the b12 Mab, and that these antigenic mimics can then be used to elicit broadly neutralizing antibodies against HIV-1. Experiments will be conducted to identify mimics of a discontinuous neutralizing epitope in the CD4 binding site of the HIV-1 envelope, recognized by Mab b12. To do this, we will screen diversified discontinuous protein libraries, constructed using a unique display scaffold, and presented on the surface of bacteriophage. We will then derive mimotopes that bind with high affinity to Mab b12, by using alanine-scanning mutagenesis and affinity selection. We will perform competition ELISA experiments to test whether these proteins can compete with oligomeric HIV-1 Env for binding to Mab b12. The immunogenicity of these proteins will then be assessed in rabbits, to determine if they elicit Env-specific antibody responses (including virus-neutralizing antibodies). These experiments are expected to provide a proof-of-concept evaluation of our hypothesis. The use of a novel scaffold to display multiple discontinuous peptides that can better preserve the conformation of the b12 epitope to induce b12-like BNA is a powerful, innovative approach that has not been explored previously. Moreover, if this work is successful, the same scaffold could be used for other conformational epitopes, in addition to b12. Thus, this proposal delineates a high risk but very high reward vaccine strategy - consistent with the intent of the R21 grant mechanism. PUBLIC HEALTH RELEVANCE: This application seeks to develop an improved method to produce vaccines for human immunodeficiency virus type-1 (HIV-1), by taking an innovative approach to the generation of broadly neutralizing antibodies (BNA) that recognize the HIV-1 envelope. We propose to use a novel method to produce novel antigenic mimics of key conformational epitopes on the HIV-1 envelope. We will then use these antigenic mimics to elicit broadly neutralizing antibodies capable of inhibiting the infectivity of HIV-1.
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1 |
2011 — 2015 |
Dewhurst, Stephen |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) R33Activity Code Description: The R33 award is to provide a second phase for the support for innovative exploratory and development research activities initiated under the R21 mechanism. Although only R21 awardees are generally eligible to apply for R33 support, specific program initiatives may establish eligibility criteria under which applications could be accepted from applicants demonstrating progress equivalent to that expected under R33. |
The Semen Enhancer of Hiv Infection as a Novel Microbicide Target @ University of Rochester
PROJECT SUMMARY/ABSTRACT Human semen contains cationic amyloid fibrils, termed the Semen Enhancer of Virus Infection (SEVI), which strongly enhance HIV-1 infection and may play an important role in viral transmission. Our preliminary data show that amyloid-binding molecules bind to SEVI, and block semen-mediated enhancement of HIV-1 infection. This suggests that (i) SEVI is responsible for semen-mediated enhancement of HIV infection and (ii) SEVI represents a novel microbicide target. We therefore propose to explore a novel, innovative approach to HIV-1 microbicide development, using agents that selectively target SEVI. This high-risk/high-reward approach is fundamentally different from traditional microbicidal strategies that target the virus itself, and is expected to be highly complementary with direct antiviral approaches. Indeed, our long-term goal is to use SEVI-targeting agents in combination with traditional microbicides, to achieve optimal antiviral effectiveness. In the R21 phase, we will test whether novel amyloid-binding small molecules inhibit semen-mediated enhancement of HIV infection. The feasibility of this approach has been established using two amyloid-binding small molecules which contain shielding oligo-ethylene glycol (EG) moieities: BTA-EG4 and -EG6. These agents efficiently inhibit SEVI- and semen-mediated enhancement of HIV infection. In Aim 1, we will generate and test novel derivatives of these and other amyloid-binding molecules, including oligovalent molecules that are expected to possess increased SEVI binding affinity. We will then test their ability to inhibit SEVI- and semen- mediated enhancement of HIV infection using a panel of R5 virus strains (including different clades and transmitted strains). In Aim 2, we will examine the interaction between novel amyloid-binding small molecules and cells from the female reproductive tract. We will evaluate whether our compounds are toxic to human cervicovaginal epithelial cells (HCEC), and we will test whether they inhibit SEVI-enhanced binding of HIV-1 to HCEC and/or SEVI-enhanced trans-infection of PBMC by HCEC exposed to HIV-1 virions. The R33 phase will be undertaken only if well-defined milestones are achieved. In Aim 3, we will use structure-activity relationship (SAR) data to refine our chemical compositions. We will also test whether our lead molecules have efficacy in a cervical explant model for HIV-1 infection, and whether they have a synergistic or additive effect on the ability of other candidate microbicides to inhibit HIV-1 infection in the presence of semen. In the final Aim, we will assess the toxicity and inflammatory effects of the most promising candidate molecules, using beneficial Lactobacilllus strains and cervical explants. The R33 phase will culminate with an evaluation of the safety and tolerability of the most promising compound in the rabbit vaginal irritation (RVI) model. The overall goal of these studies is to carefully determine whether small molecules that target SEVI have potential utility as a novel class of microbicides.
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1 |
2013 — 2018 |
Dewhurst, Stephen |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Biostatistics, Bioinformatics & Computational Biology Core @ University of Rochester
PROJECT SUMMARY (See instructions): The Biostatistics, Bioinformatics & Computational Biology Core (BBCB; Core E) will assist CFAR members with the management, analysis, modeling and annotation of complex and massive data generated by laboratory and clinical studies. The overall objective will be to provide a comprehensive solution that integrates expertise and resources in biostatistics, bioinformatics, computation, mathematical modeling and data management. Since its inception in 2010, Core E has developed and refined an innovative approach to optimally address investigator needs. This combines an integrated service model (one stop shopping) with an active and novel outreach strategy. Thus, rather than taking a traditional approach, in which requests for data analysis services are often initiated too late (after data are already generated, when one can no longer modify study design). Core E proactively engages with researchers. It does so by assigning core members to attend lab meetings (house calls) and to assist at the very earliest stages of study planning. Building on this innovative approach, five Aims are proposed. Aim 1 will provide biostatistics support for experimental design and data analysis. Aim 2 will provide bioinformatics and computational biology support, and will also promote interdisciplinary collaborations by supporting new applications of computationally-intensive methods to HIV/AIDS research (e.g., analyses of imaging data for our CNS Reservoirs/Aging SWG, and structural modeling for our RNA Biology SWG). Aim 3 will provide data management and informatics services, and Aim 4 will provide education and training services. Finally, Aim 5 will leverage other available resources (including methodological research grants/projects and institutional support) to create novel statistical, computational, modeling and bioinformatics tools for HIV/AIDS research.
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1 |
2013 — 2018 |
Dewhurst, Stephen |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
University of Rochester Center For Aids Research @ University of Rochester
DESCRIPTION (provided by applicant): The mission of the University of Rochester (UR) Center for AIDS Research (CFAR) is to support a multidisciplinary environment that promotes and enhances HIV/AIDS research at UR, with the goal of improving the prevention, detection and treatment of HIV infection, AIDS and related disease processes. The UR CFAR will achieve this mission by providing the leadership, services and infrastructure necessary to: establish multidisciplinary collaborations that achieve high-impact discoveries; support the early career development of diverse young HIV/AIDS investigators; and to establish a distinctive scientific identity for the Rochester CFAR, placing it at the forefront of HIV/AIDS research. During our funding cycle as a Developmental CFAR (D-CFAR), we have successfully recruited many new investigators into HIV/AIDS research at the UR. As a result, almost two-thirds (63%) of our membership are NIH-defined early stage or new investigators, or investigators new to HIV/AIDS (in roughly equal proportions). We have also developed innovative approaches to program and collaboration building, with the result that the number of HIV/AIDS investigators at UR with R01 or equivalent support has risen by 53% since inception of our D-CFAR, while collaborative research activity (publications and funded grants) have risen by 40% and 56%, respectively. Building on this success, we propose five Aims. Aim 1 will provide leadership that creates an outstanding scientific environment, and that strategically positions UR at the forefront of HIV/AIDS research. Aim 2 will stimulate new, innovative research and multidisciplinary collaborations that result in high impact discoveries. It will also establish a unique scientific identity for the UR CFAR in Optics & Imaging Sciences and in RNA Biology. Aim 3 will identify and mentor the next generation of HIV/AIDS investigators, and Aim 4 will provide an integrated set of scientific Cores that enable cutting-edge HIV research, and that proactively meet investigator needs. Finally, Aim 5 will stimulate communication and engagement with the full range of communities that the UR CFAR serves.
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2013 — 2018 |
Dewhurst, Stephen |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Basic Sciences Core @ University of Rochester
PROJECT SUMMARY (See instructions): The Basic Science Core (BSC; Core D) will enhance basic and laboratory-based HIV/AIDS research by CFAR members, by providing access to cutting-edge instrumentation and technologies, and the necessary support, education and training to enable efficient use of these resources. The services provided by Core D will create added value by addressing resource gaps on campus, and by providing CFAR SWG members with access to enhanced services for chemical biology and drug development. Over the funding period of our D-CFAR, Core D has been highly successful in leveraging new equipment valued at over $2M (a 18:1 ROI), and in helping to create a new strategic partnership between UR and Temple University's Moulder Center for Drug Discovery Research. The Core has also developed a highly proactive, user-oriented, approach that has allowed it to serve almost half (42%) of the total DCFAR membership. Building on this solid foundation, five Aims are proposed. Aim 1 will provide cutting-edge tools and standardized reagents for virology, immunology, and molecular biology of HIV-1, including recombinant Tat for our CNS Reservoirs/Aging SWG, and a new FPLC resource for our RNA Biology SWG. Aim 2 will provide expertise and resources for chemical and structural biology, including full-service medicinal chemistry resources and a new pilot program with the Moulder Center, of value to both SWGs. Aim 3 will provide access to next-generation flow cytometry, including imaging- and mass- cytometry. Finally, Aim 4 will provide training and education to promote the use of new tools, and Aim 5 will integrate Core D services with other Cores and institutional resources - thus ensuring comprehensive attention to investigator needs.
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2013 — 2018 |
Dewhurst, Stephen |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Clinical and Translational Sciences Core @ University of Rochester
PROJECT SUMMARY (See instructions): The Biostatistics, Bioinformatics & Computational Biology Core (BBCB; Core E) will assist CFAR members with the management, analysis, modeling and annotation of complex and massive data generated by laboratory and clinical studies. The overall objective will be to provide a comprehensive solution that integrates expertise and resources in biostatistics, bioinformatics, computation, mathematical modeling and data management. Since its inception in 2010, Core E has developed and refined an innovative approach to optimally address investigator needs. This combines an integrated service model (one stop shopping) with an active and novel outreach strategy. Thus, rather than taking a traditional approach, in which requests for data analysis services are often initiated too late (after data are already generated, when one can no longer modify study design). Core E proactively engages with researchers. It does so by assigning core members to attend lab meetings (house calls) and to assist at the very earliest stages of study planning. Building on this innovative approach, five Aims are proposed. Aim 1 will provide biostatistics support for experimental design and data analysis. Aim 2 will provide bioinformatics and computational biology support, and will also promote interdisciplinary collaborations by supporting new applications of computationally-intensive methods to HIV/AIDS research (e.g., analyses of imaging data for our CNS Reservoirs/Aging SWG, and structural modeling for our RNA Biology SWG). Aim 3 will provide data management and informatics services, and Aim 4 will provide education and training services. Finally, Aim 5 will leverage other available resources (including methodological research grants/projects and institutional support) to create novel statistical, computational, modeling and bioinformatics tools for HIV/AIDS research.
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2014 — 2015 |
Dewhurst, Stephen |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Enhanced Live Attenuated Influenza Virus With Improved Safety and Immunogenicity @ University of Rochester
DESCRIPTION (provided by applicant): The Live Attenuated Influenza Vaccine (LAIV) has been shown to have greater efficacy in children than its inactivated counterpart. However, due to an unacceptable safety profile, it is not licensed in either asthmatics or children under the ag of two. If one could further attenuate LAIV while retaining immunogenicity, these safety concerns could be alleviated and LAIV usage could be extended to cover these groups. We recently discovered a novel influenza virus mutant that has increased temperature sensitivity, compared to conventional LAIV. The genome of this virus (designated SGR-ts) is characterized by five point mutations within the viral polymerase, when compared to a phenotypic revertant virus with normal temperature sensitivity. Three of these mutations (in PB1 and PB2) are sufficient to almost completely eliminate viral polymerase activity at 37oC, while having no effect on activity at 34oC; importantly, none of these mutations is shared with the current LAIV. These findings suggest that it should be possible to increase the safety of LAIV, by reducing its shutoff temperature (the temperature at which polymerase activity is abolished) to 37oC. Our central hypothesis is that the safety and effectiveness of LAIV can be increased by: (1) using newly discovered polymerase mutations to decrease the shutoff temperature for viral replication (increasing safety) and (2) using selective codon optimization to increase expression of the major virus antigen, hemagglutinin [HA] (increasing immunogenicity). Aim 1 will focus on the construction and in vitro characterization of an enhanced LAIV. To do this, we will identify the minimal essential mutations necessary for the ts polymerase phenotype of SGR-ts, using viral replication assays at selected temperatures (33, 37, and 39oC). We will test whether introduction of these mutations into a conventional H1N1 LAIV can further reduce the viral shutoff temperature, while preserving replication at 33oC - thus creating a ts enhanced H1N1 LAIV. Finally, we will confirm the reproducibility of our findings in the context of an H3N2 LAIV, and we will test whether the ts-enhanced H1N1 LAIV can be further improved by using a codon optimization strategy to increase HA expression. Aim 2 will compare the safety and efficacy of a ts-enhanced H1N1 LAIV (+/- a codon optimized HA) to that of a conventional H1N1 LAIV (also +/- a codon optimized HA). Safety will be assessed by determining MLD50 in mice, as well as weight loss over the course of infection, and virus titers in lung and nasal tract following high-dose infection. Immunogenicity and protective efficacy will be assessed by measuring titers of HA-binding and virus-neutralizing antibodies in immunized mice, and by testing the protection of immunized mice from a lethal H1N1 virus challenge. Finally, we will examine the safety and efficacy of our LAIVs in a second animal model - ferrets - since this model was used during studies that led to the original licensure of LAIV.
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2014 — 2018 |
Baas, Tracey L (co-PI) [⬀] Dewhurst, Stephen Peyre, Sarah Elizabeth (co-PI) [⬀] |
DP7Activity Code Description: To stimulate transformative approaches to training and/or workforce management with the intent of promoting culture change in the field of biomedical training. |
Urbest: the University of Rochester Best Training Program @ University of Rochester
? DESCRIPTION (provided by applicant): Traditional biomedical research training programs fail to adequately prepare trainees for the full diversity of careers that they will ultimately experiene in the biomedical workforce. The UR Broadened Experiences in Scientific Training (URBEST) program will therefore provide a flexible, autonomy-supportive learning program that allows pre- and post-doctoral trainees to better prepare themselves for diverse career paths. Unlike traditional graduate curricula, which often have rigidly defined course requirements, the URBEST program will establish highly flexible educational pathways, curricula and experiential learning opportunities that allow trainees to meet their own self-defined learning needs. Foundational instruction in leadership and professionalism will be combioned with access to educational programs and aligned experiential learning opportunities in three URBEST Training Pathways. As trainees progress through these Pathways, they will participate in common, shared experiences that will include training in the Communication of Science, an Annual Retreat, and a Career Stories seminar series. Internship and externship programs will provide hands- on experiences relevant to diverse careers, both within the University and in partnership with a broad range of private sector companies, government and science policy organizations. URBEST will also implement mentoring practices that better support diverse career outcomes. We will mentor our mentors through: (a) a Program Orientation Session that will delineate the goals of the URBEST program, (b) instruction in Autonomy Supportive Mentoring and the use of Individual Development Programs (IDPs) and (c) a Faculty Development Workshop Series that will promulgate best mentoring practices. We will also mentor our mentees, using approaches that are expected to encourage diverse career options, and we will actively facilitate the on-boarding of trainees in their first position post-UR. First, a URBEST Trainee Network will be established to provide a robust community of scholars that trainees can leverage for peer mentoring support during their time at UR, and for long-term support throughout their careers. Second, an Alumni Mentoring Network will be established, and trainees will be partnered with UR alumni in career sectors of interest. Third, we establish an Extended Individualized Career Mentoring Program to provide continued mentoring support for URBEST trainees after they leave UR. Finally, we will rigorously evaluate our program, and disseminate our model. A comprehensive evaluation and assessment of the URBEST program and its participating trainees and faculty will be structured around three key areas: (1) trainee and faculty participation, (2) URBEST curriculum, and (3) assessment of URBEST trainees. Short-, intermediate- and long- term measures of progress will be evaluated in all areas. In addition, continuous program assessment will be used improve and refine URBEST, and to ensure that it accomplishes its goals. Finally, we will develop a plan for the sustainability and dissemination of our training model.
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2015 — 2020 |
Dewhurst, Stephen Doolittle, Richard L |
K12Activity Code Description: For support to a newly trained clinician appointed by an institution for development of independent research skills and experience in a fundamental science within the framework of an interdisciplinary research and development program. |
Rochester Partnership to Advance Research and Academic Careers in Deaf Scholars @ University of Rochester
DESCRIPTION (provided by applicant): The overall goals of the Rochester Partnership to Advance Research and Academic Careers in Deaf Scholars are: a) to provide highly trained biomedical and behavioral scientists who are Deaf and Hard-of-Hearing (D/HH) with the knowledge and skills to pursue research and teaching careers in academia; and b) to partner the faculty and programs of the University of Rochester (UR), including its National Center for Deaf Health Research (NCDHR) and Clinical and Translational Science Institute (CTSI), with those of the Rochester Institute of Technology (RIT), including its National Technical Institute fo the Deaf (NTID), with the long term objective of promoting linkages between the partners and strengthening their excellence in research and education. The program has four specific aims: 1) To develop a mentored postdoctoral research experience for D/HH biomedical and behavioral PhD Scholars at the UR, a research-intensive institution. To do this, we will leverage the well-developed Mentor-Scholar Program established by the UR CTSI, to provide interdisciplinary team mentoring and to define and meet career development goals for each Scholar, as set forth in their Individual Development Plan. We will also take advantage of the CTSI's novel Mentor the Mentor Program, and will enhance this program to increase the D/HH cultural competency of UR faculty, and their ability to effectively mentor D/HH Scholars; 2) To establish career development activities at UR and a mentored practicum teaching experience at NTID/RIT to develop the academic and teaching skills of program Scholars, and to strengthen and expand educational offerings at RIT in the areas of biomedical and behavioral science; 3) To evaluate program success, by measuring the effectiveness of training in both research and teaching. This will include assessment of short-term objectives and acquired competencies related to teaching and research skills, knowledge and attitudes; and evaluation of long-term career development and academic performance outcomes related to teaching and research. We will also measure the impact of the program on: the diversity of science educational offerings at RIT; entry by D/HH students into biomedically-related and behavioral science majors and programs at RIT; research collaborations between RIT and UR; and 4) To recruit 3 Scholars from a national pool of D/HH persons with biomedical and behavioral doctorates for 3-year periods of training, for a steady state of 9 D/HH Scholars at any one time. This recruitment will build on prior experience of recruiting D/HH postdoctoral fellows to UR, NTID's leadership role in the national networks that promote postsecondary education and career development in D/HH students, and the global reputation of Rochester, NY as a center for D/HH culture and education. This innovative inter-institutional partnership is the first of its kind in the world an will begin to address the dearth of D/HH faculty at academic institutions serving both hearing and D/HH students. A long-term outcome will be the attraction of more D/HH Scholars into careers in the biomedical and behavioral sciences, fields in which D/HH persons are greatly under-represented.
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2015 — 2019 |
Dewhurst, Stephen |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Infection and Immunity: the Pathogenesis of Host-Microbe Interactions @ University of Rochester
? DESCRIPTION (provided by applicant): Infectious diseases remain a major threat to U.S. health, exemplified by the spread of antibiotic resistant microbes such as methicillin resistant Staphylococcus aureus (MRSA) and the emergence and re-emergence of infectious disease threats (such as pandemic influenza). The goal of this predoctoral T32 program is to train the next generation of researchers in microbiology, and to prepare them with the skills necessary to address the nation's critical needs in the battle against infectious disease. To do this, the program takes a student-centric, autonomy-supportive approach with the goal of training self-motivated, independent research scientists who are well prepared for diverse research careers. Innovative program features include: a student-centric, autonomy-supportive educational approach that encourages self-directed exploration of diverse career options; instruction in the soft skills necessary for research career success (i.e., in communication, leadership, mentoring and professionalism); and the establishment of faculty mentoring practices that support student autonomy and self-directed learning. The program has 5 key objectives. First, it will provide outstanding interdisciplinary research training in microbial pathogenesis, in part by leveraging unique opportunities created by signature NIH-funded centers that include the Respiratory Pathogens Research Center (the only center of its kind in the nation), a Center of Excellence for Influenza Research and Surveillance (one of only 5 such centers in the nation), an Environmental Health Science Center and the UR's Clinical and Translational Sciences Institute. Second, it will provide outstanding education in microbiology and pathogenesis. To do this, the program incorporates four major components: (1) a required core didactic curriculum; (2) required program-specific experiences (including courses, workshops and career/professional development activities); (3) optional elective courses and experiences designed to encourage student exploration and (4) hands-on thesis research. Third, it will train self-directed, autonomous scientists who are prepared for diverse research career options. To facilitate this, all students will complete a personality inventory and an annual Individualized Development Plan (IDP). Students will also be offered the opportunity to participate in the new URBEST program, which provides avenues for exploration of diverse career options, and will participate in a Microbiology Career Stories seminar to familiarize them with diverse (microbiology) research careers. Fourth, we will provide training in the soft skills necessary fo success. Students will receive training in the communication of science, will participate in a Leadership Academy Program, and will undertake supervised training in mentoring. Finally, we will also improve faculty mentoring practices. To do this, we will mentor our mentors through instruction in autonomy supportive mentoring and the use of IDPs, and we will create a new Microbiology Alumni Mentoring Network, which will permit trainees to seek advice from alumni in non-academic research settings.
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2021 |
Buckley, Gerard J. Dewhurst, Stephen |
K12Activity Code Description: For support to a newly trained clinician appointed by an institution for development of independent research skills and experience in a fundamental science within the framework of an interdisciplinary research and development program. |
Iracda At Rochester Partnership to Advance Research and Academic Careers in Deaf Scholars @ University of Rochester
PROJECT SUMMARY/ABSTRACT The primary objective of the Rochester Partnership to Advance Research and Academic Careers of Deaf (RPP-DEAF) Scholars is to rigorously train and support the career advancement of deaf and hard of hearing (D/HH) post-doctoral Scholars for independent academic careers that support the biomedical research enterprise. This is an important unmet national need, because the D/HH community is greatly underrepresented in the biomedical sciences academic workforce. In order to address this disparity, we have partnered the faculty and programs of the University of Rochester (UR) with those of the Rochester Institute of Technology (RIT) and its National Technical Institute for the Deaf (NTID). To achieve our program goals, we will pursue four Specific Aims; 1) To provide outstanding program leadership that ?mentors the mentors?, builds community for D/HH Scholars, and successfully coordinates program recruitment. This goal will be achieved through (A) special training specific to this IRACDA program (including training in Deaf-aware mentoring practices and Deaf culture), (B) training in mentoring diverse learners and (C) advanced mentoring training (for research mentors) or leadership mentoring training (for program leaders).; 2) To provide individualized, mentored teaching experiences and career development activities for all Scholars. Teaching experiences will be provided principally at RIT/NTID, the teaching-intensive partner institution.; 3) To provide individualized, mentored research experiences for all Scholars. Research experiences will be provided principally at UR, the research-intensive partner institution.; and 4) To rigorously, comprehensively and continuously evaluate the RPP-DEAF program. We will ensure that RPP-DEAF meets its goals by conducting comprehensive and ongoing program evaluation of: Scholar Achievement, Faculty Mentorship & Program Leadership; and Institutional Impact. We will recruit three new D/HH scholars per year, with a maximum of a three-year appointment, in order to maintain a steady state cohort of 9 D/HH Scholars. Overall, this unique IRACDA program will equip our Scholars with the comprehensive set of knowledge and skills in research, teaching and professionalism necessary for successful academic careers - with the goal that all of our Scholars will acheive full-time academic appointments in higher education and/or research institutions. This innovative inter- institutional partnership is the first of its kind in the world and will begin to address the dearth of D/HH faculty at academic institutions serving the nation's biomedical research needs. A long-term outcome will be the attraction of more D/HH Scholars into careers in the biomedical sciences, a field in which D/HH persons are greatly underrepresented.
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2021 |
Dewhurst, Stephen Foxe, John J [⬀] Zand, Martin S |
OT2Activity Code Description: A single-component research award that is not a grant, cooperative agreement or contract using Other Transaction Authorities |
Cov-Idd: Testing For Covid-19 in High Risk Children With Intellectual and Developmental Disabilities @ University of Rochester |
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2021 |
Dewhurst, Stephen Keefer, Michael C |
UM1Activity Code Description: To support cooperative agreements involving large-scale research activities with complicated structures that cannot be appropriately categorized into an available single component activity code, e.g. clinical networks, research programs or consortium. The components represent a variety of supporting functions and are not independent of each component. Substantial federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of the award. The performance period may extend up to seven years but only through the established deviation request process. ICs desiring to use this activity code for programs greater than 5 years must receive OPERA prior approval through the deviation request process. |
University of Rochester Hiv/Aids Clinical Trials Unit @ University of Rochester
The University of Rochester (UR) Infectious Diseases Division (IDD) has meaningfully contributed to the NIAID HIV/AIDS Clinical Research Networks (CRNs) for over 30 years. The enduring mission of the UR Clinical Trials Unit (CTU) is to support and conduct clinical research on HIV/AIDS that contributes to the discovery of a preventive vaccine for HIV, as well as to the discovery of a cure for HIV, and of treatments that reduce the burden of disease due to HIV infection and its complications. It will acheive this mission by providing exceptional scientific and administrative leadership, and outstanding clinical trials infrastructure, and by engaging with all relevant stakeholders and communities, to ensure that the research it conducts is responsive to community needs. Five aims are proposed. The first is to strengthen our well-established Clinical Research Sites (CRSs). To do this, we will support 2 domestic CRSs that will participate in the following NIAID CRNs: (i) the `AIDS Clinical Trials Group' (ACTG); and (ii) the `HIV Vaccine Trials Network' (HVTN). We will also develop a plan to diversify UR CTU leadership, and to enhance integration and coordination of these CRSs. The second aim is to provide exceptional administrative leadership that accelerates and enhances NIAID clinical research. We will do this by continuing and enhancing effective financial management procedures and a robust quality management program, and by continuously assessing well-defined metrics of operational performance and capacity; these measures will be used to determine improvement opportunities that will be addressed by targeted actions and follow-up evaluation to assess the efficacy of such interventions. Performance data will be coupled to resource allocation, and poorly performing CTU components will be terminated, if necessary. The third aim is to provide exceptional scientific leadership that promotes important contributions to the advancement of HIV/AIDS science, and mentors the next generation of CTU researchers. The CTU will oversee and coordinate groundbreaking research activities at the participating CRSs, develop and execute a strong research agenda for the ACTG and HVTN, mentor and train the next generation of CTU researchers, and draw upon campus-wide intellectual capital. Aim four will provide outstanding clinical trials infrastructure, including data and quality management, regulatory support, laboratory, pharmacy and other resources. Innovations will include procedures that facilitate flexibility and surge capacity, allowing a rapid response to emerging Network needs, as well as shared resources that promote cost efficiency. Finally, our fifth aim is to communicate and engage effectively with all UR CTU stakeholders. The Rochester Community Advisory Board (CAB) and our diverse Community Education and Recruitment (CER) Team will engage with local communities, to increase community awareness and education, and facilitate recruitment and retention of research participants. Finally, we will also continue highly responsive communication and engagement with NIAID, its CRNs, and all other key constituencies.
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