1998 — 2002 |
Hinton, David R. |
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. |
The Role of Cd4 Cells in the Trafficking of Ctls in Cns Tissue @ University of Southern California
Infection of the central nervous system (CNS) with the neurotropic murine coronavirus JHMV results in acute encephalomyelitis, primary demyelination , and persistent infection in susceptible strains. Complete elimination of virus during the acute infection by multiple effectors including CD8+ cytotoxic T lymphocytes (CTL), is critical in preventing viral persistence and chronic demyelination. We have recently shown that the absence of CD4+ T cells in JHMV infection results in decreased numbers of activated CTL in the brain and this is associated with a marked increase in the number of cells undergoing programmed cell death or apoptosis. As a direct extension of this work, we propose the general HYPOTHESIS that the infiltration and survival of CTL in CNS during JHMV infection is dependent, at least in part, upon CD4+ T cells. The first aim of the project will be to determine the mechanism by which CTL infiltrate into CNS tissue from the perivascular space and how this is modified by CD4+ cells. We suggest that CTL infiltration is increased by secretion of metalloproteinases (MMP-7, MMP-9) and in response to chemokine gradients (MIP-1alpha, RANTES) and that these processes are stimulated by the secreted products of CD4+ T cells. The second aim will be to determine the mechanism by which CTL undergo apoptosis in the CNS of JHMV-infected mice and how this is modulated by CD4+ T cells. We suggest apoptosis of CTL occurs secondary to deletion of the growth factor interleukin-2 (IL-2) OR by Fas-mediated killing, processes associated with decreased levels of bcl-2 and that CD4+ T cell depletion further accentuates IL-2 depletion. Both brains and isolated CTL from normal mice and CD4-deficient mice will be studied as well as specific mutant and transgenic strains. Pathogenesis will be altered by over expression of specific MMP, chemokines of apoptosis- related molecules using a Defective Interfering vector system. The results of these experiments will provide a better understanding of the mechanisms involved in CTL trafficking within the specialized microenvironment of the brain.
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2000 — 2002 |
Hinton, David R. |
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. |
Core--Specialized Microscopy
digital imaging; confocal scanning microscopy; vision; biomedical facility; transmission electron microscopy; fluorescence microscopy; electron microscopy; scanning electron microscopy; measurement; bioimaging /biomedical imaging;
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0.901 |
2006 — 2010 |
Hinton, David R. |
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. |
Cell and Tissue Imaging Core Facility @ University of Southern California
The Cancer Center "Cell and Tissue Imaging Core Facility" (previously the "Confocal Core Facility") is entering its sixth year of operation. Its mission, as developed by the Cancer Center Executive Committee, is to provide advanced cell and tissue imaging technology, services, and scientific consultation that facilitate scientific interaction and enhance scientific productivity of Cancer Center investigators. The Facility was originally developed as a partnership with the Doheny Eye Institute;the partner institutes jointly purchased a 5th generation confocal microscope and housed the instrument in an existing electron microscopy imaging facility adjacent to the Cancer Center. The Facility is jointly managed by the Cancer Center and the Doheny Eye Institute. The 2,000 square foot laboratory space for this shared facility is provided by the Doheny Eye Institute at no cost to the Cancer Center. The Facility is therefore used 50% by the Cancer Center and 50% by Doheny Eye Institute. All funds requested in this proposal are for costs directly related to the Cancer Center's 50% use of the facility. The primary users of this shared resource facility are Cancer Center investigators with peerreviewed, funded projects. The Facility is also open to other Cancer Center members who need its facilities to develop pilot project data. Since its establishment, the Facility has provided the Cancer Center membership with easy access to "state-of-the-art" cell and tissue imaging equipment and technical support. Daytime usage of the confocal microscope remains heavy (90% utilization of available hours);approximately 50% of this usage comes from Cancer Center members (consistent with the 50:50 use arrangement with Doheny Eye Institute). Importantly, the range of imaging equipment and services available to Cancer Center members has expanded (beyond laser scanning confocal/multiphoton microscopy) to include full access to transmission electron microscopy (TEM), scanning electron microscopy (SEM), digital light and fluorescence microscopy, fluorescence and bright field laser capture microdissection, thin sectioning, cryo-sectioning and embedding procedures, and computer aided graphics. We are continuously upgrading our imaging software and advising and instructing Cancer Center investigators in novel methodologies and protocols to enhance their cell and tissue imaging capability.
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2009 — 2013 |
Hinton, David R. |
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. |
Neuropathology Core @ Cleveland Clinic Lerner Com-Cwru
The Neuropathology Core (Core D) functions as an integral component of each of the Projects providing histopathologic services and Neuropathologic expertise. The Core PI (David R Hinton MD) and Core Colnvestigator (Roscoe Atkinson MD) are both board certified Neuropathologists with extensive experience in the evaluation of murine central nervous system (CNS) tissues. Support provided to each of the projects includes: 1) participation in development of experimental design for animal experiments; 2) tissue processing; 3) tissue sectioning (frozen sections and paraffin-embedded sections); 4) histochemical and immunohistochemical staining of tissue sections; 5) neuropathologic interpretation of tissue sections (by light microscopy or confocal microscopy); 6) documentation ofthe pathology by digital microscopy; 7) preparation of figures for manuscripts; 8) storage and retrieval of stained slides for each of the projects. Expert preparation and neuropathologic evaluation of tissues ensures high quality, unbiased assessment of CNS tissues for pathologic alterations including inflammation, demyelination and viral infection.
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0.919 |
2013 — 2016 |
Hinton, David R. |
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. |
An Experimental Approach to Maculopathy @ University of Southern California
Project Abstract Continued studies on basic mechanisms of atrophic age related macular degeneration (AMD) are proposed with translation of this work to establish novel therapies. Early AMD progresses to late blinding forms of the disease by following one of two divergent pathways; atrophic AMD or geographic atrophy (GA) is associated with progressive senescence and death of the retinal pigment epithelium (RPE), while choroidal neovascularization (CNV) is associated with growth of new vessels under the retina. In the last grant period we developed strong support for our hypothesis that increased expression of bone morphogenetic protein-4 (BMP4) in RPE induces features characteristic of atrophic AMD, and inhibits CNV; thus mediating a molecular switch that determines which late form of AMD a patient develops. One of the major responses to increased BMP4 expression in RPE is upregulated protein expression of the chaperone aB crystallin. We hypothesize that in early AMD, increased BMP4 expression leads to RPE senescence and a novel reactive neuroprotective response with increased expression of aB crystallin from RPE; however as disease progresses, this response is overwhelmed and further sustained oxidative stress results in progression to GA. We then hypothesize that aB crystallin-derived oligopeptides with chaperone activity can provide similar protection of RPE from oxidative stress and other injuries and can be selectively transported into the RPE. Furthermore, novel aB crystallin peptide nanoparticles can be assembled and optimized to effectively rescue dysfunctional RPE in culture, and in multiple murine models with features of GA. This work is highly significant since there is currently no effective therapy for GA. The hypotheses will be tested using the following Specific Aims: Aim #1. Determine the molecular, cellular, and functional inter-relationships between BMP4 and aB crystallin in RPE and the effect of oxidative stress on these processes. Aim # 2. Develop and optimize aB crystallin peptide nanoparticles that inhibit effects of various forms of stress in RPE cells grown in culture. Aim # 3. Determine the pharmacokinetics of aB crystallin peptide nanoparticles after intraocular or systemic delivery and determine the ability of these nanoparticles to inhibit progression of disease in multiple murine models with features of GA .
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