Michael B. Oldstone - US grants
Affiliations: | Scripps Research Institute, La Jolla, La Jolla, CA, United States |
Area:
Viral immunobiologyWebsite:
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High-probability grants
According to our matching algorithm, Michael B. Oldstone is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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1985 — 1988 | Oldstone, Michael B | P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Demyelinating (Ms) and Degenerative (Als) Cns Diseases @ Scripps Clinic and Research Foundation Persistence of virus in whole cells may be a result of immune regulation and stripping of viral antigens off the plasma membranes of infected cells or by virus induced formation of mutants and appropriate genetic selection. In either case the sparsity of viral antigens expressed on the plasma membrane surface allows persistent infected cells to escape immunologic surveillance. Furthermore, potential cytolytic viral infections are regulated to become noncytopathic, viral polypeptides may store in the cytoplasm of specialized cells and the luxury functions of these cells ultimately embarrassed. We have focused our attention on three main model systems which are likely to lead to relevant information on regulation of persistent virus infections and associated cell pathobiology or tissue injury and disease state. These models may well shed light on mechanisms in degenerative and demyelinative diseases of man like multiple sclerosis and amyotrophic lateral sclerosis. Attention has focused on measles virus because we are aware that this virus may remain latent or persistent in man and eventually become activated. Studies look at cell-viral interrelationship, alterations of HLA gene products by virus, and the ability of the humoral and cellular immune system to eliminate virus infected cells. A second model of interest is the formation of defective interfering virus and/or temperature sensitive mutants in regulation of viral persistence and allowing such infected cells to escape immunologic attack. Here our interest focuses both in vitro and in vivo on the role of DIV in acute and persistent LCMV infection as well as the role of ts mutants of mouse hepatitis virus and its wild type in causing primary demyelination and destructions of oligodendrocytes. The third model of interest is a slow virus disease, of which destruction of anterior horn cells is a prominent feature. This is the central nervous system disease caused by WM-1504 virus. Here using a quantifiable and identifiable viral gene product and genetically defined recombinant mice, the controlling factors in resistance and susceptibility can be mapped. Studies on patients with multiple sclerosis have focused on the responses of their peripheral blood lymphocytes against measles virus infected targets. In addition, the presence of thymus derived suppressor cells and the activity of such cells is under investigation. |
0.945 |
1985 — 1989 | Oldstone, Michael B | 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. |
Virologic and Immunologic Studies On Aging @ Scripps Clinic and Research Foundation It is our hypothesis that acute or persistent virus infection can cause degenerative progressive diseases of neurons, endocrine cells, immunocompetent cells or cells of the renal glomeruli and choroid plexus. Such diseases, manifested in aging populations, occur through the basic mechanisms. The first relates to the ability of a virus to persist in specialized cells (i.e., neurons) and turn off or abrogate the differentiated or luxury function of these cells (i.e., neurotransmitters, peptide hormones). Included are viruses that are noncytopathic, that are associated with the formation of amyloid plaques, that deposit pigments in cells leading to injury and disease. The second mechanism relates to the formation and action of autoantibodies leading to cell injury. We propose that viruses can cause autoantibody through a process of "molecular mimicry" and/or through the effects on B or T lymphocyte subsets. In the proposed venture, we intend to combine the skill of investigators with expertise in experimental and molecular biology, immunopathology, immunology, virology, neuropathology and cell biology. This group will study 1) persistent infection of neurons, endocrine and immunocompetent cells, 2) generation of amyloid plaques in scrapie infected mice, pigmentary neuronal degeneration in retrovirus infection of neurons and disease of immune complex or antitissue antibody types related to cross-reactive antigens, and 4) molecular mimicry between viral polypeptides and host cell antigens. |
0.945 |
1985 — 1993 | Oldstone, Michael B | 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. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Pathogenesis of Disease From Persistent Viral Infection @ Scripps Clinic and Research Foundation The cause and pathogenesis of tissue injury in most chronic degenerative diseases of man are unclear, although some of these diseases are clearly linked with slow or persistent viral infections. The objective of work described in this continuation proposal is to study the interactions between virus, virus infected cells and the immune response in clearing virus during acute infection or, alternatively, allowing virus to escape immune surveillance and establish persistent infection. Specifically, researc ongoing or planned within this research proposal (1) evaluates the formation, identification and genetic regulation of virus-antibody immune complexes in the circulation; (2) establishes cloned cytotoxic T lymphocyte (CTL) lines in which to identify virus receptors, molecular mechanisms of membrane lysis, diversity and crossreactivity of CTLs and the structural relationship between H02 antigens and viral antigens on the plasma membrane during cytotoxic assult; (3) examines the genetic basis underlying immunopathologic disease induced by acute and persistent virus infections; (4) studies virus infection of lymphocytes as a model of persistent infection and (5) assays the ability of a persistent virus infection to affect the differentiated ("luxury") function of lymphocytes, i.e., alter the production of specific antibodies made by hybridomas and abrogate the lytic activity of CTLs. |
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1985 — 2002 | Oldstone, Michael B | 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. |
@ Scripps Clinic and Research Foundation tissue /cell culture; biomedical facility; hybridomas; |
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1988 | Oldstone, Michael B | P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Pathogenesis of Demyelinating &Degenerative Disorders @ Scripps Clinic and Research Foundation |
0.945 |
1988 | Oldstone, Michael B | 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. |
Virologic and Immunologic Studies: Molecular Basis of Ag @ Scripps Clinic and Research Foundation This program project grant brings together molecular biologists, virologists, and experimental biologists to address the hypothesis that environmental agents (Viruses) can cause several diseases currently attributable to aging. We propose that acute or persistent virus infection can cause degenerative progressive diseases of endocrine cells, immunocompetent (lymphocytes) cells, neurons, or cells of the renal glomeruli and tubules. Such diseases, manifested in aging populations can occur through the ability of a virus to persist in specialized cells (i.e., islets of Langerhans, thyroid follicular cells, lymphocytes, endothelial cells and neurons) and turn off or abrogate their differentiated or luxury function (i.e., hormones, lympho and monokines and neurotransmitters). Such viruses may be noncytolytic and hence disease occurs by altering a cells' normal or physiologic function in the absence of the cells' destruction. Because virus induced disease can occur in the absence of tissue injury any illnesses not previously thought to be infectious in origin may be so. The second mechanism relates to the formation and action of autoantibodies leading to tissue injury. He propose that viruses can cause autoantibody (cross-reactive antibodies against self) through a process of "molecular mimicry" and/or through its effects on B or T lymphocyte subsets. In the proposed venture this group will study 1) persistent or latent infection of endocrine, immune and endothelial cells, 2) central nervous system disease associated with human retrovirus infection, 3) basic principles by which the immune system recognizes and removes foreign materials and how this is subverted by a virus to allow persistence and 4) normal and abnormal renal and vascular (endothelial) function in aging. |
0.945 |
1989 | Oldstone, Michael B | P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Demyelinating Ms and Degenerative Als-Cns Diseases @ Scripps Clinic and Research Foundation Persistence of virus in whole cells may be a result of immune regulation and stripping of viral antigens off the plasma membranes of infected cells or by virus induced formation of mutants and appropriate genetic selection. In either case the sparsity of viral antigens expressed on the plasma membrane surface allows persistent infected cells to escape immunologic surveillance. Furthermore, potential cytolytic viral infections are regulated to become noncytopathic, viral polypeptides may store in the cytoplasm of specialized cells and the luxury functions of these cells ultimately embarrassed. We have focused our attention on three main model systems which are likely to lead to relevant information on regulation of persistent virus infections and associated cell pathobiology or tissue injury and disease state. These models may well shed light on mechanisms in degenerative and demyelinative diseases of man like multiple sclerosis and amyotrophic lateral sclerosis. Attention has focused on measles virus because we are aware that this virus may remain latent or persistent in man and eventually become activated. Studies look at cell-viral interrelationship, alterations of HLA gene products by virus, and the ability of the humoral and cellular immune system to eliminate virus infected cells. A second model of interest is the formation of defective interfering virus and/or temperature sensitive mutants in regulation of viral persistence and allowing such infected cells to escape immunologic attack. Here our interest focuses both in vitro and in vivo on the role of DIV in acute and persistent LCMV infection as well as the role of ts mutants of mouse hepatitis virus and its wild type in causing primary demyelination and destructions of oligodendrocytes. The third model of interest is a slow virus disease, of which destruction of anterior horn cells is a prominent feature. This is the central nervous system disease caused by WM-1504 virus. Here using a quantifiable and identifiable viral gene product and genetically defined recombinant mice, the controlling factors in resistance and susceptibility can be mapped. Studies on patients with multiple sclerosis have focused on the responses of their peripheral blood lymphocytes against measles virus infected targets. In addition, the presence of thymus derived suppressor cells and the activity of such cells is under investigation. |
0.945 |
1989 — 1993 | Oldstone, Michael B | 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. |
Virology and Immunology of Aging @ Scripps Clinic and Research Foundation This program project grant brings together molecular biologists, virologists, and experimental biologists to address the hypothesis that environmental agents (Viruses) can cause several diseases currently attributable to aging. We propose that acute or persistent virus infection can cause degenerative progressive diseases of endocrine cells, immunocompetent (lymphocytes) cells, neurons, or cells of the renal glomeruli and tubules. Such diseases, manifested in aging populations can occur through the ability of a virus to persist in specialized cells (i.e., islets of Langerhans, thyroid follicular cells, lymphocytes, endothelial cells and neurons) and turn off or abrogate their differentiated or luxury function (i.e., hormones, lympho and monokines and neurotransmitters). Such viruses may be noncytolytic and hence disease occurs by altering a cells' normal or physiologic function in the absence of the cells' destruction. Because virus induced disease can occur in the absence of tissue injury any illnesses not previously thought to be infectious in origin may be so. The second mechanism relates to the formation and action of autoantibodies leading to tissue injury. He propose that viruses can cause autoantibody (cross-reactive antibodies against self) through a process of "molecular mimicry" and/or through its effects on B or T lymphocyte subsets. In the proposed venture this group will study 1) persistent or latent infection of endocrine, immune and endothelial cells, 2) central nervous system disease associated with human retrovirus infection, 3) basic principles by which the immune system recognizes and removes foreign materials and how this is subverted by a virus to allow persistence and 4) normal and abnormal renal and vascular (endothelial) function in aging. |
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1990 — 1994 | Oldstone, Michael B | P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Pathogenesis of Demyelinating and Degenerative Disease @ Scripps Research Institute The goal of this program project remains fixed on understanding the etiology and pathogenesis of demyelinating and chronic degenerative diseases of the nervous system. The hypothesis tested is that many such human disorders, like multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and other progressive CNS disorders, are likely caused by a persisting virus infection and/or aberrant immune response(s) against the virus and/or host self antigens. Our strategy is utilization of both in vitro studies and experimental animal models to shed information towards understanding and treating human CNS disease. Hence, the approaches followed are understanding (1) molecular and cellular mechanisms of viral tropism for cells of the nervous and immune systems; (2) means by which viruses regulate their genes to persist in infected cells (go from lytic to non-lytic phenotype), escape immune surveillance and alter normal cell's physiologic (differentiated) functions; (3) humoral and cellular (cytotoxic T cell) immune responses serving to eliminate infectious agents and lyse infected cells to prevent viral persistence; (4) environmental and genetic factors enhancing susceptibility to virus infection and injury, and causing aberrant immune responses; (5) the molecular and cellular events that mediate viral and/or immune destruction of cells and tissues leading to demyelinating and degenerative disease; (6) functional-structural (crystallographic) correlates that define why viruses are tropic and demyelinative for CNS cells. This program blends the skills of investigators with expertise in experimental medicine and pathology, neurologic diseases, immunology, virology, molecular biology, biochemistry, cell biology, molecular genetics and x-ray crystallography. By this means a focussed attack is made on understanding the cause, pathogenesis and hopefully therapeutic approaches to preventing demyelinating and degenerative disorders of the nervous system. |
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1990 — 1994 | Oldstone, Michael B | 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. |
Nervous-Immune System Interactions: Cns Effects of Hiv I @ Scripps Research Institute |
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1993 — 2002 | Oldstone, Michael B | 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. |
Neurobiologic and Immunologic Aspects of Aging @ Scripps Research Institute |
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1994 | Oldstone, Michael B | R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
1994 Faseb Summer Research Conference @ Federation of Amer Soc For Exper Biology This application requests support for the 1994 FASEB Summer Research Conference on "Principles in Viral, Bacterial, and Protozoan Pathogenesis." This conference is to be held 19-24 June 1994 at the Vermont Academy in Saxtons River, Vermont. It represents the first attempt to bring together virologists, bacteriologists, protozoologists and immunologists in one setting to allow an exchange (cross talk) among these disciplines. The goal is to take advantage of the recent and rapid development of information and technology in order to look for common or separate threads in understanding principles of microbial pathogenesis and to foster collaborative efforts between disciplines. Towards this end an outstanding collection of scientists in virology, bacteriology, protozoology, structural and cell biology, and immunology have been assembled by the chairpersons (Michael B. A. Oldstone, Bernard N. Fields) and their advisory board (John J. Mekalanos and Barry R. Bloom). Our anticipation is a highly successfully conference that will run every other year beginning in 1994. Eight platform and two poster sessions/panel discussions are planned. The scientific program will include sessions on: l) binding; 2) entry (penetration); 3) uncoating, replication, transcription, intracellular trafficking and assembly; 4) cell-cell passage and systemic dissemination; 5) recognition; 6) immunologic surveillance or its lack; 7) molecular genetics and genetic manipulations; and 8) vaccines and antimicrobial therapy. The program is designed to bring together established and developing investigators in both basic and clinical science, to provide interdisciplinary forums, and to recruit and finance several minority students and junior faculty. |
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1994 — 1998 | Oldstone, Michael B | 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. |
Aging Disease--Transgenic/Virologic/Immunology Studies @ Scripps Research Institute This Program Project grant brings together molecular biologists, virologists, immunologists, and experimental biologists to study neurodegenerative, endocrine and renal disorders of aging using transgenic models. The purpose is to understand pathogenesis and to develop therapeutic approaches to treat such disorders. Two interlocking hypotheses are addressed. The first is that expression of amyloid protein, its precursor or mutant proteins, prion or viral proteins in specialized cells of the central nervous system (CNS) using CNS specific promoters for expression in astrocytes or neurons will provide models of neurodegenerative disorders like Alzheimer's Disease. The second hypothesis addresses the issue that environmental agents (viruses) cause diseases in the aging population. It is proposed that acute or persistent infection can cause degenerative progressive diseases of endocrine cells, immunocompetent (lymphocytes) cells, neurons, or cells of the renal glomeruli and tubules. Such diseases; i.e., neurodegenerative, diabetes, glomerulosclerosis, etc., can occur through the ability of a virus to persist in specialized cells (i.e., islets of Langerhans, lymphocytes, neurons, etc.) and turn down such cells differentiation or luxury function (i.e., hormones, cytokines, neurotransmitters, etc.). Such viruses need be non-cytolytic and hence disease occurs by altering a cell's physiologic function in the absence of the cell's destruction. Because virus induced disease can occur in the absence of tissue injury many illnesses not previously thought to be infectious in origin may be so. Studies of this hypothesis utilize investigation of replication of a non-cytolytic virus in differentiated cells in vitro and in vivo as well as transgenic technology to express viral genes in specialized cells using the insulin promotor (beta cells of the islets of Langerhans), GFAP promoter astrocytes) and NSE promoter (neurons). In such instances cell and tissue injury and disease may occur through the expression of the viral gene itself or through the formation and action of antiself (antiviral) cytotoxic T lymphocytes or antibodies following infection or immunization with the homologous or closely related virus (cross-reactive immune response against self) through a process we term molecular mimicry. |
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1994 — 2007 | Oldstone, Michael B | 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. |
Measles Virus Studies in a Transgenic Model @ Scripps Research Institute Measles virus causes significant morbidity and mortality in the human population. Despite a successful attenuated vaccine, measles virus still kills over one million children a year. The problem being that the vaccine is inefficient in children infected prior to their ninth month of age. This is believed due to the presence of maternal antibody and/or virus induced immunosuppression or other late effects following vaccination. Further, measles causes a hyperacute allergic disease and a chronic persistent (subacute sclerosing panencephalitis) neuronal disorder. Yet our understanding and knowledge of the molecular features of measles virus, the immunologic and immunopathologic responses to both infection and vaccination and how the virus persists in neurons are poorly understood. In order to understand the pathogenesis of measles virus infection and to identify the immune protective response, including B and T cell epitopes, we will develop and exploit a novel small animal model. We and our colleagues have identified the putative receptor for measles virus, the membrane cofactor protein (MCP, CD46). Measles virus is permissive for human and simian but not murine cells. However, murine MC57 and 3T3 cells barely permissive to measles virus become permissive and produce progeny virus when stably expressing any of the four CD46 isoforms, although isoform BC1 and BC2 are associated with a higher degree of syncytial formation. We propose expressing the cDNA of CD46 in mice under its own, a beta actin (universal) and cell-specific (neuron specific enolase, RIP) promoters. This will allow us to generate a transgenic model of measles virus in a small, inexpensive, genetically manipulable host, the mouse, whose immunologic response(s) can be easily manipulated. Transgenic mice expressing the measles virus receptor will be useful for studying measles virus pathogenesis including virulence, tissue tropism, eliciting immune responses in the presence or absence of adoptively transferred antibodies, for mapping human HLA restricted CTL epitopes using double transgenic mice expressing CD46 and HLA class I molecules, creating a subunit vaccine and for testing of newly developed vaccines. |
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1994 — 2016 | Oldstone, Michael B | 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. R37Activity Code Description: To provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. Investigators may not apply for a MERIT award. Program staff and/or members of the cognizant National Advisory Council/Board will identify candidates for the MERIT award during the course of review of competing research grant applications prepared and submitted in accordance with regular PHS requirements. |
Pathogenesis of Persistent Viral Infection @ Scripps Research Institute The cause and pathogenesis of tissue injury in most chronic degenerative diseases of man are unclear, although some of these diseases are clearly linked with slow or persistent viral infections. The objective of work described in this continuation proposal is to study the interactions between virus, virus infected cells and the immune response in clearing virus during acute infection or, alternatively, allowing virus to escape immune surveillance and establish persistent infection. Specifically, researc ongoing or planned within this research proposal (1) evaluates the formation, identification and genetic regulation of virus-antibody immune complexes in the circulation; (2) establishes cloned cytotoxic T lymphocyte (CTL) lines in which to identify virus receptors, molecular mechanisms of membrane lysis, diversity and crossreactivity of CTLs and the structural relationship between H02 antigens and viral antigens on the plasma membrane during cytotoxic assult; (3) examines the genetic basis underlying immunopathologic disease induced by acute and persistent virus infections; (4) studies virus infection of lymphocytes as a model of persistent infection and (5) assays the ability of a persistent virus infection to affect the differentiated ("luxury") function of lymphocytes, i.e., alter the production of specific antibodies made by hybridomas and abrogate the lytic activity of CTLs. |
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1995 — 1999 | Oldstone, Michael B | 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. |
Nervous-Immune System Interactions: Cns Effects of Hiv @ Scripps Research Institute |
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1996 — 2000 | Oldstone, Michael B | 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. |
Anatomy of Measles Virus/Receptor Interaction @ Scripps Research Institute DESCRIPTION (Adapted from Applicant's Abstract): Dr. Oldstone and his colleagues have recently identified the putative receptor for measles virus (MV), the membrane cofactor protein CD46, a member of the regulators of complement activation family. MV is permissive for human and simian but not hamster or murine cells. However, CHO or murine MC57 and 3T3 cells barely permissive to MV become permissive and produce progeny virus when stably expressing any of the four CD46 isoforms. This occurs with Edmonston strain MV as well as field isolates. The CD46 molecule is composed of four short consensus repeats (SCR) of 60 amino acids each, an enriched serine, threonine and proline region and a transmembrane tail at the carboxy terminus. Only antibodies against SCR-1 and SCR-2 were effective at blocking MV binding and infectivity. In addition, mutants of CD46 mapped MV binding to the first and second but not the third and fourth SCR domain. the proposed research is to molecularly dissect CD46-MV interactions and study the biology and consequences of that interaction. First, mutant CD46 constructs will be generated, relevant peptides from CD46 and MV H protein will be synthesized and MV H protein will be solubilized to map out the specific sequences on CD46 SCR-1 and SCR-2 domains that serve as the MV receptor and on MV H protein that bind to CD46. Second these data will be used to develop molecules that compete with MV binding. SCR-1 domain of CD46 is not required for CD46 interaction with the complement system. Since SCR-1 has no known housekeeping role in cells, it may be possible to block viral attachment while maintaining functional integrity of the CD46 molecule. |
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1997 — 2001 | Oldstone, Michael B | 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. |
Viruses and Autoimmune Disease @ Scripps Research Institute A variety of DNA and RNA viruses cause autoimmune responses in humans and autoimmune disease in experimental models. This grant is concerned with dissecting and understanding the molecular mechanism(s) whereby multiple and sequential virus infections break immunologic unresponsiveness to "self" antigens and cause autoimmune manifestations and disease. We developed two models where a viral protein (virus A) is expressed in beta cells of the islets of Langerhans or in oligodendrocytes using cell-specific promoters. In both, disease does not occur unless the host is challenged with virus A (disease incidence >90%, beta cell destruction by T cells resulting in hyperglycemia and hypoinsulinemia or T cell infiltration from the periphery into the CNS [white matter] and focal myelin loss). When a different virus B or C are used for the initial challenge disease does not occur but when viruses B or C are given four to six weeks after the initial inoculation with virus A, the kinetics and severity of disease is enhanced. The first business of this grant is to determine the mechanism by which multiple related or unrelated viral infections can enhance autoimmune disease. We will determine, by the use of the well established RIP-LCMV model of virus-induced autoimmune diabetes, whether the cross-reactive immune response is specific (shared peptide T cell epitopes) or due to bystander (cytokines, adhesion molecules) effects. Further, responses to self antigens (peptides) might contribute to activation and maintenance of autoreative T-lymphocytes. "Self" antigens that contain the same MHC motif as the transgene's CTL epitope and bind at high affinity to the MHC allele have been uncovered. The ability of these "self" peptides to be recognized by anti-viral T cells, maintain antiviral T cell memory and participate in autoimmune disease will be evaluated. Immunopathologic changes occur in normal islets transplanted under the renal capsule of transgenic mice developing IDDM. The second order of business is to determine the role of "self" (islet-cell) antigens other than the initial triggering viral antigen in the pathogenetic process leading to and determine their role in IDDM. |
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1999 — 2001 | Oldstone, Michael B | 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. |
Studies of a New Myelin Gene That Causes Cns Disease @ Scripps Research Institute DESCRIPTION: (adapted from applicant's abstract): The investigators have cloned a new myelin gene that encodes the Myelin-associated Oligodendrocytic Basic Protein (MOBP). The MOBP gene generates by alternative splicing several small (10kD range) and highly basic (pI>10) intracellular MOBP proteins. MOBP differs from other myelin genes like Myelin Basic Protein (MBP) or Proteolipid Protein (PLP) by structure, by expression only in CNS oligodendrocytes and not in PNS Schwann cells, and by a delayed expression (onset of transcription) during development. The kinetics of the developmental expression of MOBP coincide with the appearance of compact myelin and MNBP in the signaling of myelin sheath compaction. To test this hypothesis they plan to knock-out the Mobp gene and study the development of myelin and the compaction of the myelin sheath as well as to determine the clinical phenotype(s) in such MOBP null mice. They (A. Holz, M.B.A. Oldstone) have recently expressed recombinant MOBP protein and documented that it produced EAE-like disease in SJL/J mice. Several months after this grant was submitted, Maatta et al. (immunology 95:383, 1998) also found that recombinant MOBP protein caused EAE in mice. Thus, two laboratories have documented the encephalitogenic activity of MOBP. Utilizing overlapping MOBP peptides, the investigators mapped the encephalitogenic domain to a single 24 amino acid site. They propose here to map out the precise amino acid residues of MOBP that comprise the encephalitogenic site, perform a detailed immunohistochemical analysis of the CNS lesion(s), generate and characterize T-cells clones from these mice and determine their role and how they cause EAE, and analyze whether MOBP can cause remitting/relapsing demyelinating disease. An area in human MOBP corresponding to the encephalitogenic domain of rodent MOBP fits a HLA DR motif associated with enhanced susceptibility to Multiple Sclerosis (MS). Studies suggested by them and in progress by Roland Martin at the NIH show that lymphocytes taken from patients with remitting/relapsing MS proliferate to selected huMOBP peptide(s). Their studies in rodents combined with those of their collaborator, Dr. Martin, should begin to characterize the role played by MONP in neurologic disease. |
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1999 — 2002 | Oldstone, Michael B | 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. |
@ Scripps Research Institute gene targeting; animal breeding; genetically modified animals; biomedical facility; disease /disorder model; model design /development; genetic manipulation; laboratory mouse; |
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1999 — 2003 | Oldstone, Michael B | 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. |
Aging Disease--Transgenic/Virologic/Immunologic Studies @ Scripps Research Institute Transmissible spongiform encephalopathies (TSE) (prion disease, scrapie) are fatal neurodegenerative diseases that occur in humans and animals. This grant's focus is on elucidating the pathogenic mechanism(s) contributing to the neuronal injury and on utilizing molecular approaches to treat and/or about disease. We hypothesize that the disease of the CNS characterize by spongiosis, astrocytosis, neural death, neural dropout and accumulation of an abnormal isoform (PrP/sc) from the host-encoded cellular PrP (PrP/c) occurs by two distinct pathways. The first is by direct accumulation of PrP/sc in neurons. However, the presence of exogenous PrP/c delays/aborts the onset of disease. A major aim of this proposal is to continue studies and to expand the evaluation of exogenous PrP/c in aborting/treating TSE disease. The second major aim of this proposal evaluates the possibility that neuronal injury also occurs from bystander (indirect) effects. TNF- alpha, a cytokine-implicated in apoptosis, is markedly increased in the CNS during scrapie disease. TNF-alpha expression parallels the onset of clinical symptoms and experiments using TNF-alpha ko mice are designed to determine its role in disease. In addition, in prion + (mPrP+) but not in prion/null (ko) (mPrP/null) mice, inoculation of murine scrapie leads to infiltration of T lymphocytes into the brain that parallels the clinical course of disease. Initial experiments show it takes a significantly longer time for MHC class I ko mice given murine scrapie agent to develop clinical and histological scrapie when compared to MHC class I sufficient mice, strongly suggesting that CD8+ T cells may contribute to the pathogenesis of scrapie when compared to MHC class I sufficient mice, strongly suggesting that CD8+ T cells may contribute to the pathogenesis of scrapie. The enigma of immune tolerance to PrP is to be re-evaluated. The role played by MHC molecules and T cell subsets in the pathogenesis of TSE disease will be investigated, and regions on PrP recognized by T cell determined. |
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2000 — 2007 | Oldstone, Michael B | 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. |
Arenavirus Receptor--Structure/Function Studies @ Scripps Research Institute We isolated a peripheral membrane protein interactive with lymphocytic choriomeningitis virus (LCMV) from cells permissive to LCMV infection. Examination of tryptic peptides revealed its identity as alpha-dystroglycan (alpha-DG). Four strains of LCMV, ARM 53b, Traub, E-350, WE54 and ARM C1 13 and other arenaviruses, Lassa fever virus (LFV), Oliveros, Mobala and Mopeia bound to purified alpha-DG protein. Several lines of evidence indicated that alpha-DG is required for virus infection: 1) soluble alpha- DG blocked either LCMV or LFV infection; 2) cells bearing a null mutation of the DG gene were resistant to LCMV infection; 3) reconstitution of DG expression in null mutant cells restored susceptibility to LCMV infection. Some viruses bound at high affinity to alpha-DG (C1 13, Traub, WE54, LFV) while others (ARM 53b, E-350) bound at lower affinity (100- to 1000-fold less). The high affinity alpha-DG binders, when injected into mice, preferentially infected cells in the splenic white pulp (preliminary identified as interdigitating dendritic cells (IDDC), the major antigen presenting cell), caused immunosuppression and a persistent infection. In contrast, low alpha-DG binders preferentially bound to cells in the red pulp (primarily F4/80+ cells), there was no suppression of immune response, CD8+ T cells were generated and infection terminated. We propose three specific aims. First, to determine whether alpha-DG is a common cellular receptor for all arenaviruses. Study of BSL-4 and BSL-3 arenaviruses will be done in the BSL-4 facilities at CDC and BSL-2 arenaviruses at TSRI. Second, we will make a series of alpha-DG deletion mutants and reconstitute these into DG null cells to map out the portion on alpha-DG that arenaviruses bind to to determine different or similar sites on alpha-DG that these viruses recognize. Third, we will test the hypothesis that binding to IDDC is dependent on specific aa(s) in the viral GPI (aa 260 aliphatic: high affinity binder; aromatic: low affinity). We will also analyze alpha-DG content on IDDC and F4/80+ cells and look for coreceptor(s). |
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2001 | Oldstone, Michael B | 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. |
Aging Disease: Transgenic/Virologic/Immunologic Studies @ Scripps Research Institute This proposal is for continuing a highly successful Program Project grant that links the fields of virology, molecular genetics and immunology to approach the problem of degenerative of aging with a focus on neurodegenerative and pancreatic. Through the use of targeted transgenic animal models, complemented with models of persistent viral infection, we seek a greater understanding of the pathogenesis of neuronal diseases caused by PrP (prions), beta-amyloid precursor proteins or persistent expression of viral genes, and the effects of persistent viral gene expression and antiviral (self) immune responses on beta cells of the islets of Langerhans. Such studies will allow the development of novel forms of therapeutic intervention. Two interlocking hypotheses are addressed. The first is that expression of amyloid protein, its precursor or mutant proteins, prions or viral proteins in specialized cells of the central nervous system (CNS) using CNS-specific promoters for expression in astrocytes or neurons provide models of neurodegenerative disorders like Alzheimer's disease. It is also proposed that persistent infections can cause progressive degenerative disease. In this instance disease occurs owing to the ability of a virus to persist in specialized cells and turn down the ability of those cells to make differentiation or luxury function products such as GAP-43, neurotransmitters, hormones, cytokines, etc. The second hypothesis is that initiation of the immune-response or alterations in immune responses to PrP, beta-amyloid, viral or other related proteins can contribute to these degenerative disorders. Protocols are designed to test the various possibilities to address both pathogenic mechanisms and therapeutic interventions. We believe these targeted models that we have developed closely resemble aspects of corresponding human diseases, allowing us the unique opportunity to attempt novel, discrete, and localized means of anti-viral and other therapies, and immune intervention that will have relevance to the clinical disease in humans. |
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2002 — 2005 | Oldstone, Michael B | 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. |
@ Scripps Research Institute DESCRIPTION (Provided by applicant): This is the second revision of a grant requesting funds to continue a highly productive 5 year grant to study how viruses cause autoimmune insulin-dependent diabetes mellitus (IDDM). Utilizing recent information we derived from a transgenic (tg) model created to mimic human IDDM together with reports of other investigators a unifying hypothesis of how viruses cause IDDM and other autoimmune diseases is presented. The testing of this hypothesis comprises this grant proposal. We hypothesize for the initial event to occur the virus must be both tropic for the target organ and via infection of the target organ induce cytokines/chemokines in the local milieu allowing upregulation of MHC and T cell activation molecules, APC and attraction of antiself T cells. When the unresponsive but potential autoimmune antigen-specific T cell population in the periphery is of sufficient numbers and affinity then the virus through stimulation of the innate immune system can cause disease. However, when the antigen-specific antiself T cell pool in the periphery is of low numbers and of low affinity (as often in most instances of autoimmune disease) then the virus must provide a mimic, through the process we initially termed molecular mimicry, so that the T cell pool is sufficiently expanded (adoptive immune system) to cause disease. This grant tests the components of this hypothesis with studies of the role of virus tropism, the role of selected components of the innate and adoptive immune response and determines numbers of antigen-specific anti "self" T cells deposited in the target organ in situ in comparison to non-antigen-specific T cells in causing IDDM. To do these experiments we utilize both our established RIP-LCMV and MBP-LCMV tg mice, create new tg models that specifically inhibit viral replication in the target organ, use recombinant viruses tropic or not tropic for pancreas or CNS that carry the "autoimmune self" "viral" antigen, and use MHC tetramers and functional assays to identify and quantitate the antiself antigen-specific T cells deposited in the target organ as well as following their trafficking to that tissue. |
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2003 | Oldstone, Michael B | 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. |
Pathogenesis Studies in Scrapie (Tse Diseases) @ Scripps Research Institute DESCRIPTION (provided by applicant): Transmissible spongiform encephalopathy (TSE) or prion diseases are rare fatal neurodegenerative illnesses of humans and other animals. The recent awareness of TSE diseases has accelerated due to the appearance of bovine encephalopathy or mad cow disease in Europe, especially the United Kingdom, and its potential for transmission via the food chain to humans and the awareness that the majority of deer and elk on farms as well as 10 to 20% of wild deer and about 1% of elk develop TSE disease (CWD). The transmission of CWD to humans is unknown and although there is currently no evidence of passage of TSE via blood products in humans exposed to BSE, the reported transmission by blood in ruminants is of concern. Our hypothesis is that uniquely designed and developed transgenic (tg) models offer the opportunity to address important but as yet unknown or unresolved issues in TSE diseases. Towards that end we have successfully developed a tg model using PrP ko mice as a host in which expression of PrPsen can be induced in a rev tet system with administration of doxycycline, and a tg model in which GP1 anchorless PrPsen is also expressed in other PrP ko mice. The former will allow data on the turnover of PrPres in vivo and provide information as to its removal, information of value to determine the potential efficacy of anti-PrP therapy during different timed stages of disease. The later GP1-/- model should provide data on glycosylation, spread or failure to spread PrPres from the inoculated site, the ability of GP1 anchorless PrPsen to be converted to PrPres to cause disease, as well as analysis of potential differences in incubation time/disease incidence among different strains of mouse scrapie. The third tg model is the expression of white tail deer (WTD) prion under control of the mouse PrP promoter in PrP ko mice. This model should be useful to study pathophysiology of CWD as well as probing CWD strain differences. |
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2003 — 2010 | Oldstone, Michael B | 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. 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.) |
Therapeutics to Prevent/Treat Lassa Fever Virus @ Scripps Research Institute DESCRIPTION (provided by applicant): For a virus to infect a cell and subsequently cause disease it must first bind to its cellular receptor. The Oldstone laboratory isolated and characterized the cellular receptor, alpha-dystroglycan ((-DG) for several arenaviruses including Lassa fever virus (LFV) and LCMV CI 13. We provided evidence that (-DG is the receptor required for infection (Cao et al., Science, 1998; Spiropoulou et al., J. Virol., 2002) as: 1) LFV and LFV glycoprotein (GP) bind at high affinity to purified (-DG immobilized on membranes; 2) normally permissive cells bearing a null mutation of the DG gene are resistant to LFV infection; 3) reconstitution of (-DG expression in null mutant cells using an adenovirus vector restored susceptibility to LFV. We have established a high-output assay to analyze LFVGP-mediated infection of target cells under BSL2 conditions. In the Boger laboratory solution-phase synthetic techniques have been utilized to create unique combinatorial libraries of small molecules that can be screened to identify therapeutic compounds that promote protein-protein interactions (agonists) or inhibit protein-protein interactions (antagonists). We propose three specific aims: First, to screen combinatorial chemical libraries to discover small molecules that inhibit LFVGP-mediated infection of cells using retroviral vectors that contain LFVGP in their envelope and a green fluorescent protein reporter gene. Second, to develop a drug that would neutralize free LFV by engineering anti-viral receptor-bodies, in which the Fab part of an IgG molecule is replaced by a virus-binding (-DG fragment. Third, to validate this inhibition in vivo by blocking LCMV CI 13 infection in a mouse model (CI 13 and LFV binds at high affinity to (-DG and predictably utilizes the same binding site). Final verification would be done at CDC using the experimentally defined chemical inhibitor(s) and virulent LFV. |
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2004 | Oldstone, Michael B | 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. |
@ Scripps Research Institute |
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2004 — 2006 | Oldstone, Michael B | 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. |
Transgenic Models of Transmissible Spongiform Encephalop @ Scripps Research Institute DESCRIPTION (provided by applicant): Transmissible spongiform encephalopathy (TSE) or prion diseases are rare fatal neurodegenerative illnesses of humans and other animals. The recent awareness of TSE diseases has accelerated due to the appearance of bovine encephalopathy or mad cow disease in Europe, especially the United Kingdom, and its potential for transmission via the food chain to humans and the awareness that the majority of deer and elk on farms as well as 10 to 20% of wild deer and about 1 % of elk develop TSE disease (CWD). The transmission of CWD to humans is unknown and although there is currently no evidence of passage of TSE via blood products in humans exposed to BSE, the reported transmission by blood in ruminants is of concern. Our hypothesis is that uniquely designed and developed transgenic (tg) models offer the opportunity to address important but as yet unknown or unresolved issues in TSE diseases. Towards that end we have successfully developed a tg model using PrP ko mice as a host in which expression of PrPsen can be induced in a rev tet system with administration of doxycycline, and a tg model in which GP1 anchorless PrPsen is also expressed in other PrP ko mice. The former will allow data on the turnover of PrPres in vivo and provide information as to its removal, information of value to determine the potential efficacy of anti-PrP therapy during different timed stages of disease. The latter GP1-/- model should provide data on glycosylation, spread or failure to spread PrPres from the inoculated site, the ability of GP1 anchorless PrPsen to be converted to PrPres to cause disease, as well as analysis of potential differences in incubation time/disease incidence among different strains of mouse scrapie. The third tg model is the expression of white tail deer (WTD) prion under control of the mouse PrP promoter in PrP ko mice, This model should be useful to study pathophysiology of CWD as well as probing CWD strain differences. These studies will be complimented by providing the appropriate PrP ko and PrP reconstituted mice for studies by Jose Criado and mouse models to test efficacy of both antibody and small molecules that mimic antibody in treatment of TSE. |
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2004 — 2008 | Oldstone, Michael B | 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. |
Aging Disease--Prion/Transgenic/Immunologic Studies @ Scripps Research Institute DESCRIPTION (provided by applicant): Transmissible spongiform encephalopathies (TSE) are degenerative brain diseases that occur in primates and ruminants, and include scrapie in sheep, bovine spongiform encephalopathy (BSE) and several human diseases such as Creutzfeldt-Jakob disease, Kuru, fatal familial insomnia and Gerstmann-Straussler-Scheinker syndrome. Recent evidence indicates transmission of BSE across species barrier to humans resulting in a distinct Creutzfeldt-Jakob disease (vCJD). Although roughly only 130 cases of vCJD have occurred, several million persons including over 3 million Americans have been exposed to meat from contaminated BSE cows. The long incubation period of TSE disease suggests this may turn out to be a major health problem in the future. Prion protein (PrP) plays an essential role in TSE disease as the presence of both the normal PrP (PrPsen) and the abnormal prbtease resistant PrP (PrPres) is required for disease associated with TSE. This Program Project is designed to test the hypothesis that antibodies directed to PrP can both map the structure of the molecule and act to prevent the conversion of PrPsen to PrPres. These antibodies and small molecules that mimic their interaction with PrP may be useful both as diagnostic markers and therapies. Anthony Williamson who, with Dennis Burton, developed recombinant phage antibodies to PrP will continue to obtain and clone novel anti-PrP antibodies and use these reagents to study function-structure of PrP. Dennis Burton will focus primarily on study of PrP antibody-PrP interactions in order to develop small molecules that can pass the blood-brain-barrier. Michael Oldstone will continue to generate novel transgenic mouse models designed to analyze PrP turnover, role of GP1 anchor of PrP and use models that shorten the incubation time to develop TSE to test the efficiency of the antibodies and small mimicking molecules designed by Williamson and Burton, respectively. Lastly, Jose Criado will continue his electrophysiology and behavioral studies on the normal function of PrP and on its aberrations during TSE disease. |
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2006 — 2010 | Oldstone, Michael B | 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. |
Arenavirus Receptor-Structure/Function Studies @ Scripps Research Institute DESCRIPTION (provided by applicant): This is a corrected and revised resubmission to study the structure/biology of the arenavirus receptor. We found alpha-dystroglycan (alpha-DG) was the receptor for arenaviruses (Science 282, 1998). All specific aims proposed on the initial 5 yr grant have been accomplished. The first was to determine whether alpha-DG was a receptor for all arenaviruses. We found alpha-DG was the only receptor required for all Old World (LCMV, Lassa fever virus [LFV]) and New World Clade C viruses (Latino, Oliveros) (J. Virol. 76, 2002). The second aim was to map the portion(s) of alpha-DG that arenaviruses and the cell's natural ligand laminin bound to. This was accomplished by constructing and using alpha-DG deletion mutants and Fc fragments transfected into alpha-DG-/- cells (JEM 192, 2000; J. Virol. 75, 2001; Virology 325, 2004; JCB 155, 2001; Cell 117, 2004). The third aim was to study biologic consequence of virus binding to alpha-DG and extension of those findings form the bulk of this application. We found alpha-DG was expressed in the immune system almost exclusively on dendritic cells (DC) and in the peripheral nervous system on Schwann cells (SC). High affinity alpha-DG binding viruses infected (>75%) DC and their bone marrow (BM) precursors and >98% of SC while low affinity binders (bind at 2-3 logs less) infected <10% of these cells. Infected DC were neither able to arm T cells and terminate infection (JEM 192, 2000) nor expand in vivo or in vitro (JCI 113, 2004). Infected BM cells failed to develop and differentiate into DC (JCI 113, 2004; Immunity, in press, 2005). Infected SC failed to make myelin (PNAS 100, 2003). We propose identifying the signaling pathways and the molecules that alter differentiation of BM cells, dysfunction of DCs and cause the failure of SC to form myelin during viral infection. These findings have relevance for biodefense of several viruses including LFV. |
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2007 — 2008 | Oldstone, Michael B | 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. |
Transgenic Models of Transmissible Spongiform Encephalopathy @ Scripps Research Institute DESCRIPTION (provided by applicant): Transmissible spongiform encephalopathy (TSE) or prion diseases are rare fatal neurodegenerative illnesses of humans and other animals. The recent awareness of TSE diseases has accelerated due to the appearance of bovine encephalopathy or mad cow disease in Europe, especially the United Kingdom, and its potential for transmission via the food chain to humans and the awareness that the majority of deer and elk on farms as well as 10 to 20% of wild deer and about 1 % of elk develop TSE disease (CWD). The transmission of CWD to humans is unknown and although there is currently no evidence of passage of TSE via blood products in humans exposed to BSE, the reported transmission by blood in ruminants is of concern. Our hypothesis is that uniquely designed and developed transgenic (tg) models offer the opportunity to address important but as yet unknown or unresolved issues in TSE diseases. Towards that end we have successfully developed a tg model using PrP ko mice as a host in which expression of PrPsen can be induced in a rev tet system with administration of doxycycline, and a tg model in which GP1 anchorless PrPsen is also expressed in other PrP ko mice. The former will allow data on the turnover of PrPres in vivo and provide information as to its removal, information of value to determine the potential efficacy of anti-PrP therapy during different timed stages of disease. The latter GP1-/- model should provide data on glycosylation, spread or failure to spread PrPres from the inoculated site, the ability of GP1 anchorless PrPsen to be converted to PrPres to cause disease, as well as analysis of potential differences in incubation time/disease incidence among different strains of mouse scrapie. The third tg model is the expression of white tail deer (WTD) prion under control of the mouse PrP promoter in PrP ko mice, This model should be useful to study pathophysiology of CWD as well as probing CWD strain differences. These studies will be complimented by providing the appropriate PrP ko and PrP reconstituted mice for studies by Jose Criado and mouse models to test efficacy of both antibody and small molecules that mimic antibody in treatment of TSE. |
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2007 — 2011 | Oldstone, Michael B | U01Activity 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. |
Novel Chemical and Immunological Approaches to Influenza Therapy @ Scripps Research Institute [unreadable] DESCRIPTION (provided by applicant): Influenza virus remains a major public health concern for the USA and the world. To best insure that a pandemic like the 1918-1919 episode does not reoccur, national and international surveillance, effective vaccine and novel and effective antiviral therapy are required. Here we propose a multi-institute cooperative research project focused on discovery and use of novel chemicals that selectively manipulate the immunologic response in the lung as a therapeutic approach to better control influenza viral infection. We and others have evidence in animal models that the immune response (immunopathology) to influenza contributes significantly to morbidity and mortality. We have preliminary but impressive data that low doses of sphingosine analogs administered as a single dose intratracheally but not systemically acts locally in the lung to specifically suppress antiviral T cell proliferative responses. We propose that: 1) single aerosol exposure of the lungs to a sphingosine analog will inhibit antiviral proliferation thus modulating the resultant immunopathologic injury; 2) this mechanism will synergize with classic antiviral protective therapy; 3) combination of these therapeutic approaches will protect the host during H5N1 infection. To test this proposal Hugh Rosen, with expertise in immunology, medicinal chemistry and human therapeutics, will continue the development of sphingosine compounds and their testing with Michael Oldstone, experienced in viral-immunobiology and use of the WSN recombinant virus expressing immunodominant CDS and CD4 T cell epitopes of LCMV. WSN recombinant infection is preceded with transfer of GFP, RFP or Th1.1 congenically labeled CD4 and CDS T cells to these LCMV epitopes allowing quantitation of flu-specific T cells in the lung. The LCMV recombinant as well as GFP-labeled WSN virus used has been prepared by the third partner in this enterprise, Yoshihiro Kawaoka, an expert in influenza viruses. Kawaoka will test novel sphingosine analogs against H5N1 influenza virus. [unreadable] [unreadable] [unreadable] [unreadable] |
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2009 — 2011 | Oldstone, Michael B | 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. |
In Vivo Analysis of T Lymphocytes in the Persistently Infected Cns @ Scripps Research Institute DESCRIPTION (provided by applicant): The central nervous system (CMS) poses a unique challenge to the immune system, as it is considered an immunologically specialized compartment that resides behind a non-fenestrated barrier and significantly limits the expression of antigen-presenting machinery. Because the CNS is compartmentalized and imposes strict regulatory mechanisms on the adaptive immune system, a multitude of pathogens that infect humans (e.g. HIV, herpes virus, measles virus, HTLV-1, JC virus, etc.) are capable of establishing persistence in the CNS. These persistent infections can give rise to severe behavioral alterations and neurological dysfunction, which adversely affects human health. Persistent infections that gain access to the CNS often do so by first establishing persistence in the periphery. This common scenario consequently presents biomedical researchers with the challenge of eradicating the pathogen from both the periphery as well as the CNS. Given that the CNS provides such a favorable environment to viruses seeking persistence, we postulate that achieving clearance from this specialized compartment will be far more challenging than from peripheral tissues. The proposed study will explore a murine model system in which an immunosuppressive virus is introduced through a peripheral route and then establishes prolonged persistence in the CNS despite the eventual clearance from the periphery. Clearance from the periphery coincides with a functional reactivation of virus-specific T cells (a scenario we hope to achieve in humans), yet this response is unable to prevent prolonged viral persistence within the CNS. Importantly, administration of exogenous memory T lymphocytes at the peak of CNS viral infection results in efficient clearance of the virus from both the periphery and the CNS. Thus, an adoptively transferred population of memory T lymphocytes can achieve successful clearance despite an inadequate endogenous immune response. The proposed study is designed to significantly advance our understanding of T cell immunity to persistent viral infections in the CNS by establishing the shortcomings of the endogenous T cell response (Specific Aim#1) and the modus operand of a highly successful adoptive response (Specific Aim#2). The main objective of this research is mechanistically define the factors that give rise to successful CNS viral clearance so that we are better able to supplement a failing (or inadequate) endogenous response. |
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2013 — 2016 | Oldstone, Michael B | 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. |
Host Genetic Factors to Combat Lassa Hemorrhagic Fever @ Scripps Research Institute DESCRIPTION (provided by applicant): This grant focuses on arenavirus pathogenesis (how viruses cause disease) and why during infection some hosts become severely ill and die while others remain relatively unscathed. Lessons learned from lymphocytic choriomeningitis virus (LCMV) are applied to Lassa fever virus (LASV). LASV infects over 300,000 individuals per year resulting in over 20,000 deaths. LASV has been transported by travelers from Western Africa to the USA. Its potential as a weapon of biowarfare is a source of national concern. LASV is placed on the Category A list of microbial agents. My laboratory identified alpha-dystroglycan (?-DG) as the host cell receptor for LCMV and LASV and demonstrated preferential localization of ?-DG on dendritic cells (DCs). We then showed that post- translational modification of ?-DG by the glycosyltransferase LARGE is absolutely critical for the functional maturation of ?-DG as a receptor for LASV and LCMV binding, entry and replication. P. Sabeti and colleagues found that mutations in LARGE were common in West African populations of Nigeria and Sierra Leone where LASV infection is endemic, but absent in those populations in West Africa where LASV is not endemic. Polymorphisms of the LARGE allele are present in about 35% of the population where LASV is endemic with about 45% of individuals heterozygous and 16% homozygous for it. Mutations in LARGE are found in LASV survivors. Since high viremia (> 9 logs of plaque forming units [PFU/ml of sera]) is routinely associated with signs of severe LASV infection and death, whereas lower viremia (< 8 logs of PFU/ml or less) with recovery, and the ?-DG/LARGE complex controls LASV entry and subsequent replication, it is likely that mutations in LARGE shape evolution by favoring survival of the host against this virus. Limiting the amount of virus made provides the host's immune system a window of opportunity to mount an effective anti-LASV immune response thereby preventing severe disease and promoting virus clearance. This grant's purpose is to determine if LARGE mutations are responsible for survival to LASV infection. We will assay cells permissive to LASV infection (DCs/monocytes) that contain LARGE mutations in a functional LARGE enzyme assay, and for virus binding, entry and replication using a LASV Gp/LCMV recombinant virus. The recombinant virus can be used in BSL/2 laboratory and has been shown to bind, enter and replicate in permissive human and mouse cells. Thereafter those DCs and monocytes from individuals having LARGE mutations and displaying altered LASV binding, entry or replication or enzymatic activity will be tested at CDC with wtLASV. The fruits of these studies provide the opportunity to identify forces shaping human evolution in that individuals possessing LARGE mutant alleles are likely selected for resistance to LASV. Further, these studies may also identify surrogate markers to classify susceptible or resistant individuals to this viral infection. |
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2014 — 2018 | Oldstone, Michael B.a. | N01Activity Code Description: Undocumented code - click on the grant title for more information. |
Identification and Validation of Novel Human T Cell Epitopes in Lassa Fever @ Scripps Research Institute The contracts awarded under the Large Scale T Cell Epitope Discovery program establish highly interactive multi-disciplinary teams whose research efforts are focused on large-scale discovery of T cell epitopes associated with microorganisms responsible for emerging and re-emerging infectious diseases and potential agents of bioterrorism. Projects are milestone driven and must include: 1) epitope identification; 2) in vitro epitope validation studies with primary human T cells to demonstrate the immunogenicity/antigenicity or diagnostic potential of all newly defined T cell epitopes shown to bind to classical or non-classical MHC molecules; and 3) submission of all epitope information and computer software to the Immune Epitope Database to facilitate access and use of the data and tools by the broader research community. |
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