1985 — 1990 |
Baltimore, David |
S07Activity Code Description: To strengthen, balance, and stabilize Public Health Service supported biomedical and behavioral research programs at qualifying institutions through flexible funds, awarded on a formula basis, that permit grantee institutions to respond quickly and effectively to emerging needs and opportunities, to enhance creativity and innovation, to support pilot studies, and to improve research resources, both physical and human. |
Biomedical Research Support Grant @ Whitehead Institute For Biomedical Res |
0.937 |
1985 — 1989 |
Baltimore, David |
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. |
Interactions of Oncogenes With Developing Systems @ Whitehead Institute For Biomedical Res
virus genetics; oncogenes;
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0.937 |
1985 — 1995 |
Baltimore, David |
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. |
Molecular Biology of Picornaviruses @ Whitehead Institute For Biomedical Res
The proposed program will continue our studies on the mechanisms involved in the growth of picornaviruses. The major focus will be on poliovirus RNA replication. Purification of both the host and viral proteins that make up the replicase system is planned. The mechanism of initiation of viral RNA replication and the possible involvement of a protein primer will be examined. Three other areas of proposed investigation are: the mechanism of virus-induced inhibition of host cell protein synthesis; studies of the role of protein NCVPX in the viral life cycle; and derivation of a cloned DNA replica of the poliovirus genome in an E. coli plasmid and studies of its infectivity and structure.
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0.972 |
1987 |
Baltimore, David |
S10Activity Code Description: To make available to institutions with a high concentration of NIH extramural research awards, research instruments which will be used on a shared basis. |
Automated Gas Phase Protein Sequencer @ Whitehead Institute For Biomedical Res |
0.937 |
1987 |
Baltimore, David |
S15Activity Code Description: Undocumented code - click on the grant title for more information. |
Photo Invertomicroscope Tv Camera Set @ Whitehead Institute For Biomedical Res |
0.937 |
1988 |
Baltimore, David |
S15Activity Code Description: Undocumented code - click on the grant title for more information. |
Small Instumentation Program @ Whitehead Institute For Biomedical Res
biomedical equipment purchase; ultracentrifugation;
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0.937 |
1988 — 1996 |
Baltimore, David |
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. |
Lymphocyte and Hiv Transcription @ Whitehead Institute For Biomedical Res
This program is designed to develop as complete as possible an understanding of the control of transcription of certain genes in lymphoid cells and in a lymphocyte-specific virus. The topics to be investigated are the following questions: 1. What determines the B lymphocyte-specific transcriptional activity of immunoglobulin genes?; 2. How is transcription of T cell receptor (TCR) genes controlled?; 3. What controls IL-2 induction in T lymphocytes?; 4. What controls the induction and repression of terminal deoxynucleotidyl transferase in early lymphoid cells?; 5. What controls induction of human immunodeficiency virus in T lymphocytes?; 6. What is the mechanism of action of the tat gene system in human immunodeficiency virus? Characterization of transcriptional control for these various systems involves, in many cases, the same set of experimental activities. We first use a transient transfection protocol with various cell types to demonstrate that the cloned gene shows transcriptional control. This can be done with the intact gene or with fragments connected to a reporter gene (usually chloramphenicol acetyl transferase). Then deletion analysis can grossly demarcate the important regions. Electrophoretic mobility shift assays with regions to which putative regulatory proteins can bind allow a fine mapping binding sites. Point mutations in these binding sites then show if the sites have regulatory significance. Purification of the proteins followed by cloning can then allow further physical and functional study, especially using in vitro transcriptional systems.
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0.972 |
1989 |
Baltimore, David |
S15Activity Code Description: Undocumented code - click on the grant title for more information. |
Small Instrumentation Program @ Whitehead Institute For Biomedical Res
biomedical equipment resource; biomedical equipment purchase;
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0.937 |
1990 — 1993 |
Baltimore, David |
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. |
Malignancy and Normal Development in Pre-B Lymphocytes @ Whitehead Institute For Biomedical Res
On-going studies on the transformation of cells by Abelson murine leukemia virus (A-MuLV) and the mechanism of inducing immunoglobulin gene rearrangements will be continued. Both lines of investigation relate to early steps of B-lymphoid cell differentiation. In the A-MuLV program, three major approaches are planned: (1) mapping the regions of the cellular c-abl gene that suppress its inherent oncogenic activity and studying the regions required for oncogenesis; (2) localizing by immunofluorescence techniques the abl-related normal and oncogenic proteins within normal and malignant cells and (3) developing mouse models in which the bcr-abl fused gene, from chronic myelogenous leukemic cells, is able to induce myeloid proliferation. In the immunoglobulin gene rearrangement program, two major approaches are planned: (1) finding and characterizing the gene (RAG-1) that induces rearrangement of implanted immunoglobulin genes in fibroblasts; (2) developing a better understanding of the molecular and enzymatic events of gene rearrangement and probing the regulatory events that determine which genes will rearrange at a given stage of immunodifferentiation and how the events are integrated. These studies should increase understanding of events in immunodifferentiation and help to understand how they are deranged during oncogenesis. They should also help in understanding immunopathogenesis, especially defects in lymphocyte development.
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0.937 |
1994 |
Baltimore, David |
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. |
Malignancy and Normal Development in Preb Lymphocytes @ Massachusetts Institute of Technology
On-going studies on the transformation of cells by Abelson murine leukemia virus (A-MuLV) and the mechanism of inducing immunoglobulin gene rearrangements will be continued. Both lines of investigation relate to early steps of B-lymphoid cell differentiation. In the A-MuLV program, three major approaches are planned: (1) mapping the regions of the cellular c-abl gene that suppress its inherent oncogenic activity and studying the regions required for oncogenesis; (2) localizing by immunofluorescence techniques the abl-related normal and oncogenic proteins within normal and malignant cells and (3) developing mouse models in which the bcr-abl fused gene, from chronic myelogenous leukemic cells, is able to induce myeloid proliferation. In the immunoglobulin gene rearrangement program, two major approaches are planned: (1) finding and characterizing the gene (RAG-1) that induces rearrangement of implanted immunoglobulin genes in fibroblasts; (2) developing a better understanding of the molecular and enzymatic events of gene rearrangement and probing the regulatory events that determine which genes will rearrange at a given stage of immunodifferentiation and how the events are integrated. These studies should increase understanding of events in immunodifferentiation and help to understand how they are deranged during oncogenesis. They should also help in understanding immunopathogenesis, especially defects in lymphocyte development.
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0.972 |
1995 — 1999 |
Baltimore, David |
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. |
Leukemogenesis by Ab1 and Other Oncogenes @ Massachusetts Institute of Technology
This is a continuation of a 20-year program designed to understand leukemogenesis by the Abl oncogene and related issues. Because the gene is modular, we have focused on individual domains, most recently on SH3 because of its apparent anti-oncogenic properties. We plan to study the binding properties of SH3's from Abl and other proteins, using and comparing three quantitative methodologies. We will continue collaborative structural determinations and will use mutagenic methodologies to study the amino acids that determine specificity. We have found a number of binding sites for different SH3's, including Src, Crk, Nck, Grb2, Btk and Uau. In many cases, we have candidate molecules with SH3 binding sites and we want to put them into a biological content. We plan to characterize another modular protein element, the PH domain, which is found in many proteins. Here, as elsewhere, the yeast two-hybrid system will be an important tool. We also want to find new proteins that interact with Abl and to examine how Grb2 and Abl can synergize in cause cell transformation. We plan to study the Abl homologue in C. elegans to take advantage of the power of genetic analysis in that organism. Using a transient retrovirus packaging system we have recently developed, we plan to study further the tumors induced in mice by Bcr-Abl and other oncogenes, particularly the notch homologue TAN-1. With an amphotropic packaging line, we will examine the potential of using oncogenes to transform human cells. These studies can be expected to shed light on the causation of human chronic myelogenous leukemia by Bcr-Abl and on the general issues of the role of protein tyrosine kinases as signaling molecules in normal and tumor cells.
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1 |
1997 — 2008 |
Baltimore, David |
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. |
Molecular Biology of Lymphocyte and Neuronal Growth @ Massachusetts Institute of Technology
DESCRIPTION: The overall aim of this program is to gain as complete a knowledge as possible of the events that transpire during the differentiation of B lymphocytes and to begin to extend the analysis to the nervous system. This work is particularly relevant to the study of autoimmune disease, immunologic responses, immunologic memory and neuronal deficits. The specific aims of the next granting period are to understand the role of a single transcriptional enhancer, the intron enhancer of the Kappa (K) light chain; to understand the immunoglobulin gene rearrangement process and its control at a biochemical level; to develop a method to mark memory cells and to extend the methods of analysis of immunodifferentiation to the study of neuronal differentiation. Kappa gene expression is thought to be controlled by 2 enhancers. The various roles of these enhancers in immunodifferentiation will be analyzed using homologous recombination to make critical mutants in ES cells that can then be used to reconstitute the lymphoid systems of RAG-2-deleted mice. ES cell homologous recombination will also be used to insert K regulatory elements into the l genes to examine whether the K/l light chain ratio in the mouse is a consequence of the relative strengths of the transcriptional regulatory elements of the two light chain genes. The immunoglobulin gene rearrangement process is a unique process of DNA rearrangement. To study it, the various relevant proteins will be purified and their in vitro activities will be examined. This analysis will be extended to chromatin and methylated DNA to attempt to understand the various levels of control of the rearrangement process. Analysis in cells will be used to uncover more complex levels of control. There is no unambiguous marker on the surface of memory B and T cells. Transgenic mice will be generated in which the memory B and T cells will be genetically marked and thus can be identified and examined unambiguously. The study of immunodifferentiation has benefitted from the availability of clonal cell lines and methods of chimeric analysis. To extend these benefits to the study of neuronal differentiation, methods will be developed to prepare clonal derivatives of differentiated neurons using oncogenes and a precise labeling procedure. Also to study the role of otherwise lethal genes in neuronal development, a method of chimeric analysis will be developed. It will be applied particularly to analyzing the role of the NF-KB transcription factor in nervous system signaling.
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1 |
1998 — 2008 |
Baltimore, David |
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. |
Hiv Induced Cellular Pathology @ Massachusetts Institute of Technology
DESCRIPTION: The goal of this proposal is to understand the nature of transcription factor binding, apoptosis and the role of Nef and Nef-binding proteins in the avoidance of killing by MHC class I-restricted CTLs. The role of Nef in down regulating MHC class I expression will be assessed using techniques that allow characterization by flow cytometric analysis of events in primary and cultured cells with high-titered mutant or wild-type viruses.
|
1 |
2000 — 2004 |
Baltimore, David |
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. |
Leukemogenesis by Abl and Other Oncogenes @ California Institute of Technology
This proposal has 5 parts representing 5 on-going efforts by different groups of junior investigators in the laboratory. They are: 1. Conditional Abl knockout. Having knocked out both the Abl and Arg genes and found that one of the two genes is needed for development beyond embryonic day 10, we plan to construct a conditional knockout of Abl on an Arg-deficient background so that the roles of the genes in later stages of mouse development and function can be examined. 2. Abl in C. elegans. Abl function has been investigated in mice and Drosophila but the putative functions of the gene are so variable that examination of another organism is warranted. We have chosen C. elegans because its entire genome is known and it is possible to examine it genetically at very high resolution. 3. NF-kappaB control of transcription. While there is much fragmentary knowledge of the genes controlled by NF-kappaB, a global analysis of gene expression in cells with defined genetic lesions in the NF-kappaB-related proteins will give more precise knowledge of which genes are controlled and by which subunits. 4. NF-kappaB activation by TANK and TBK1. There are numerous pathways of NF-kappaB activation but none are known in precise detail. We have found a new kinase, TBK1, that interacts with TANK and appears to act along with TRAF proteins and may phosphorylate them. A deeper knowledge of the details of the biochemistry of these events could help to understand the precise mechanisms of NFkappaB activation. 5. ATR kinase. This very large kinase has been implicated in checkpoint control of the cell cycle in mammalian cells. We have knocked out the gene for this protein and the mice die very early in gestation, in a manner similar to mice lacking the BRCA genes. We plan to construct a conditional allele of this gene to examine in more detail its function and, in particular, its relation to p53, BRCA1 and 2, and Chk1. These studies are all aimed at a deeper understanding of both the processes of oncogenic transformation and the normal development and function of mammals.
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1 |
2001 — 2004 |
Baltimore, David |
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. |
Molecular Biology of Lymphocyte &Neuronal Growth @ California Institute of Technology
APPLICANT'S DESCRIPTION: There are six fairly disparate aims in this proposal linked by a general concern with how intracellular signaling events in the immune and nervous systems control physiological activities of organisms. Aim is to ask whether the NF-KB transcription factor plays a role in neuronal transmission of signals from synapses. NF-kB is found at synapses and its known control mechanisms make it attractive to think that it could be involved in such activities as long term potentiation. Aim 2 is to use genetic methods to understand activation of NF-kB and of the JNK signaling pathway by tumor necrosis factor and Fas ligand. These pathways have been extensively studied but with conflicting results that genetic methods can resolve. Aim 3 is to try to determine when and how olfactory neurons chose among the 1000 genes encoding potential odor receptors so that one cell expresses only one receptor. This is a problem of gene control in the nervous system that might be analogous to what occurs in the immune system. Aims 4 and 5 relate to the development of improved methods of investigation of mammalian physiology using genetic modifications in mice. Aim 4 is to study the parameters that control homologous integration of transfected DNA in mouse and human cells. Aim 5 is to perfect a method of using lentivirus vectors to bring genes into the mouse male germ cell line, thus doing trangenesis through the sperm. This involves making new better vectors that allow for gene expression. We will also try to extend the work from mice to other species. Aim 6 is to understand how a mouse's immune system avoids reacting with normal tissues of the body and how this system fails in autoimmunity. We will focus here on the role of the IL-2 receptor and the molecules by which it sends intracellular signals.
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1 |
2004 |
Baltimore, David |
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. |
Planning and Evaluation @ Salk Institute For Biological Studies |
0.934 |
2004 — 2005 |
Baltimore, David |
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.) |
Inhibition of Hiv by Lentivector-Encoded Interfering Rna @ California Institute of Technology
[unreadable] DESCRIPTION (provided by applicant): HIV growth in infected people is now partially controlled by anti-retroviral therapies. If we are to eliminate HIV, more effective means of countering the virus are needed. One conceivable mode of therapy is to program CD4-positive T cells, the main cells that grow HIV in the body, to make a molecule that would prevent HIV from growing in the cells. We have called this "intracellular immunization." We have successfully demonstrated such an approach using a lentivirus vector to carry into the cell genome a cassette that can specify synthesis of a small RNA able to interfere with the production of the cellular receptor for HIV, CCR5. We now propose to develop this idea further. We will optimize the interfering RNA so that it is as efficient as Possible at inhibiting CCR5 synthesis. This will be done by an efficient but comprehensive tiling process. Because HIV can mutate so that it no longer requires CCR5, we need to hit multiple targets. Thus we will develop vectors with multiple cassettes, some against the viral genome. These too will have to be optimized. Then the vectors must be tested in human T cells in culture. Ultimately, their safety and efficacy in humans will have to be investigated. [unreadable] [unreadable]
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1 |
2008 — 2018 |
Baltimore, David |
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. |
Microrna Function in the Immune System @ California Institute of Technology
DESCRIPTION (provided by applicant): The inflammatory response is one of the body's most important defenses against infection. One initiator of inflammation is bacterial lipopolysaccharide (LPS). We found some years ago that LPS will induce in macrophages 3 microRNAs. These are small RNAs that can have huge regulatory influences on protein levels. We have therefore been characterizing these 3 RNAs from various points of view and this request is for funds to study these RNAs in depth. One of the microRNAs has been linked to cancer induction and may provide a link between inflammation and cancer. We have also included plans to study another microRNA family because of its potential relationship to immune cell maturation. The planned studies take advantage of today's ability to manipulate the genetics of mice. Thus, overexpression and knockout studies will allow us to examine the consequences to mouse physiology of too much or none of the particular microRNAs. The overexpression studies will be done by incorporating into viral vectors genes that express the microRNAs, infecting bone marrow stem cells with these vectors and transferring the infected cells to lethally irradiated host mice. We will use high resolution surface marker analysis to characterize the role of these microRNAs in the generation and behavior of particular subsets of immune cells. In this work, we will also use in vitro expression in cells through vectored delivery of genes to the cells. MicroRNAs are processed from precursors and we have found that the processing itself is regulated. We plan to examine how this regulation is achieved. To understand how these microRNAs work we will characterize the target genes that they regulate. This involves bioformatics to find candidates, determining the genes whose expression is sensitive to a particular microRNA and then study of the role of those genes. For the microRNA family that may be involved in immune cell development, we suspect that it could be controlling the final stage of differentiation of the cells that make antibodies. We will therefore concentrate on examining that stage of immune cell development with an emphasis on the possible role of a protein usually associated with protecting the genome, p53. PUBLIC HEALTH RELEVANCE: Scientists have long thought that the immune system is controlled by proteins. Our recent work has implicated some small RNA molecules as controllers of inflammatory and immune responses. We plan to examine how such RNAs might work with an emphasis on the relationship between cancer and inflammation. Microbial infections and cancer are among the leading causes of human diseases worldwide. Therefore, it is imperative that we continue to define the molecular basis underlying these devastating problems. Very recently, micro-RNAs have emerged as a novel class of gene expression regulators that are implicated in both immune system regulation and cancer biology. Our group has found that a small number of miRNAs are potently induced by the innate immune response to infection, and therefore propose to characterize the roles of these miRNAs in host defense against infection and tumorigenesis
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1 |
2009 — 2010 |
Baltimore, David |
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. |
Nf-Kappab: Orchestration of the Inflammatory Response @ California Institute of Technology
This project is a continuation of a line of investigation we started more than 20 years ago. We then discovered a protein, called NF-KB, that subsequent work has shown to playa key role in inflammation and immunity. Here we propose four lines of investigation (aims) that seek to increase our knowledge of the roles of NF-KB in the inflammatory response. Inflammation is a process that continues for days following an initiating stimulus and NF-KB plays a role throughout: our first aim is to understand the temporal control processes that allow the inflammatory response to unfold in an orderly manner. Our second aim is to probe the role played by an enigmatic regulator of NF-KB responses called B94. It potentiates induction of some genes by NF-KB but there is no mechanistic or physiological understanding of its effects. NF-KB is extensively modified as part of its mode of action: our final two aims are to investigate previously uncharacterized modifications for which we have preliminary indications of importance: methylation and glycosylation.
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1 |
2010 — 2014 |
Baltimore, David |
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. |
Administrative Core @ California Institute of Technology
The Administrative Core will provide oversight and coordination for the PPG projects and cores which encompass investigators from 4 research universities, 3 teaching hospitals, several institutes and multiple academic departments. This core will serve five purposes: C.I. standard administrative support, C.2. scientific oversight, C.3. biostatistical and data management support, C.4. biomedical ethics oversight and consultation and 0.5. gene medicine regulatory compliance. This core will serve projects 1-5 and cores A and B.
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1 |
2010 — 2014 |
Baltimore, David |
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. |
Stem Cell-Engineered Tumor Immunity in Man @ California Institute of Technology
DESCRIPTION (provided by applicant): The human immune system is a potentially powerful line of defense against cancer. Many biological obstacles exist in cancer patients that thwart tumor-specific T cell expansion, activation, tumor trafficking and killing. Among these is inadequate T cell precursor frequency and low T cell receptor (TCR) binding affinity for tumor antigen. Our hypothesis is that transplantation of high affinity TCR-transduced stem cells will create in the recipient an engineered immune system with potent antitumor biology. Thus, the single goal of this Program Project Grant (PPG) is to test this hypothesis by attempting to control or cure metastatic melanoma. This application is a key part of the strategy to arise from a 3-year collaboration among a score of investigators from four research universities (Caltech, UCLA, USC, UCONN) representing 4 cancer centers, 2 gene medicine programs, 13 departments and several institutes. Our research group will converge the disciplines of immunology, genetic engineering, stem ceil biology, virology, biological imaging and human gene medicine to engineer a tumor-specific human immune system. This will be accomplished in a PPG with 5 projects supported by 3 cores. The PPG will: (1) undertake two first-in-human clinical investigations in which a MART-1 melanoma antigen TCR will be introduced into T cells and hematopoietic stem cells using a lentiviral vector also expressing a PET reporter allowing serial noninvasive imaging of the development of an engineered immune system, (2) fundamental studies of the biology of TCR engineered hematopoietic and embryonic stem cells, and (3) basic biology of TCR engineering. State of the art cores in cell and gene therapy, immunological monitoring and biological imaging will support this science. In this PPG, basic and clinical science will be conducted in parallel, each informing the other; basic scientists and physician-scientists will work together as a team to develop discovery-based science that will change the care of patients.
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1 |
2010 — 2014 |
Baltimore, David |
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. |
Study of Tcr Engineering Against Melanoma in Mice @ California Institute of Technology
The adoptive transfer of T cell receptor (TCR) engineered T cells and hematopoietic stem cells (HSCs) can potentially provide a patient with a large supply of tumor-specific T cells, enhancing immune-based therapies for cancer. A full understanding of the basic biology of these TCR engineered cells will be very valuable to help design a more potent therapy. In this project, we propose to use the B16 melanoma tumor model to conduct a comprehensive study of the Pmel TCR engineered peripheral CDS T cells, CD4 T cells and HSCs. For this purpose, retroviral and lentiviral vectors will be constructed to co-deliver the genes encoding the Pmel TCR and a bioluminescence reporter into the target cells. The in vivo fate of the TCR-engineered T cells and HSCs will be monitored using Bioluminescence Imaging (BLI) in a live animal in real-time. We plan to study the antimelanoma immunity generated by the adoptive transfer of TCR-engineered T cells (Specific Aim1), HSCs (Specific Aim2), and their combination (Specific Aim3). Various conditions for the in vitro TCR transduction, recipient animal pre-conditioning, adoptive transfer, and post-transfer immunization will be evaluated for their contribution to an effective therapy. In particular, we will study the synergy between the anti-tumor CD4 and CDS T cells, and the influence of the CD4+CD25+ regulatory T cells (Tregs) for adoptive therapy. We will also try to enhance the anti-tumor effectiveness of the engineered anti-tumor T cells by co-delivery of an enhancement gene together with the TCR genes into the target cells. From the proposed study, we expect to gain a thorough understanding of the basic biology of TCR-engineered peripheral T cells and HSCs, and the anti-tumor immunity generated through adoptive transfer of these engineered cells. This basic biology will inform the clinical investigations being conducted in Project 1 and Project 3.
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1 |
2011 — 2015 |
Baltimore, David |
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. |
Mechanism of Bach1-Mediated Transcriptional Regulation and Immune Function @ California Institute of Technology
DESCRIPTION (provided by applicant): Precise regulation of the immune system is required for protection from foreign invaders and tolerance of self. Dysfunctional immune regulation can lead to impaired immune responses to infections as well as development of autoimmune diseases. The role of the transcription factor Bach1 in regulating immune processes has been indirectly implicated but has not been directly explored; thus, the broad and long-term objective of this project is to determine the function of Bach1 and the mechanism by which it mediates protective immunity and autoimmune diseases at a cellular and molecular level. The following research design and methods will be employed to achieve this goal. 1) First, the mechanism by which Bach1 regulates transcription will be elucidated. Specifically, chromatin immunoprecipitation followed by microarray (ChIP-chip) will be used to determine whether Bach1 binds promoter proximal and/or distal regulatory elements to directly elicit transcriptional activation and repression. Computational motif analyses and luciferase reporter assays will be used to define those functional domains of Bach1 important for transcriptional regulation. 2) Second, the role of Bach1 during viral and bacterial infections will be determined. Bach1 will be ablated in macrophages and in mice during infection in order to characterize the molecular pathways by which Bach1 regulates protective immune responses. 3) Third, the role of Bach1 in autoimmunity will be investigated. Preliminary data demonstrated that Bach1 promotes the development of murine experimental autoimmune encephalomyelitis (EAE), which mimics human multiple sclerosis. Accordingly, bone marrow reconstitution and adoptive transfer experiments will be used to identify those immune cell(s) in which the intrinsic function of Bach1 modulates EAE. Microarray experiments will be performed in those cells to identify potential targets and downstream signaling pathways regulated by Bach1. 4) Fourth, Bach1 targets responsible for mediating its role in the development of EAE will be identified and characterized. The effect of Bach1-mediated EAE upon ablating these targets will be examined by generating double knockout animals of Bach1 and the target(s) of interest. Furthermore, functional domains of Bach1 necessary for its regulatory function in vivo will be identified. Overall, this project will identify a new regulator of the immune system (Bach1) and reveal those signaling cascades by which it modulates protective immunity during infection and autoimmunity during dysfunction. The successful completion of this project will therefore benefit public health by identifying new targets for therapy against immune-related and autoimmune diseases.
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1 |
2016 — 2017 |
Baltimore, David |
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.) |
Regulatory Role of Splicing in Inflammation @ California Institute of Technology
PROJECT SUMMARY Regulation of inflammation is of crucial importance, both for the advancement of therapeutic intervention and for the limiting of deleterious autoimmune complications. The precise tuning of the inflammatory response involves transcription and, from our recent unpublished studies, meticulous regulation of hundreds of mRNAs at many levels. Since we discovered NF-?B in 1986, we have been examining a variety of properties of this transcription factor system, focusing most of our attention on the role of NF-?B in the immune system, particularly in orchestrating the inflammatory response to pathogen challenge. In recent years, we have studied the regulatory events underpinning the precise timing of gene expression during the inflammatory response. We used RNA-seq to target only inflammatory transcripts and have quantified splicing kinetics of introns of inflammatory genes, finding that some are orders of magnitude slower to splice than expected. We find that they confer a significant reduction in gene expression as delays in splicing are often concomitant with RNA exosome engagement. We predict this may be a regulatory mechanism, and call them ?bottleneck introns.? In this proposal, we propose to test the biological relevance of bottleneck introns in tissue culture and by making mice (Aim 1) to see if limits to inflammation are altered in the context of a repaired intron. In addition, we propose to investigate whether there are biological contexts (stimulus, cell-type, developmental state) that confers improved splicing of a bottleneck (Aim 2), therefore providing a regulatory framework for this finding.
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1 |