J. Thomas Parsons - US grants
Affiliations: | University of Virginia, Charlottesville, VA |
Area:
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The funding information displayed below comes from the NIH Research Portfolio Online Reporting Tools and the NSF Award Database.The grant data on this page is limited to grants awarded in the United States and is thus partial. It can nonetheless be used to understand how funding patterns influence mentorship networks and vice-versa, which has deep implications on how research is done.
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High-probability grants
According to our matching algorithm, J. Thomas Parsons is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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1985 — 1986 | Parsons, J Thomas | 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. |
Avian Sarcoma Virus Specific Tumor Antigens @ University of Virginia Charlottesville Genetic and biochemical experiments have shown that the product of the Rous sarcoma virus src gene is required for the initiation and maintenance of cellular transformation. As a part of our long-term goal of understanding how the src gene product, pp60src, mediates the molecular events involved in cellular transformation, we have isolated and partially characterized monoclonal antibodies directed against pp60src. The experiments outlined in this proposal employ monoclonal antibodies to unique determinants within pp60src as immunochemical probes to define and characterize the structural and functional domains of the molecule and attempt to elucidate the role of individual functional domains in mediating cellular transformation. We further propose to utilize monoclonal antibodies to pp60src as immunochemical probes to compare the structure and function of other retrovirus tyrosine protein kinase as well as normal cell tyrosine protein kinases. These studies will permit us to define the structural and functional domains of pp60src and allow us to relate this information to other proteins which may be members of a family of related tyrosine protein kinases. |
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1985 — 1987 | Parsons, J Thomas | 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. |
Oncogenes and Mitogens: Intracellular Mechanisms @ University of Virginia Charlottesville This project will implement an interdisciplinary program focusing on growth control of normal and malignant cells, and the relationships of mitogens, receptors, oncogenes, and intracellular events. The research projects address three related general questions: how do cells respond to mitogenic factors; what are the roles of cellular oncogene products in these responses; and finally, how are these responses altered in a cancer cell. The program utilizes the expertise of individual investigators within the areas of cell biology, molecular genetics, protein biochemistry, immunology, and molecular pharmacology, and seeks to integrate this expertise in an environment that will accelerate our knowledge about cellular growth and differentiation. In Project 1, we will investigate the possible interactions between growth factor receptors and the viral src protein or its normal cell homologue, c-src. Project 2 outlines an in vitro genetic approach to study the structure and function of v-src and c-src. Experiments proposed in Project 3 (particularly src) are involved in specialized cellular functions, such as secretion of the hormones epinephrine or norepinephrine from adrenal chromaffin cells. In Project 4, experiments which extend previous studies on the response of liver hepatocytes to defined hormones and growth factors will be conducted. (V) |
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1985 — 1995 | Parsons, J Thomas | 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. |
Expression of Avian Retrovirus Transforming Genes @ University of Virginia Charlottesville The long term goals of the studies outlined in this proposal are to understand how tyrosine kinase onco-proteins (e.g., pp60src) and effectors of normal mitogenic responses (e.g., growth factors and their receptors) function together to influence cellular growth regulation. Oncogenic transformation mediated by pp60src induces the expression of a novel growth factor receptor, c-sea. C-sea expression is also induced in response to serum stimulation of quiescent fibroblasts, suggesting that c-sea expression may be linked to mitogen induced proliferation. We propose to study the molecular events linking pp60src expression, mitogen stimulation and expression of the c-sea growth factor receptor. In Aim 1 we will identify and characterize the c-sea gene product. The sequence analysis of chicken c-sea and cloning and sequencing of the human homologue of c-sea will be carried out. Antibodies to both extra-cellular and cytoplasmic domains of the c-sea protein will be used to identify and characterize the c-sea protein. We will use both c-sea cDNA probes and antibodies to determine the tissue and cell type distribution of c-sea expression, and investigate the cell cycle dependent expression of c-sea. In Aim 2 we will characterize the c-sea protein and assess its possible function as a receptor-like tyrosine protein kinase. We will isolate cell lines over- expressing the complete c-sea gene and various structurally permuted variants of c-sea. These cell lines will be analyzed with respect to morphological phenotype, growth factor responses and tyrosine phosphorylation of the c-sea protein and tyrosine phosphorylation of putative cellular targets for c-sea. We will attempt to activate the over- expressed c-sea receptor in a ligand-dependent manner and initiate experiments to identify the natural ligand for the c-sea receptor. In Aim 3 we will determine the role of c-sea expression in contributing to and/or mediating the transformed phenotype of src transformed cells. We will attempt to block functional expression of c-sea in src transformed cells and assess the phenotypic consequences of such a block and we will carry out studies to identify the src induced signalling pathways that lead to c- sea induction. The analysis of the c-sea receptor may provide insights into the possible altered expression of c-sea in human and animal tumors and provide information regarding the mechanisms of c-sea gene expression during the cell cycle. |
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1987 — 1991 | Parsons, J Thomas | 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. |
Avian Sarcoma Virus Tumor Antigens @ University of Virginia Charlottesville Genetic and biochemical experiments have shown that the product of the Rous sarcoma virus src gene is required for the initiation and maintenance of cellular transformation. As a part of our long-term goal of understanding how the src gene product, pp60src, mediates the molecular events involved in cellular transformation, we have isolated and partially characterized monoclonal antibodies directed against pp60src. The experiments outlined in this proposal employ monoclonal antibodies to unique determinants within pp60src as immunochemical probes to define and characterize the structural and functional domains of the molecule and attempt to elucidate the role of individual functional domains in mediating cellular transformation. We further propose to utilize monoclonal antibodies to pp60src as immunochemical probes to compare the structure and function of other retrovirus tyrosine protein kinase as well as normal cell tyrosine protein kinases. These studies will permit us to define the structural and functional domains of pp60src and allow us to relate this information to other proteins which may be members of a family of related tyrosine protein kinases. |
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1988 — 1998 | Parsons, J Thomas | 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. |
Oncogenes and Mitogens--Intracellular Mechanisms @ University of Virginia Charlottesville The long term goals of this revised Program Project are to understand the molecular pathways that regulate cell growth and trigger specialized cell functions. Understanding these fundamental signalling pathways will contribute to our knowledge of abnormal signalling pathways operative in cancer cells. The mechanisms that control cell growth, differentiation and specialized cell functions involve the complex interactions of cellular receptors with a variety of hormones and mitogens. In addition these cellular processes are profoundly influenced by the interaction of the cell with components of the extracellular matrix, as well as with molecules present on the surface of neighboring cells. The projects outlined in this Program Project application have a common theme in that each project seeks to define and understand the role of protein phosphorylation, catalyzed by tyrosine and/or serine/threonine kinases, in the regulation of well studied and characterized signal transduction pathways. Michael Weber continues his investigation of the EGF receptor and its interactions with pp60src. T. Parsons proposes to study the role of a recently discovered tyrosine kinase, termed Focal Adhesion Kinase, in cellular signalling. J. Garrison builds on studies carried out during the past project period addressing the effects of v-src on inositol lipid signalling. Garrison proposes to explore in detail the nature of v-src stimulation of the enthothelin receptor pathway, focusing on the interactions among the receptor, the G protein, Gq and PLC beta. T. Bender will study the c-myb protein determining how protein phosphorylation regulates its activity as a transcription factor. Projects by Parsons and Crentz involve studies on the signalling pathways that control secretion events in adrenal chromaffin cells. S. Parsons will continue her studies on the role of pp60src of phosphorylation on annexin function. The Program Project will be supported by two Cores, an Administrative Core and a Scientific Core devoted to production of antibodies, productions and purification of proteins and handling of radioactive materials. |
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1992 — 1999 | Parsons, J Thomas | 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. |
@ University of Virginia Charlottesville The long term goals of the experiments proposed in this application are to understand the functional consequences of tyrosine phosphorylation of tyrosine protein kinase substrates and the role of these substrates in the molecular signalling pathways induced by non-receptor tyrosine kinases and by ligand activated receptor tyrosine kinases. The proposed experiments build on the progress made during the past granting period in identifying novel substrates for pp60src and the epidermal growth factor (EGF) receptor. We will focus on the functional analysis of three tyrosine kinase substrates that appear to play important and perhaps novel roles in the mitogenic signalling process. In addition we will investigate the role of the ras gene product, p21ras, in the cascade of events mediated by receptor tyrosine protein kinases. The specific aims are: 1) To functionally characterize an 80 kDa tyrosine kinase substrate (TKS/80), recently identified in our laboratory as an actin binding protein. This analysis will include identification of the sites of phosphorylation within TKS/80, a study of its association with other cellular proteins, and an investigation f its role in pp60src and EGF receptor mediated signalling. 2) Purification and analysis of SH2bp130, a pp60src SH2 domain binding protein. These experiments will include the isolation of additional antibodies to SH2bp130, isolation of cDNAs encoding SH2bp130, and a functional characterization of SH2bp130 in cell transformation and EGF mediated signalling. 3) Purification and analysis of GAPbp64, a 64 kDa protein that associates with GTPase activating protein (GAP) in src transformed and EGF stimulated cells. This analysis will include the isolation of antibodies to GAPbp64, isolation of GAPbp64 cDNAs and a functional characterization of its interactions with EGF receptor, pp60src, and GAP.4) The dominant inhibitory mutant of H-ras, Asn17 will be used to assess the role of p21ras in receptor mediated tyrosine phosphorylation of cellular substrates. These experiments will test the hypothesis that functional p21ras is required for the efficient mobilization of components within certain signal transduction pathways. Together these studies will shed light on the relationship between receptor activation, tyrosine phosphorylation, activation of signalling pathways and the regulation of cell growth. |
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1993 — 2002 | Parsons, J Thomas | 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. 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. |
Focal Adhesion Tyrosine Kinases and Cell Signaling @ University of Virginia Charlottesville The long term goals of this revised project are to understand the nature of cellular signalling events mediated by cellular receptors that recognize components of the extracellular matrix and/or other cell surface molecules. We will focus specifically on the role of tyrosine phosphorylation in regulating these pathways, seeking to define the molecular mechanisms by which tyrosine kinases contribute to the regulation and control of such pathways. The proposed experiments build and extend the progress made during the past four years. We have identified a novel protein tyrosine kinase, that is associated with cellular focal adhesions, designated Focal Adhesion Kinase, FAK. Evidence from our own laboratory as well as other has indicated that FAK plays a role in regulating signalling events initiated by interactions of surface integrins with extracellular matrix. In addition, our own studies have demonstrated a stable association of FAK with pp60src in src transformed cells. We outline three specific aims: First, we will define and characterize the mechanisms that lead to activation of FAK in response to engagement of integrins with defined extracellular ligands. These studies will include an analysis of the interaction of FAK with cytoplasmic domains of specific integrins and components of focal adhesions as well as possible functional interactions with proteins that regulate mitogen and hormone activated signal transduction pathways. Second, we will examine the role of FAK in the regulation of the formation and/or breakdown of cellular focal adhesions, in the regulation of other cellular activities (e.g., adhesion, cell spreading, cell migration) and the possible control of second messenger pathways. In these studies we will investigate the phenotypic and biochemical properties of cells expressing variant FAK proteins and attempt to correlate known defects in FAK activity with alterations in cellular metabolism. Finally, we will characterize the function interactions between FAK and pp60src in src transformed cells and extend this paradigm to the analysis of possible interactions of FAK and pp60src or other src family kinases in normal cells. These experiments seek to delineate the role of pp60src in the structural perturbation of focal adhesions in transformed cells and explore the possibility that FAK regulates or is regulated by src family kinases in normal cells. |
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1999 — 2002 | Parsons, J Thomas | 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. |
Adhesion Signaling and Tumor Cell Progression @ University of Virginia Charlottesville The long range goal of this Project is to understand how alterations in cellular environment, particularly change in the interactions of cells with the extracellular matrix (ECM) and growth factors with their receptors, influencing the progression and metastatic behavior of prostate tumor cells. We probe to investigate the changes in adhesion signaling pathways using a well characterized panel of prostate cell lines, representing different stages of progression along a pathway from poorly tumorigenic to highly tumorigenic and metastatic. We will focus on key components of the integrin signaling pathway: the protein tyrosine kinases. Focal Adhesion Kinase (FAK) and Src; a putative downstream effector of FAK/Src function, paxillin (a focal adhesion protein); downstream effectors of integrin signaling, MAP kinase; and putative integrin regulated genes. We will also investigate the role of growth factor mediated signaling pathways as co-regulators of integrin signaling, focusing on the possible synergistic role of growth factors in modulating adhesion signaling through the integrin pathway. The specific aims are three-fold: 1) Using a panel of prostate cancer cell lines we will compare the repertoire of integrin receptors and determine their functional binding to ECM proteins; characterize the integrin-specific signaling responses in the different cell lines by assessing the activation of FAK, the tyrosine phosphorylation of paxillin, and the activation of MEK/MAP kinase; compare the repertoire of growth factor receptors expressed in these cells, and establish biological parameters of adhesion signaling by comparing the motility and tumorigenicity of individual cell lines. 2) Using the poorly tumorigenic cell line LNCaP as a recipient cell, we will determine whether the exogenous activation of integrin signaling pathways significantly enhances "progression" of cells to a more metastatic cell population. 3) Using the tumorigenic cell lines, C4-2, derived from LNCaP, as well as the unrelated tumorigenic cell lines, PC3, we will determine if inhibitor of the integrin signaling pathway using specific dominant negative )dn) expression constructs, block tumorigenicity and/or metastasis. These experiment seek to verify the importance of the adhesion signaling pathways in the development and progression of prostate cancer. |
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1999 — 2002 | Parsons, J Thomas | 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. |
@ University of Virginia Charlottesville DESCRIPTION: (Applicant's Description) The Cellular Imaging Core (Core C) will provide instrumentation and data analysis capability to support the study of intracellular signaling in single cells. This Core will allow us to create and staff a facility that brings cutting edge technology to the analysis of cell structure and cell movement and migration. Understanding signaling in "time and space" requires the development of technologies to visualize signal transduction events in single cells and furthermore to visualize signals within defined compartments of such cells. Thus the Cell Imaging Core is key to the success of each of the projects. |
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1999 — 2002 | Parsons, J Thomas | 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. |
@ University of Virginia Charlottesville The goal of the Cell Analysis Core is to provide support for those investigators studying the cellular biology of normal and metastatic prostate tumor cells. The analysis of cell structure, cell movement and cell dynamics are important components of each of the research projects described in this Program Project. In addition the ability the ability to detect the expression of macromolecules in individual cells and in tissue samples is key to the success of all of the projects. Therefore, the Core will seek to provide instrumentation and technical support to accomplish these objectives. |
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1999 — 2003 | Parsons, J Thomas | 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. |
Focal Adhesion Kinase Signaling @ University of Virginia Charlottesville The long term goal of the proposed research is to understand how signal transduction cascades initiated by extracellular matrix-integrin interactions regulate cell adhesion, cell motility, cell growth and differentiation. Our goal is to understand how such signaling pathways are organized (wired) in normal cells and to ultimately define the cellular alterations (both genetic and environmental) that lead to abnormal adhesion signaling in cancer cells. Studies over the past five years have identified two major classes of signaling molecules that participate in and regulate adhesion signaling, protein tyrosine kinases and members of the family of small GTPases. How these two classes of regulatory proteins function to organize the complex signaling required for cell adhesion and movement is a central theme of this proposal. The proposed studies focus specifically on the role of focal adhesion kinase in mediating signals from the extracellular matrix through the beta- integrin receptors. The three aims emphasize the identification and characterization of molecules that directly interact with FAK and link both upstream and downstream signaling components; defining the role of FAK and interacting partners in mediating signals that regulate cell motility and growth; and finally studying how cells utilize a potentially novel mechanism to regulate adhesion signaling during development. The specific aims are: 1) Using our base of knowledge about the structural organization of the domains of FAK and the related protein tyrosine kinase PYK2, identify new structural and functional linkages by defining new binding/interacting partners for FAK; 2) examine the functional role of FAK in the regulation of cell migration, focusing initially on fibronectin induced motility. We will also explore the role of FAK in the regulation of cell motility using FAK null fibroblasts derived from mice containing a conditional deletion of FAK (Cre-mediate deletion of a FAK exon flanked by lox P sites); 3) explore the possible in vivo regulation of adhesion signaling by the cell/tissue type-specific expression of the C-terminal domain of FAK, FRNK FAK-related Non-Kinase) and examine the consequences of knocking out FRNK on the course and extent of normal development of the mouse. |
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1999 — 2009 | Parsons, J Thomas | 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. |
Signal Transduction in Time and Space @ University of Virginia DESCRIPTION (provided by applicant): The goal of this Program Project application, entitled "Signal Transduction in Time and Space", is to understand cell signaling by cell surface receptors, protein and lipid kinases, phosphatases and GTPases within the context of a four dimensional process, organized and expedited by the actin cytoskeleton, adapter proteins and targeting molecules. Understanding how signals are propagated in time and space requires the identification of novel molecular scaffolds required for targeting molecules toward defined intracellular compartments, new experimental approaches for measuring signals generated in intracellular compartments, and a better understanding of the dynamics of signal propagation and regulation. The spatial and temporal analysis of signal transduction is fundamental to understanding normal cellular regulation and critical to understanding abnormal cellular signaling processes, central hallmarks of cancer cells. The Program Project endeavors to facilitate the analysis of cellular signaling in time and space by fostering a highly interactive environment, one in which exchanges of ideas, expertise and technical resources occur freely and efficiently in time and space. In the first Project, Parsons and Horwitz focus on understanding the role of protein tyrosine kinases and small GTPases in the spatial and temporal regulation of cell adhesion assembly and turnover. In the second Project, Brautigan and Eto will examine how targeting subunits of cellular phosphatases localize to sites of dynamic reorganization, such as adhesion complexes and cell-cell junctions. These proteins are activated by phosphorylation and integrate multiple signals to control actin organization in cells, a key step in mobilizing the tensional forces needed to drive cell migration and cell polarization. The Program is supported by aMicroscopy Core that provides cutting edge imaging capabilities, image analysis and training to the Program. |
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2001 — 2005 | Parsons, J Thomas | 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. |
Function of Cortactin, a Src Target @ University of Virginia Charlottesville DESCRIPTION (provided by applicant): Research supported by this grant over the past two decades, has focused on using the oncogenic protein tyrosine kinase, Src, as a molecular guide to identify tyrosine phosphorylated proteins that play key roles in cellular signaling. Characterization of so-called "Src targets" has led to the identification of a number of cellular proteins, such as Focal Adhesion Kinase (FAK), p130Cas and paxillin, proteins that function within the context of specific actin-based cytoskeletal structures, e.g., focal adhesions, as well as Cortactin, a protein that localizes predominantly to cortical actin, a site of dynamic actin remodeling. The long range goal of the studies outlined in this proposal is to understand how proteins such as Cortactin, function in the context of the cortical actin cytoskeleton to integrate cell surface receptor mediated cell signaling in a "temporal and spacial" context. Information garnered over the past granting period shows that the Src-substrate Cortactin is a multifunctional adapter protein that interacts on the one hand with the "cortical actin network" present in filopodia and lamellipodia by binding the Arp2/3 complex and links via its carboxyl-terminal SH3 domain to a number of functionally interesting and potentially important signaling and scaffolding proteins. This revised application again outlines four specific aims to address the function of Cortactin: In Aim 1 we will use molecular genetic, cellular and biochemical approaches to study the factors that regulate the interaction of Cortactin with the Arp2/3 complex of proteins. In Aim 2, we will extend and further develop our studies aimed at identifying and characterizing proteins that interact with the Cortactin SH3 domain. We will continue to characterize proteins that function as binding partners for Cortactin, including two recently identified SH3 effectors, WIP, Wasp Interacting Protein, a regulator of Arp2/3-dependent actin polymerization and dynamin, a GTPase implicated in the regulation of endocytic and secretory pathways. We will also extend and further develop studies to identify possible interactions of cellular proteins with the "helical-proline-ser-rich" region of Cortactin, here-to-fore unstudied interaction domain. In Aim 3 we will examine how tyrosine phosphorylation influences the interactions of Cortactin with known cellular binding partners. Finally in Aim 4, we will examine whether expression of full length Cortactin or predicted dominant inhibitory forms of Cortactin function to alter the dynamics of EGF-induced lamellipodia formation or cell migration. We will also determine whether Cortactin or Cortactin variants influence the dynamics of growth factor receptor signaling to downstream effectors, with particular attention to Ras signaling and EGF receptor internalization. Finally we propose to generate mice bearing a genetically altered allele of Cortactin, allowing for Cre-mediated excision and replacement of the Cortactin SH3 domain. Such mice, bearing a mutated form of Cortactin will allow one to directly test the role of Cortactin in mediating specific cellular functions in a cell type specific fashion. |
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2008 — 2009 | Parsons, J Thomas | 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. |
@ University of Virginia Charlottesville Adenocarcinoma; Adenoma, Malignant; Affect; Androgenic Agents; Androgenic Compounds; Androgens; Angiogenic Peptides; Animal Model; Animal Models and Related Studies; Animals; Biometrics; Biometry; Biometry and Biostatistics; Biostatistics; Body Tissues; Bone; Bone Metastasis; Bone Tumor; Bone and Bones; Bone cancer metastatic; Bone neoplasms; Bones and Bone Tissue; Bony metastasis; Cancer Biology; Cancer Induction; Cancer of Prostate; Cell Communication and Signaling; Cell Line; Cell Lines, Strains; Cell Signaling; Cell-Extracellular Matrix; CellLine; Cells; Cellular Expansion; Cellular Growth; Cessation of life; Characteristics; Clinical; Co-culture; Cocultivation; Coculture; Coculture Techniques; Cultured Cells; Data; Death; Dependence; Dependency; Dependency (Psychology); Development; Diagnosis; Disease; Disorder; Distant; EC 2.7; EC 3.4.21.34; ECM; Electromagnetic, Laser; Environment; Evaluation; Extracellular Matrix; Extracellular Matrix, Integrins; FAK; FAK1; Family; Figs; Figs - dietary; Fletcher Factor; Focal Adhesion Kinase 1; Generalized Growth; Genes; Genital System, Male, Prostate; Growth; Heterograft; Human; Human Prostate; Human Prostate Gland; Human, General; Image; In Vitro; Incidence; Integrins; Intracellular Communication and Signaling; Invasive; KLK3; Kallikrein 3; Kinases; Laboratories; Lasers; Lead; Lesion; Link; Malignant Cell; Malignant Tumor of the Prostate; Malignant neoplasm of prostate; Malignant prostatic tumor; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediating; Metastasis; Metastasis to bone; Metastasize; Metastatic Cancer to the Bone; Metastatic Neoplasm; Metastatic Neoplasm to the Bone; Metastatic Tumor; Metastatic Tumor to the Bone; Metastatic malignant neoplasm to bone; Mice; Microdissection; Modeling; Molecular; Monomeric G-Proteins; Monomeric GTP-Binding Proteins; Murine; Mus; Nature; Neoplasm Metastasis; Neuroendocrine; Neuroendocrine Cell; Neuroendocrine System; Neurosecretory Systems; Organ; Osseous Neoplasm; Osseous Tumor; Osseous metastasis; Overexpression; P-30 Antigen; PTK2; PTK2 Protein Tyrosine Kinase 2; Patients; Pb element; Phenotype; Phosphotransferases; Plant Embryos; Plasma Kallikrein Precursor; Plasma Prekallikrein; Play; Primary Neoplasm; Primary Tumor; Process; Programs (PT); Programs [Publication Type]; Prostate; Prostate CA; Prostate Cancer; Prostate Gland; Prostate Specific Antigen Preproprotein; Prostate-Specific Antigen; Prostatic Cancer; Prostatic Gland; Protein Overexpression; Radiation, Laser; Receptor Protein; Role; Secondary Neoplasm; Secondary Tumor; Secondary cancer of bone; Secondary malignancy of bone; Secondary malignant neoplasm of bone; Seeds; Semenogelase; Seminin; Signal Transduction; Signal Transduction Systems; Signaling; Site; Skeletal metastasis; Small G-Proteins; Small GTPases; Soil; Stromal Cells; Testing; Therapeutic Androgen; Tissue Growth; Tissues; Transgenic Animals; Transgenic Organisms; Transphosphorylases; Transplantation, Heterologous; Tropism; Tumor Angiogenesis; Tumor Cell Migration; VEGFs; Vascular Endothelial Growth Factors; Vegf; Work; Xenograft; Xenograft Model; Xenograft procedure; Xenotransplantation; Zygotes, Plant; angiogenesis; biological signal transduction; bone; bone neoplasm secondary; cancer cell; cancer metastasis; cancer progression; carcinogenesis; cell growth; cultured cell line; design; designing; disease/disorder; emotional dependency; endogenous substrate pp120; experiment; experimental research; experimental study; focal adhesion kinase; focal adhesion protein tyrosine kinase; focal adhesion-associated protein tyrosine kinase pp125FAK; gamma-Seminoprotein; hK3 Kallikrein; heavy metal Pb; heavy metal lead; imaging; in vivo; interest; kininogenin; mRNA Expression; member; model organism; morphometry; neoplasm progression; neoplastic progression; ontogeny; overexpress; p125(FAK); p125FAK; paracrine; pp125(FAK); pp125FAK; programs; receptor; research study; response; seed; social role; statistics/biometry; tool; transgenic; tumor; tumor growth; tumor progression |
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2009 — 2010 | Bauer, Todd W Parsons, J Thomas |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
A Primary Human Xenograft Model of Pancreatic Cancer. @ University of Virginia DESCRIPTION (provided by applicant): The five-year survival for patients with pancreatic cancer is less than 5%. Several novel therapies have been shown to be highly effective in mouse models of pancreatic cancer;however, in human clinical trials these agents have failed. There is a compelling need for preclinical models of pancreatic cancer that more accurately reflect the process of disease progression in patients. The objective of this proposal is to develop an orthotopic mouse model of pancreatic cancer using primary human tumors implanted into the pancreas of immune compromised mice. A key component of this model will be the genetic and molecular characterization of tumors and correlation of this with the biologic behavior of the tumors (e.g. grade, invasiveness). The orthotopic model is based on studies described in the literature and previous work of the PI. The establishment of a robust and well characterized orthotopic model will facilitate preclinical testing on an individualized basis of therapeutic agents that target defined signaling pathways important for pancreatic cancer progression and metastasis. A central hypothesis driving the development of the model is that orthotopic implantation of primary human xenografts into the pancreas will more closely recapitulate the growth environment of human pancreatic cancers. Thus, the molecular and cellular analysis of the orthotopically implanted tumors should more accurately reflect the biologic behavior of individual patient tumors, allowing the assessment of the repertoire of cell surface receptor expression/activation and cell signaling pathways activated in each tumor. The Experimental Plan details the following two specific aims: 1) To collect human pancreatic cancer specimens then propagate tumors orthotopically in mice and evaluate growth kinetics, tumor invasion, and metastasis. 2) To perform molecular characterization of human and xenografted tumors and correlate the molecular signaling profile of each tumor with its growth, invasive, and metastatic behavior. While previous studies have described the transplantation of pancreatic tumors subcutaneously and orthotopically, the model described herein will be the first attempt to correlate the clinical properties of pancreatic tumors with the molecular and cellular properties of the tumors propagated orthotopically in the pancreas. In addition to providing fundamental information about the molecular and cellular properties of primary pancreatic cancers, development of this model will be the next step toward arriving at a personalized approach to therapy for pancreatic cancer. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth leading cause of cancer deaths in the United States and has the shortest survival time of any cancer. Our goal is to develop a novel approach to therapy for pancreatic cancer, with treatment individualized for each patient depending on the best target for therapy of their specific tumor. We plan to achieve this by developing a mouse model of pancreatic cancer in which portions of patients'tumors are grown in the mouse pancreas, and then assessed for their molecular characteristics and response to treatment. |
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2009 — 2010 | Bouton, Amy H [⬀] Parsons, J Thomas |
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.) |
Regulation of Breast Cancer Progression by Fak Expression in Tumor Macrophages @ University of Virginia DESCRIPTION (provided by applicant): The growth and metastatic spread of solid tumors is controlled by signals emanating from tumor cells as well as by immune cells and fibroblasts in the surrounding stroma, components of the extracellular matrix, and soluble growth factors and cytokines. While this complexity creates challenges for therapeutic intervention, it also provides unique opportunities by making available a number of distinct cellular and molecular targets that can be exploited to control tumor growth and progression. The focus of this proposal is on Focal Adhesion Kinase (FAK), a protein tyrosine kinase whose expression is significantly increased in many late-stage cancers, including breast cancer. We hypothesize that FAK expression in two components of the tumor microenvironment, the tumor cells and tumor-associated macrophages (TAMs), plays a critical role in promoting breast tumor progression and metastasis. We will use mouse models of breast cancer to gain an understanding of how FAK expression in breast carcinoma cells and/or the ancillary tumor-associated macrophages controls primary breast tumor growth and metastatic spread. By combining genetic manipulation of these mice with FAK inhibitors currently in Phase I clinical trials, we propose to 1) determine how the loss of FAK expression in macrophages alters or ablates macrophage functions that drive breast tumor growth/progression and metastasis (Aim 1);2) assess how the dual modulation of FAK expression in breast tumor cells and in tumor-associated macrophages alters breast tumor growth and metastasis (Aim 2A);and 3) assess how systemic inhibition of FAK expression alters breast tumor growth and metastasis (Aim 2B). Successful completion of this study will provide new insights into features of the tumor that can predict a clinical response to the FAK-targeted drugs currently in clinical trials and the optimal timing for these treatments. More globally, we will learn about mechanisms through which tumor cells and other cells within the tumor microenvironment communicate to promote breast tumor growth and metastasis. We anticipate that this work will help to move the paradigm for breast cancer treatment away from the tumor cells per se and toward the full complement of factors that contribute to tumor growth and metastasis. PUBLIC HEALTH RELEVANCE: By focusing on the role of FAK in both macrophages and tumor cells, this work will uncover novel features of macrophage - tumor cell synergy that contribute to breast tumor behaviors. In addition to providing critical information about how FAK inhibitors should be used to treat breast cancer patients, this work will potentially identify new strategies for targeting distinct cellular compartments within the tumor that can be exploited therapeutically to control tumor growth and progression. It is anticipated that, through the knowledge gained from these studies, there will be a significant reduction in mortality from breast cancer. |
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