1984 — 1985 |
Shortle, David Brugge, Joan Mckelvy, Jeffrey Halegoua, Simon Wimmer, Eckard (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Acquisition of Instruments For Peptide Synthesis |
0.96 |
1986 — 2010 |
Halegoua, Simon |
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 Mechanisms of Neuronal Differentiation @ State University New York Stony Brook
DESCRIPTION (provided by applicant): Nerve Growth Factor (NGF) is the prototypic and best studied member of the Neurotrophin family of neuronal growth factors, which are required for the survival and maintenance of many neuronal populations throughout the peripheral and central nervous systems. The principal mode of NGF signaling occurs over long distances, and has been postulated to occur by internalization and retrograde transport of an NGF-receptor complex within a "signaling endosome" from the nerve terminal to the cell body. The process by which the endosome is formed and trafficked, as it relates to intracellular signaling, has remained largely intractable due to a lack of understanding of the mechanism of internalization and tools with which to manipulate the endosome. We have discovered, through our recent identification of a protein we term "Pincher," the means to attack this important problem. Pincher mediates the formation of an endosome from which NGF mediates long-term signaling. Our preliminary findings suggest a model whereby signals emanating from the signaling endosome are fundamentally different from those generated at the plasma membrane, permitting differential signaling during and after retrograde transport to the cell body. To further explore and extend this model, we propose two specific aims: (1) to determine the relative importance of the differential signaling pathways mediated by NGF at the plasma membrane vs. the endosome and (2) to elucidate the process by which Pincher forms and trafficks signaling endosomes. Our proposed studies are intended to elucidate the mechanism by which Neurotrophins such as NGF regulate neuronal phenotype and survival. Neuronal death and defective phenotypic function are the major causes of nervous system disorders such as those seen in Parkinson's and Alzheimer's diseases, stroke, and peripheral neuropathies. Our work addresses these diseases of the nervous system, in which trophic support is defective and/or restoration of such support can be therapeutic in preventing neuronal loss and dysfunction. An understanding of the mechanisms for trophic factor signaling and delivery as proposed herein is essential to the rational design of therapeutics for combating these diseases.
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1 |
1996 — 2000 |
Halegoua, Simon |
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. |
Growth Factor Regulation of the Pn1 Sodium Channel in Pc12 Cells @ State University New York Stony Brook
The events leading to neuronal differentiation have been shown clearly to depend upon interactions of growth factors with receptors on the neuronal cell surface. In both the peripheral and central nervous systems Nerve Growth Factor (NGF) is required for the development of distinct neuronal populations in vivo. The rat pheochromocytoma cell line, PC 12, is the premier cell culture model for the differentiating actions of the neurotrophin, NGF. A major action of NGF on PC12 cells is the induction of membrane excitability. Through collaborations described in this program project we have determined that the membrane excitability is the result of induced expression of CNS- and PNS-type sodium channel genes through distinct signal transduction pathways. We have also revealed a new signal transduction pathway utilized by NGF, as well as by FGF, EGF and the cytokine interferon-gamma, to selectively induce expression of the peripheral nerve type sodium channel gene, PN1. We have termed the new pathway the "triggered" pathway because it is stimulated by only a one-minute exposure to the factors. A major goal of project 2 is to define the molecular intermediates responsible for triggered PN1 gene induction. We will determine which domains in the NGF and FGF receptors are responsible for PN1 regulation (aim 1), using techniques of site- directed mutagenesis and generation of transfected PC12 clones expressing the mutant receptor proteins. We will use techniques of microinjection, immunochemistry and genetics to examine a possible role for the STAT family of proteins in PN1 gene induction (aim 2). By defining the domains in the NGF and FGF receptors that lead to type II sodium channel induction (aim 3), we will begin to define the independent signaling pathways regulating the CNS (type II) and PNS (PN1) channel types. Our studies will provide insights into the unique signaling pathways regulating neuronal excitability in both the PNS and CNS, and into how these signaling pathways converge onto the transcriptional factors that ultimately regulate the sodium channel genes. Results from these studies will be integrated into projects 3 and 4, which are aimed at understanding growth factor regulation of excitability in primary neuronal cell cultures and in vivo.
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1 |
1997 — 2000 |
Halegoua, Simon |
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. |
Ion Channel Expression in Peripheral Nervous System @ State University New York Stony Brook
The broad goal of this revised program project grant is to reveal the molecular mechanisms controlling expression of genes encoding voltage-dependent ion channels, and to understand how the expression and subcellular targeting of different members of the gene family contribute to cell-specific firing properties in neurons. The thrust of the program is towards addressing these issues in the peripheral nervous system (PNS), but comparisons between channels in the PNS and CNS are proposed where this information provides specific insights into control mechanisms. Goal l seeks to identify the functional counterparts of specific sodium channel structures in neurons. The strategy will be to compare the functional "fingerprints" of alpha and accessory sodium channel subunits expressed in Xenopus oocytes with the fingerprints of sodium currents expressed differentially in PC12 cells through stimulation of distinct signal transduction pathways. Goal 2 is to compare the mechanisms controlling sodium channel gene expression in the PNS and CNS. The DNA elements and transcription factors required for neural-specific expression of a sodium channel gene expressed exclusively in PNS neurons will be identified. Receptor domains and cytoplasmic molecular intermediates involved in the up-regulation of sodium channel genes by neuronal growth factors will be identified through multiple biochemical and genetic approaches. Goal 3 is to reveal the molecular mechanisms involved in targeting of sodium and potassium channels to distinct subcellular domains. Targeting in PC12 and MDCK cell lines, and in neurons, will be studied using genetic, biochemical, and immunochemical approaches. All of these goals exploit unique reagents provided by the program investigators. Core facilities will provide support, equipment, reagents, and technical expertise for molecular biology, tissue culture, and administrative functions. This program project has the potential to lead to new strategies for therapeutic treatment of sensory and sympathetic pathologies. The studies also represent an important first step toward an understanding of how ion channels involved in pain pathways are modulated in vivo.
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1 |
2006 — 2008 |
Halegoua, Simon |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
Retrograde Signaling in Axons and Dendrites @ University of California San Diego |
0.943 |
2006 — 2008 |
Halegoua, Simon |
P41Activity Code Description: Undocumented code - click on the grant title for more information. |
Trk Endocytic Trafficking @ University of California San Diego |
0.943 |