1990 — 1994 |
Talmage, David A |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Vitamin a, Signal Transduction and Cell Differentiation @ Columbia Univ New York Morningside
The project described in this proposal is directed towards defining the mechanism by which retinoic acid regulates the differentiation of F9 cells. F9 cells provide a useful model system for studying events normally occurring in the preimplantation mouse embryo. When treated with retinoic acid (RA), these cells form a primitive endoderm which becomes competent to differentiation into either parietal or visceral endoderm. Subsequent differentiation depends on a second stimulus: cAMP induces parietal endoder formation, whereas aggregation leads to visceral endoderm formation. I hypothesize that RA induces the acquisition of signal responsiveness during primitive endoderm formation by controlling the expression of genes for constituents of signal transduction pathways. The proposed experiments are designed to identify RA regulated intracellula signal transduction pathways in F9 cells. Specifically the effects of RA on the expression of three classes of protein kinases, which are critical in signal transduction in other systems, will be measured. These are the cyclic AMP dependent protein kinases, the Ca2+, phospholipid dependent protein kinases and the tyrosine specific protein kinase pp60c-src. Studie are proposed that will 1) measure retinoic acid induced changes in the activity, synthesis and mRNA levels for these enzymes; 2) determine the mechanism by which retinoic acid regulates the expression of these kinases; 3) to explore whether a correlation exists between changes in kinase activity and differentiation into either parietal or visceral endoderm; and 4) to manipulate the expression of these enzymes using a molecular genetic approach, to test direct causal relationships between kinase activity and specific differentiated phenotypes.
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0.904 |
1998 — 2002 |
Talmage, David A |
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. |
Cellular Retinol Binding Protein, Type I--Linking Retinoid Metabolism/Action @ Columbia University Health Sciences
The ability of tissues to respond to vitamin A is affected by three factors: delivery of vitamin A, predominantly as retinol, to the tissues from the circulation; uptake of vitamin A from circulating pools and subsequent metabolism into biologically active forms within the tissue; and the presence of functional retinoic acid and retinoid receptors that mediate the genomic response, or the other response to vitamin A metabolites. In this project I am proposing a genetic approach to determine the importance of cyclical CRBP expression and of retinoid status in sustaining normal cervical squamous metaplasia. These experiments will utilize mice in which either the CRBP or RARalpha genes have been disrupted by homologous recombination, and mice in which CRBP is constitutively expressed in basal and suprabasal keratinocytes. The proposed experiments are divided into two complimentary parts. In Aim 1 studies are proposed to establish the effects of dysregulated CRBP expression and of vitamin A insufficiency on the differentiation of the cervical epithelium. In Aim 2 experiments are proposed that will use cultured cervical epithelial cells isolated from CRBP+/+ and CRBP-/- mice to establish the effect of CRBP expression on differentiation of cultured CECs, on retinol uptake and metabolism in CECs, and on RAR function. The Aims of this Project are: Aim 1. Determine if CRBP modulates in vivo retinoid status in the rodent cervix. Aim 2. Determine if CRBP alters retinol uptake and metabolism, or retinol regulation of cultured cervical epithelial cell differentiation. Although these experiments focus on the role of RBP in the biology of the cervical epithelium, the insights gained should be applicable to other tissues in which vitamin A status must be dynamically regulated.
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0.943 |
1999 — 2003 |
Talmage, David A |
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 Antioncogenic Action of Retinoids @ Columbia University Health Sciences
Vitamin A and its derivatives (retinoids) control numerous, fundamental biological processes, many with relevance to human disease prevention. Notable among these is the ability of retinoids to inhibit the progression of early neoplastic lesions. The mechanism(s) by which retinoids limit oncogenesis are not clear. Retinoid effects on tumor cells involves transcriptional regulation of cellular genes by the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). The products of these genes control proliferation, differentiation and apoptosis. Relatively little progress has been made at identifying critical target genes that mediate the anti-oncogenic response to retinoids. The limited pace of these studies results in large part from the lack of an appropriate system in which to assess whether isolated genes are involved in the biological processes under study. We have developed an experimental system that allows us to study the specific effects of ligand activated RARalpha during oncogenic transformation. We used this system to demonstrate that retinoic acid inhibits signaling via a pathway that leads from plasma membrane tyrosine kinases (both receptor and non-receptor), through phosphatidylinositol 3-kinase and Jun N-terminal kinase, to the c-fos promoter. In this application, I am proposing to identify the retinoic acid induced genes that regulate signaling throughout this pathway, identify the specific step(s) in the pathway affected by these retinoid regulated gene products, and determine if regulation of these targets by retinoic acid also controls apoptosis in tumor cells. The specific aims of the project are: 1. Generation of a population of cDNA probes enriched in RA-induced sequences. 2. Identify the site of RA action in the signaling pathway that links mT activated Ptdlns 3-kinase with the c-fos promoter. 3. Identify the RA target that inhibits apoptosis in mT-transformed cells.
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0.943 |
2011 — 2013 |
Talmage, David A |
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.) R33Activity Code Description: The R33 award is to provide a second phase for the support for innovative exploratory and development research activities initiated under the R21 mechanism. Although only R21 awardees are generally eligible to apply for R33 support, specific program initiatives may establish eligibility criteria under which applications could be accepted from applicants demonstrating progress equivalent to that expected under R33. |
Neuregulin 1 Signaling and Schizophrenia: Effect of Transmembrane Domain Variants @ State University New York Stony Brook
DESCRIPTION (provided by applicant): Schizophrenia, which affects roughly 1% of the world's population, is believed to develop as a consequence of environmental conditions interacting with susceptible genomes. The genomic architecture is set at conception;the environmental challenges occur during early, in utero development of the nervous system, and during the maturation of the nervous system in the post-natal - adolescent period. The end result of these interactions is altered development and maturation of key CNS circuits that lead to the pleiotropic symptoms that define this neuropsychiatric syndrome. Understanding the nature and the mechanism of action of the underlying genomic changes and the environmental factors that contribute to schizophrenia is essential for developing strategies to treat, prevent and ultimately cure this disease. Although the NRG1 gene has been repeatedly linked to schizophrenia susceptibility, the majority of sequence polymorphisms that are associated with disease are non-coding and provide little insight into their contribution to pathology. A disease associated non-synonymous polymorphism within the NRG1 transmembrane domain has been described. Several lines of evidence demonstrate that the affected valine residue is essential for gamma secretase mediated NRG1 intramembranous proteolysis and subsequent transcriptional regulation by the NRG1 intracellular domain. These findings provide the rationale for the studies in this proposal (in response to PAR-08-158). During the R21 phase, I propose to generate lines of mice in which the endogenous transmembrane domain is replaced with the human risk allele. We will then extensively evaluate the effect of this substitution on NRG1-dependent signaling events in neurons;both in vivo and in vitro (AIMS 1 &2). During the R33 phase, once the mutant mice have been obtained, I propose, during the R33 phase, an in depth analysis of a subset of behaviors and structural phenotypes in neural circuits that underlie schizophrenia associated endophenotypes (AIM 3). PUBLIC HEALTH RELEVANCE: Schizophrenia is a devastating progressive neuropsychiatric disease that directly affects roughly 1% of the world's population. The disorder is believed to develop as a consequence of environmental conditions interacting with susceptible genomes. The end result of these interactions is altered development and maturation of key CNS circuits that lead to the pleiotropic symptoms that define this neuropsychiatric syndrome. In this project I am proposing to generate a mouse line that has been modified to carry a human mutation in the Neuregulin 1 gene, that is associated with schizophrenia. Studies of these mice should further our understanding of the mechanism by which this genetic mutation contributes to the changes in brain function that lead to schizophrenia. This understanding is essential for developing strategies to treat, prevent and ultimately cure this disease.
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