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HETEROCHROMATIN RECRUITMENT OF THE VPAC1 LOCUS BY IKAROS

IKAROS 对 VPAC1 基因座的异染色质招募

基本信息

批准号：
7278321
负责人：
GLENN Paul DORSAM
金额：
$ 10.8万
依托单位：
NORTH DAKOTA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-15 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7278321
关键词：
Affinity Alanine Binding Biological Assay CD4 Positive T Lymphocytes Cell Cycle Cells Coupled Cyclic AMP DNA Binding Disease Dominant-Negative Mutation Down-Regulation Etiology Euchromatin Event G-Protein-Coupled Receptors GTP-Binding Proteins Gel Gene Expression Gene Targeting Genes Growth Hematopoiesis Hematopoietic Hematopoietic Neoplasms Heterochromatin Hour Human Ikaros protein Immune In Situ Hybridization Incidence Intestines Knockout Mice Lead Length Lung Lymphoblastic Leukemia Lymphopoiesis Maintenance Measurement Measures Mediating Molecular Molecular Profiling Mus Mutate Neuropeptides Nuclear Organ Pathway interactions Pattern Peripheral Nervous System Phosphopeptides Phosphorylation Play Protein Isoforms Protein Kinase C Protein Overexpression Proteins RNA Interference Recruitment Activity Regulation Repression Research Role Signal Transduction Signaling Molecule Signaling Protein Spleen T-Cell Activation T-Cell Proliferation T-Lymphocyte Technology Thymus Gland Time Trans-Activators Transcription Repressor/Corepressor Transcriptional Regulation Wild Type Mouse chromatin immunoprecipitation gastrointestinal system immune function inhibitor/antagonist insight leukemia mouse model mucosa-associated lymphoid tissue mutant novel promoter receptor receptor binding transcription factor two-dimensional uncontrolled T lymphocyte proliferation vasoactive intestinal peptide receptor 1

项目摘要

DESCRIPTION (provided by applicant): The focus of this proposal is to investigate the molecular mechanisms governing Ikaros-mediated transcriptional regulation of vasoactive intestinal peptide receptor - 1 (VPACR-1) in T lymphocytes. Ikaros is a master regulator of lymphopoiesis and sets the threshold for T cell activation. Ikaros mutated mouse models develop an aggressive lymphoblastic leukemia with 100% incidence. Some human leukemias express mutated dominant negative Ikaros isoforms that inhibit full-length Ikaros DNA binding. Decreases in Ikaros DNA binding capacity may downregulate a subset of genes capable of regulating T cell proliferation. Recently, we demonstrated that the gene for VPACR-1, a G protein coupled, antiproliferative receptor expressed on na¿ve CD4 T cells, is a novel gene target for Ikaros. Signaling through the anti-proliferative VPACR-1 receptor may naturally impede cell cycle entry in CD4 T cells. Therefore, a decrease in Ikaros protein and/or DNA binding capacity, during certain etiologies of lymphoblastic leukemia, may downregulate VPACR-1 and contribute to uncontrolled proliferation. Understanding how Ikaros regulates VPACR-1 in na¿ve and activated CD4T cells may 1.) provide insight into a crucial downstream event from Ikaros that contributes to uncontrolled proliferation in hematopoietic disorders and 2.) lead to an understanding of the role Ikaros-mediated regulation of VPACR-1 plays in normal immune function, such as suppressing bystander T cell activation in certain organs including the gastrointestinal system. Therefore, the aims of this research are to 1.) confirm bi-directional effects of Ikaros on VPACR-1 expression in primary na¿ve and activated CD4 T lymphocytes, 2.) demonstrate which PKC pathway signaling proteins mediate TCR-dependent VPACR-1 downregulation, and 3.) identify IK phosphoacceptor residues that mediate IK recruitment to heterochromatin during T cell activation

描述（由申请人提供）：