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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：
7486318
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 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7486318
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

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, anti- proliferative receptor expressed on nah'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'fve 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 naive 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.

本提案的重点是研究Ikaros介导的 T淋巴细胞中血管活性肠肽受体-1（VPACR-1）的转录调节。 Ikaros是淋巴细胞生成的主要调节者，并设定T细胞活化的阈值。伊卡洛斯变异了小鼠模型发展为侵袭性淋巴母细胞白血病，发病率为100%。一些人类白血病表达抑制全长Ikaros DNA结合的突变显性负性Ikaros同种型。 Ikaros DNA结合能力的降低可能会下调一个能够调节T细胞的基因亚群，细胞增殖最近，我们证明了VPACR-1基因，一种G蛋白偶联的，抗- 增殖性受体表达于未经处理的CD 4 T细胞上，是Ikaros的新基因靶点。信令通过抗增殖性VPACR-1受体可以天然地阻碍CD 4 T细胞中的细胞周期进入。因此，我们认为，在某些淋巴母细胞疾病的病因过程中，Ikaros蛋白和/或DNA结合能力降低白血病，可能下调VPACR-1，并有助于不受控制的增殖。了解如何 Ikaros可调节幼稚和活化的CD 4 T细胞中的VPACR-1。提供了一个关键的洞察力， Ikaros的下游事件，导致造血系统疾病中不受控制的增殖和2.）了解Ikaros介导的VPACR-1调节在正常人中的作用，免疫功能，如抑制某些器官中的旁观者T细胞活化，包括胃肠系统因此，本研究的目的是1）。确认双向效应 Ikaros对原代幼稚和活化的CD 4 T淋巴细胞中VPACR-1表达的影响，2.）证明哪些PKC途径信号蛋白介导TCR依赖性VPACR-1下调，以及3.）鉴定介导T细胞过程中IK募集至异染色质的IK磷酸受体残基 activation.