Functional Characterization of NCoR/SIVIRT Corepressor Complexes in Adipocytes

脂肪细胞中 NCoR/SIVIRT 辅阻遏物复合物的功能表征

基本信息

批准号：
8355979
负责人：
M ROSENFELD
金额：
$ 42.6万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8355979
关键词：
Adipocytes Adipose tissue Alleles Amplifiers Architecture Cell Nucleus Cell Surface Receptors Cell membrane Cells Chemicals Collaborations Complex Development Distant Environment Functional RNA Future GPS2 gene Gene Activation Gene Expression Gene Expression Regulation Genes Genetic Transcription Genomics Grant Human Inflammation Inflammatory Instruction Insulin Insulin Resistance Intervention Knowledge Laboratories Ligands Location Mediating Metabolic Metabolic Diseases Metabolism Modeling Molecular Movement Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Receptors Nuclear Structure Obesity Physiological Proteins Relative (related person)Repression Resources Role Signal Transduction Structure Technology Testing Therapeutic Therapeutic Intervention Time Transcriptional Regulation Translations base cell type inhibitor/antagonist insight macrophage new technology new therapeutic target novel novel strategies overexpression prevent programs promoter research study response stem cell biology

项目摘要

The critical role of inflammation in obesity and T2D is now well established. Under this Grant, we have focused on defining the roles of components of the NCoR/SMRT co-repressor complexes in inflammation, including TBL1/TBLR1 and GPS2, and the development of a new technology that has permitted us to examine interactions between distant genomic regions. We have identified a new mechanism by which GPS2 protects cells against a hyper-infiammatory state, and we have uncovered novel roles of ncRNAs in targeting co-regulatory complexes to discreet locations In the nucleus with speciflc transcriptional functions. In this Project, we will capitalize on these recent discoveries to advance three new Specific Aims. In Specific Aim 1, we will delineate the molecular mechanisms by which GPS2, an NCoR/SMRT-associated protein, suppresses hyper-inflammatory transcriptional responses in both macrophages and adipose tissue. These studies will test the hypothesis that GPS2 functions to regulate PPARy activity and infiammatory responses by acting both in the nucleus as a component of NCoR co-repressor complexes, and at the plasma membrane as an inhibitor of cell surface receptors that mediate responses to inducers and amplifiers of inflammation. In Specific Aim II, we will define the molecular and physiological roles of SMRT in macrophages and adipocytes. In concert with the unexpected findings by Projects 1 and 3 that deletion of the related co-repressor NCoR from either adipocytes or macrophages results in protection from obesity-induced insulin resistance, these studies may facilitate the identification of chemicals/ligands that selectively regulate insulin-sensitizing functions of nuclear receptors, such as PPARy. In Specific Aim 111, we will test the hypothesis that pro-infiammatory gene activation requires regulated interactions of promoter-associated transcriptional co-regulators with non-coding RNAs resident in specific sub-nuclear architectural structures. We will investigate whether directed movements between these sub-nuclear structures are required for regulated gene expression. These studies will therefore explore conceptually new cellular mechanisms for transcriptional control of gene expression that may be targets for therapeutic intervention.

炎症在肥胖症和T2D中的关键作用现在已经建立了。根据这项赠款，我们专注于定义NCOR/SMRT共抑制剂复合物在炎症中的成分的作用，包括TBL1/TBLR1和GPS2，以及一项新技术的发展，该技术使我们能够检查遥远基因组区域之间的相互作用。我们已经确定了一种新机制 GPS2可保护细胞免受超时性状态的影响，我们发现了NCRNA在靶向具有特异性转录函数核中谨慎位置的共同调节复合物中的新作用。在这个项目中，我们将利用这些最近的发现，以促进三个新的特定目标。在特定的目标1中，我们将描述GPS2（NCOR/SMRT相关蛋白）抑制巨噬细胞和脂肪组织中的高炎性转录反应的分子机制。这些研究将检验以下假设：GPS2通过在细胞核中作用在NCOR共抑制复合物的成分以及在质膜的质膜抑制剂中，通过在细胞核中起作用来调节PPARY活性和感染反应，从而介导对炎症诱导者和膨胀剂的抑制剂。在特定的目标II中，我们将定义SMRT在巨噬细胞和脂肪细胞中的分子和生理作用。与项目1和3的意外发现一致，从脂肪细胞或巨噬细胞中删除相关的共抑制剂NCOR会导致保护侵害肥胖诱导的胰岛素抵抗，这些研究可能会促进化学/配体的鉴定，从而选择性地调节胰岛素敏感性的核受体功能，例如PPARY。在特定的目标111中，我们将检验以下假设：促触发基因激活需要启动子相关的转录共同调节剂与特定亚核体系结构中驻留的非编码RNA的调节相互作用。我们将调查这些亚核结构之间的定向运动是否需要调节基因表达。因此，这些研究将在概念上探索新的细胞机制，用于对基因表达的转录控制，这可能是治疗干预的靶标。