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

• 批准号: 8472484
• 负责人: M ROSENFELD
• 金额: $ 41.39万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/8472484
• 关键词: Adipocytes; Adipose tissue; Affect; Alleles; Amplifiers; Architecture; Cell Nucleus; Cell Surface Receptors; Cell membrane; Cells; Chemicals; Chronic; Collaborations; Complex; Development; Diabetes Mellitus; Distant; Enhancers; Environment; Functional RNA; Future; GPS2 gene; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genomics; Grant; Homeostasis; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Instruction; Insulin; Insulin Receptor; Insulin Resistance; Intervention; Investigation; JNK-activating protein kinase; Knowledge; Laboratories; Ligands; Ligation; Link; Literature; Location; MAPK8 gene; Mediating; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Movement; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nuclear; Nuclear Receptors; Nuclear Structure; Obese Mice; Obesity; Organ; Pathway interactions; Peripheral; Phosphorylation; Phosphotransferases; Physiological; Polycomb; Post-Translational Protein Processing; Prevention; Principal Investigator; Production; Progress Reports; Proteins; Reactive Oxygen Species; Recurrence; Relative (related person); Repression; Resistance development; Resources; Role; Series; Serine; Signal Transduction; Stimulus; Stress; Structure; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Transcriptional Regulation; Translations; Tyrosine Phosphorylation; autocrine; base; blood glucose regulation; cell type; cytokine; human GPS2 protein; improved; in vivo; inhibitor/antagonist; innovation; insight; insulin sensitivity; insulin signaling; lipid metabolism; macrophage; new technology; new therapeutic target; novel; novel strategies; overexpression; paracrine; prevent; programs; promoter; research study; response; stem cell biology

instmctions): 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. RELEVANCE (See instructions): The proposed studies will be of significance in advancing our understanding of central pathogenic mechanisms that drive the development of insulin resistance and contribue to the development of future therapeutic approaches to prevent and treat type 2 diabetes.

Instmctions）： 炎症在肥胖症和T2D中的关键作用现在已经建立了。根据这笔赠款，我们有 专注于定义NCOR/SMRT共抑制剂复合物在炎症中的作用， 包括TBL1/TBLR1和GPS2，以及一项新技术的开发，使我们得以 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可保护细胞免受高插头状态的影响，我们发现了NCRNA在 针对具有特定转录函数的核中谨慎位置的共同调节复合物。 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。具体 AIM 1，我们将描述GPS2（NCOR/SMRT相关蛋白）的分子机制 抑制巨噬细胞和脂肪组织中的高炎性转录反应。这些 研究将检验GPS2功能调节PPARY活性和感染反应的假设 通过在细胞核中作为NCOR共抑制络合物的组成部分以及在等离子体上作用。 膜作为细胞表面受体的抑制剂，介导对诱导剂和放大器的反应 炎。在特定的目标II中，我们将定义SMRT在 巨噬细胞和脂肪细胞。与项目1和3的意外发现一致的删除 来自脂肪细胞或巨噬细胞的相关共抑制剂NCOR可保护肥胖症 - 诱导胰岛素抵抗，这些研究可能促进化学/配体的鉴定 调节核受体的胰岛素敏化功能，例如PPARY。在特定的目标111中，我们将测试 亲插入基因激活的假设需要调节启动子相关的相互作用 具有非编码RNA的转录共同调节剂驻留在特定的亚核体系结构中。 我们将研究这些亚核结构之间是否需要进行定向运动 调控基因表达。因此，这些研究将在概念上探索新的细胞机制 基因表达的转录控制可能是治疗干预的靶标。 相关性（请参阅说明）： 拟议的研究将在促进我们对中央致病性的理解方面具有重要意义 推动胰岛素抵抗发展并有助于未来发展的机制 预防和治疗2型糖尿病的治疗方法。