Studies of nuclear receptor corepressor, NRIP1, in vitamin A signaling pathways

核受体辅阻遏物 NRIP1 在维生素 A 信号通路中的研究

• 批准号: 8007006
• 负责人: Li-Na Wei
• 金额: $ 5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-07 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8007006
• 关键词: Address; Adipocytes; Affect; Animal Model; Arginine; Biological; Biological Process; Cell Differentiation process; Cells; Chromatin; Chromatin Remodeling Factor; Clinical; Complex; Defect; Disease; EP300 gene; Embryo; Embryonal Carcinoma; Endocrine; Event; Fibroblasts; Figs - dietary; Gene Conversion; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Health; Histone Deacetylase; Histones; Homeostasis; Hormonal; Hormone Receptor; Hormones; Human; Kinetics; Knock-out; Knowledge; Left; Ligands; Maintenance; Mediating; Mediator of activation protein; Metabolic Diseases; Methylation; Modeling; Modification; Molecular; Molecular Mechanisms of Action; Mus; Mutate; NRIP1 gene; Nuclear Receptors; Nucleic Acid Regulatory Sequences; Nucleosomes; Nutrient; Nutritional; PCAF gene; PPARBP gene; Phase; Play; Post-Translational Protein Processing; Progress Reports; Property; RNA Polymerase II; RXR; Recruitment Activity; Regulation; Repression; Retinoic Acid Binding; Retinoic Acid Receptor; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Supplementation; System; Testing; Thyroid Hormones; Transferase; Tretinoin; Vitamin A; adipocyte differentiation; cell type; cellular retinoic acid binding protein I; chromatin remodeling; genetically modified cells; hormone response element; human NRIP1 protein; insight; mouse model; mutant; novel; programs; public health relevance; receptor; transcription factor

DESCRIPTION (provided by applicant): Retinoic acid (RA), the biologically active form of Vitamin A, is essential for a variety of biological processes. RA binds to nuclear receptors, retinoic acid receptor (RAR) and retinoid receptor X (RXR), to regulate target gene expression by triggering recruitment of coregulators that act, primarily, through chromatin remodeling and modification on the regulatory regions of target genes. Nuclear Receptor Interacting Protein 1 (NRIP1, originally known as RIP140) is a ligand-dependent co-repressor, i.e. it represses hormonal induction of target gene expression in a hormone-dependent manner. The long-term goal of this project is to understand the mechanisms underlying homeostatic control of vitamin A signaling. The proposal focuses on chromatin remodeling events orchestrated by RIP140 and coactivators that form complexes with hormone receptors, such as RIP140-RAR/RXR complex and coactivator-RAR/RXR complexes, as well as the biological significance of several newly identified post-translational modifications in the modulation of receptor/coregulator activities. Two questions will be addressed: 1) how does RIP140 function in hormone-induced chromatin remodeling? 2) How does protein modification regulate the biological activity of RIP140? Wild type and genetically modified cells, including RIP140-knockout (RIP-/-) and TRAP220-knockout (TRAP-/-) cells, as well siRNA mediated gene knockdown in P19 cells will be used as the principal experimental systems. Chromatin segments containing hormone response elements (HREs) will be the targets of examination to address mechanistic details in a physiologically relevant context. These studies will provide mechanistic insights into crosstalk of hormones (vitamin A and thyroid hormones) via coordinated formation of specific transcription factor complexes. These studies will also uncover potentially novel signals and cellular factors that are critical to cell differentiation program where vitamin A and other endocrine factors play vital roles. Knowledge gained from these studies could also be applied to understand clinical diseases that are affected by, or involve, hormonal and nutritional factors, such as metabolic diseases, the studies will also delineate the role of nutrients, such as vitamin A, in the maintenance of human health. PUBLIC HEALTH RELEVANCE: Retinoic acid (RA), the biologically active form of Vitamin A, is essential for a variety of biological processes. RA functions by regulating target gene expression through chromatin remodeling that involves Nuclear Receptor Interacting Protein 1 (NRIP1, originally known as RIP140). The long-term goal of this project is to understand the mechanisms underlying homeostatic control of vitamin A signaling. The current proposal focuses on the functional role of NRIP1 from a mechanistic stand point. Knowledge gained from these studies could also be applied to understand clinical diseases that are affected by, or involve, hormonal and nutritional factors, such as metabolic diseases. The studies will also delineate the role of nutrients, such as vitamin A, in the maintenance of human health.

描述（由申请人提供）：维生素A的生物活性形式的视黄酸（RA）对于多种生物过程至关重要。 RA与核受体，视黄酸受体（RAR）和类视黄素受体X（RXR）结合，通过触发基本染色质重塑和修饰靶基因的调节区域的促进剂，从而调节靶基因表达。核受体相互作用的蛋白1（NRIP1，最初称为RIP140）是配体依赖性的共抑制剂，即以激素依赖性方式抑制靶基因表达的激素诱导。该项目的长期目标是了解维生素A信号的稳态控制的基础机制。该提案的重点是由RIP140和共激活因子策划的染色质重塑事件，这些事件与激素受体形成复合物，例如RIP140-RAR/RXR复合物和共激活剂/RXR复合物，以及在受体/Coregulator的调制器中的几种新鉴定的转移后修饰的生物学意义，以及几种新近鉴定的后转化后修饰的生物学意义。将解决两个问题：1）RIP140如何在激素诱导的染色质重塑中起作用？ 2）蛋白质修饰如何调节RIP140的生物学活性？野生型和转基因细胞，包括RIP140敲除（RIP - / - ）和TRAP220-KNOCKOUT（TRAP - / - ）细胞，以及p19细胞中siRNA介导的基因敲低的细胞也将用作主要实验系统。含有激素反应元件（HRE）的染色质片段将是研究在生理相关环境中的机理细节的检查目标。这些研究将通过协调的特定转录因子复合物的配位形成激素（维生素A和甲状腺激素）来提供对激素（维生素A和甲状腺激素）串扰的机械见解。这些研究还将发现潜在的新型信号和细胞因子，这些信号和细胞分化程序至关重要，其中维生素A和其他内分泌因子起着至关重要的作用。从这些研究中获得的知识也可以应用于了解受荷尔蒙和营养因素（例如代谢性疾病）影响或涉及荷尔蒙和营养因素的临床疾病，这些研究还将描述营养素（例如维生素A）在维持人类健康中的作用。公共卫生相关性：维生素A的生物活性形式视黄酸（RA）对于多种生物过程至关重要。 RA通过调节靶基因表达来通过染色质重塑来调节核受体相互作用蛋白1（NRIP1，最初称为RIP140）。该项目的长期目标是了解维生素A信号的稳态控制的基础机制。当前的提案着重于机械角度的NRIP1的功能作用。从这些研究中获得的知识也可以应用于了解受荷尔蒙和营养因素（例如代谢性疾病）影响或涉及的临床疾病。这些研究还将描述维生素A等营养在维持人类健康中的作用。