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）：视黄酸 (RA) 是维生素 A 的生物活性形式，对于多种生物过程至关重要。 RA 与核受体、视黄酸受体 (RAR) 和类视黄醇受体 X (RXR) 结合，通过触发辅助调节因子的募集来调节靶基因的表达，这些辅助调节因子主要通过染色质重塑和对靶基因调控区域的修饰来发挥作用。核受体相互作用蛋白 1（NRIP1，最初称为 RIP140）是一种配体依赖性共阻遏物，即它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 信号传导稳态控制的机制。该提案重点关注由 RIP140 和与激素受体形成复合物的共激活剂精心策划的染色质重塑事件，例如 RIP140-RAR/RXR 复合物和共激活剂-RAR/RXR 复合物，以及几种新发现的翻译后修饰在调节受体/辅助调节剂活性中的生物学意义。将解决两个问题：1）RIP140 在激素诱导的染色质重塑中如何发挥作用？ 2）蛋白质修饰如何调节RIP140的生物活性？野生型和转基因细胞，包括 RIP140 敲除 (RIP-/-) 和 TRAP220 敲除 (TRAP-/-) 细胞，以及 P19 细胞中 siRNA 介导的基因敲除将用作主要实验系统。含有激素反应元件（HRE）的染色质片段将成为检查目标，以解决生理相关背景下的机制细节。这些研究将通过特定转录因子复合物的协调形成，提供对激素（维生素 A 和甲状腺激素）串扰的机制见解。这些研究还将揭示对细胞分化程序至关重要的潜在新信号和细胞因子，其中维生素 A 和其他内分泌因子发挥着重要作用。从这些研究中获得的知识还可用于了解受激素和营养因素影响或涉及激素和营养因素的临床疾病，例如代谢疾病，这些研究还将描述维生素 A 等营养素在维持人类健康中的作用。公共健康相关性：视黄酸 (RA) 是维生素 A 的生物活性形式，对于多种生物过程至关重要。 RA 通过涉及核受体相互作用蛋白 1（NRIP1，最初称为 RIP140）的染色质重塑来调节靶基因表达。该项目的长期目标是了解维生素 A 信号传导稳态控制的机制。目前的提案从机制的角度重点关注 NRIP1 的功能作用。从这些研究中获得的知识也可用于了解受激素和营养因素影响或涉及激素和营养因素的临床疾病，例如代谢疾病。这些研究还将阐明维生素 A 等营养素在维持人类健康中的作用。