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

描述(申请人提供)：维甲酸(RA)，维生素A的生物活性形式，是各种生物过程中必不可少的。RA与核受体--视黄酸受体(RAR)和视黄酸受体X(RXR)结合，通过激发主要通过染色质重塑和修饰靶基因调节区的协同调节因子来调节靶基因的表达。核受体相互作用蛋白1(NRIP1，最初被称为RIP140)是一种配体依赖的共抑制因子，即它以激素依赖的方式抑制激素对靶基因表达的诱导。该项目的长期目标是了解维生素A信号的体内平衡控制的潜在机制。该提案侧重于RIP140和与激素受体形成复合体的共激活剂(如RIP140-RAR/RXR复合体和共激活剂-RAR/RXR复合体)所调控的染色质重塑事件，以及新发现的几种翻译后修饰在调节受体/辅助调节因子活性方面的生物学意义。将讨论两个问题：1)RIP140如何在激素诱导的染色质重塑中发挥作用？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基因敲除(RIP-/-)和TRAP220基因敲除(TRAP-/-)细胞，以及P19细胞中siRNA介导的基因敲除将作为主要的实验系统。含有激素反应元件(HRE)的染色质片段将是在生理相关背景下解决机制细节的检查目标。这些研究将通过协调形成特定的转录因子复合体，为激素(维生素A和甲状腺激素)的串扰提供机械性的见解。这些研究还将揭示潜在的新信号和细胞因子，这些信号和细胞因子对细胞分化程序至关重要，其中维生素A和其他内分泌因子发挥着至关重要的作用。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的临床疾病，如代谢性疾病，这些研究还将阐明营养素，如维生素A，在维持人类健康方面的作用。与公共健康相关：维甲酸(RA)是维生素A的生物活性形式，对各种生物过程都是必不可少的。RA通过涉及核受体相互作用蛋白1(NRIP1，最初被称为RIP140)的染色质重塑来调节靶基因的表达。该项目的长期目标是了解维生素A信号的体内平衡控制的潜在机制。目前的提案从机械论的角度着眼于NRIP1的功能作用。从这些研究中获得的知识也可以用于了解受激素和营养因素影响或涉及的临床疾病，如代谢性疾病。这些研究还将描绘营养素，如维生素A，在维持人类健康方面的作用。

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.