TR2 nuclear receptor in vitamin A signaling

这个项目的长期目标是了解维生素A信号是如何由单核细胞调节的 受体属于TR2和TR4家族。以前的研究主要集中在抑制机制上。 TR2包括：1)直接招募组蛋白脱乙酰基酶(HDAC)、受体相互作用等共抑制因子 蛋白质140(RIP140)和SMRT(一种活性机制)，以及ii)与RA受体(RARs)竞争和 维甲酸X受体(RXR)与DNA结合(一种被动机制)。 基于最近的研究，这个更新的建议集中在新的配体非依赖的信号通路上 可以改变TR2和TR4的性质和活性，从而调节RAR|32、细胞周期蛋白D1和载脂蛋白E 基因。将检验三个假说：i)TR2和TR4的生物活性可由蛋白质调节 修饰(生化因子)及其与辅助调节因子(动力学因子)的相互作用，ii) 生理上相关的受体活性通过它们与 特定的共调节子作用于靶基因的调控区域(动态因子)，以及iii)配体- 独立激活的受体复合体可促进靶基因染色质重塑激活 抄写。目的我将通过研究配体的作用机制来解决第一和第二个假说。 通过蛋白质修饰引起的受体活性的独立调节(使用蛋白质组学 方法)，影响：i)受体的生化性质，ii)受体的一般性质，iii)受体- 共调节因子相互作用动力学和IV)TR2和TR4共调节复合体对靶基因的动力学。目标 II将通过操纵TR2和TR4来解决生理相关细胞培养中的第三个假设， 以及确定它们的修饰对靶基因的影响。待检测的生物效应 包括共调节复合体的形成和染色质构象的改变(重塑)或 组蛋白对靶基因启动子(RAR|32、Cyclin DL和apoE)的修饰及其生物学意义 P19细胞周期进程中的活性以及靶基因的转录效率。这两个项目的结果 体外(AIM 1)和体内(AIM 2)系统将被整合，以构建一个全面的概述 这些孤儿受体调节维生素A信号通路的机制， 特别是关于由受体的蛋白质修饰产生的信号。

The long-term goal of this project is to understandhow vitamin A signaling is modulated by orphannuclear receptors belonged to the TR2 and TR4 family. Previous studiesfocused on the repressive mechanisms of TR2 that include i) directly recruitingco-repressors like histone deacetylases (HDACs), receptor interacting protein 140 (RIP140) and SMRT (an active mechanism), and ii) competing with RA receptors (RARs) and retinoid X receptor (RXR) for DNA binding (a passive mechanism).By extending from these conclusions and based upon recent studies, this renewal proposal focuses on novel ligand-independent signaling pathways that can modify the property and activity of TR2 and TR4 for the regulation of RAR|32, cyclin D1 and apoE genes. Three hypotheses will be tested: i) the biological activity of TR2 and TR4 can be modulated by protein modification (biochemical factors) and their interaction with coregulators (kinetic factors), ii) the physiologically relevant receptor activity is manifested through their interaction with, or recruitment of, specific coregulators onto the regulatory region of the target gene (dynamic factors), and iii)the ligand- independently activated receptor complex can contribute to chromatin remodeling of target gene to activate transcription. Aim I will address the first and second hypotheses by examining the mechanisms of ligand- independent modulation of receptor activity elicited through protein modifications (using a proteomic approach) that affect: i) the biochemical nature of receptors, ii) the general property of receptors, iii) receptor- coregulator interaction kinetics and iv) dynamics of TR2 and TR4 coregularory complex on target genes. Aim II will address the third hypothesis in physiologically relevant cell cultures by manipulatingTR2 and TR4, and determiningthe effects of their modification on target genes. The biological effects to be examined include the formation of coregulatory complexes and alteration in chromatin conformation (remodeling) or histone modification on the target gene promoters (RAR|32, cyclin Dl and apoE) and theirbiological activities in P19 cell cycle progression as well as transcription efficiency of target genes. Results from both in vitro (aim 1) and in vivo (aim 2) systems will be integrated to construct a comprehensive overview of the mechanisms underlyingthe modulation of vitamin A signalingpathways by these orphan receptors, specifically with respect to signals generated from protein modifications of receptors.