TRANSCRIPTIONAL COREGULATORS AND MYELOID GENE EXPRESSION

描述：(改编自申请人的摘要)核成员 受体超家族在发育和动态平衡中发挥关键作用 小分子结合对基因表达的调控作用 配基。这一提议的中心假设是转录 对调节配体的反应由辅阻遏子的交换决定 一个或多个共激活剂络合物。顺序的或组合的 建议招募生物化学上不同的助活剂复合体来 对特定配体的细胞和基因特异性反应的基础。各方面的问题 这一假设将使用生化和基于细胞的分析进行验证，并通过 确定敲除小鼠NCoR和SMRT基因的后果。 这些研究的生物学重点将是探索不同的 辅活化子和辅抑制子复合体是特定程序的基础 维甲酸受体调控的造血分化 (RARs)和过氧化物酶体增殖物激活受体(PPAR)。三个具体的 目标被提出：第一个是检验这样的假设：转录 RAR和PPARGamma靶基因的激活需要顺序或协调 P160/CBP和水滴/陷阱/ARC共激活复合体的招募。这些 实验将解决这些复合体是否起作用的问题 顺序或组合，以及是否需要这两个复合体 不同的PPARGamma和RARpha靶基因。第二个具体目标是 确定NCoR和SMRT在造血调控中的作用。NCoR 基因敲除小鼠因严重贫血在胚胎第16天左右死亡。实验 来定义这种表型的分子基础，并确定 NCoR和SMRT在调节粒细胞分化中的作用 巨噬细胞。第三个具体目标是检验这一假设 PPARγ其他核对核因子-kB靶基因的配体依赖性抑制作用 受体涉及抑制分子向CBP的募集。 共激活剂复合体。PPARGamma、RARpha和许多其他配体依赖 核受体似乎通过抑制核受体发挥重要的生物效应。 其他信号依赖的转录因子的活性在一个 配体依赖的方式。初步研究表明， CBP/p300和其他受体相关蛋白在转录抑制中的作用 进程。总而言之，拟议的研究旨在带来新的见解 共激活因子和共抑制因子在生物化学和生物学中的作用 RARs和PPAR对基因表达的调控。这一知识可能表明 核受体配体开发的新途径 治疗范围广泛的人类疾病。

DESCRIPTION: (Adapted from the applicant's abstract) Members of the nuclear receptor superfamily play critical roles in development and homeostasis by regulating gene expression in response to the binding of small molecular weight ligands. The central hypothesis of this proposal is that transcriptional responses to regulatory ligands are determined by the exchange of corepressor complexes for one or more coactivator complexes. Sequential or combinatorial recruitment of biochemically distinct coactivator complexes is proposed to underlie cell and gene-specific responses to a particular ligand. Aspects of this hypothesis will be tested using biochemical and cell-based assays and by determining the consequences of knocking out the NCoR and SMRT genes in mice. The biological focus of these studies will be to explore whether distinct coactivator and corepressor complexes underlie specific programs of hematopoietic differentiation that are controlled by retinoic acid receptors (RARs) and peroxisome proliferator activated receptors (PPARs). Three specific aims are proposed: The first is to test the hypothesis that transcriptional activation of RAR and PPARgamma target genes requires sequential or coordinate recruitment of p160/CBP and DRIP/TRAP/ARC coactivator complexes. These experiments will address the question of whether these complexes act sequentially or combinatorially, and whether both complexes are required on different PPARgamma and RARalpha target genes. The second specific aim is to determine the roles of NCoR and SMRT in the control of hematopoiesis. The NCoR knockout mice die around embryonic day 16 due to profound anemia. Experiments are proposed to define the molecular basis for this phenotype and determine the roles of NCoR and SMRT in regulating the differentiation of granulocytes and macrophages. The third specific aim is to test the hypothesis that ligand-dependent inhibition of NF-kB-target genes by PPARgamma other nuclear receptors involves the recruitment of inhibitory molecules to the CBP coactivator complex. PPARgamma, RARalpha and many other ligand-dependent nuclear receptors appear to exert important biological effects by inhibiting the activities of other signal-dependent transcription factors in a ligand-dependent manner. Preliminary studies suggest important roles for CBP/p300 and additional receptor-associated proteins in the transrepression process. Together, the proposed studies are intended to lead to new insights into the biochemical and biological roles of coactivators and corepressors in the regulation of gene expression by RARs and PPARs. This knowledge may suggest new approaches for the development of nuclear receptor ligands useful in the treatment of a broad spectrum of human diseases.