Transcriptional co-regulators and macrophage gene expression

转录共调节因子和巨噬细胞基因表达

基本信息

批准号：
8432849
负责人：
Christopher K Glass
金额：
$ 43.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-04-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432849
关键词：
Accounting Actins Address Anti-Inflammatory Agents Anti-inflammatory Binding Biological Process Chronic Chronic Disease Complex Development Diabetes Mellitus Disease Docking Enzymes Excision Gene Activation Gene Expression Gene Targeting Genes HDAC3 gene Histone Acetylation Histone Deacetylase Histones Homeostasis IL13RA1 gene Immune Immunity Individual Inflammation Inflammatory Inflammatory Response Insulin Resistance Intervention Ligation Maintenance Malignant Neoplasms Mediating Methylation Microglia Molecular Normal tissue morphology Nuclear Orphan Receptor Nuclear Receptors Pathway interactions Pattern Phase Play Polycomb Process Proteins Receptor Signaling Recruitment Activity Repression Research Resolution Role Signal Pathway Signal Transduction Site TLR4 gene Testing Therapeutic Intervention Toll-like receptors Transcriptional Activation Transcriptional Regulation Work base brain cell demethylation histone acetyltransferase insight macrophage novel therapeutic intervention p65 pathogen prevent programs promoter public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Precise control of inflammation is essential for effective immunity and the maintenance of normal tissue homeostasis. Work performed under the current period of support led to the discovery of two co-repressor dependent mechanisms that enable nuclear receptors to inhibit Toll-like receptor (TLR)-dependent gene expression in a context and gene-specific manner. The first mechanism involves NCoR and SMRT co- repressor complexes. These complexes reside on the promoters of many TLR-responsive genes under basal conditions and are cleared in response to TLR ligation as a prerequisite to gene activation. These complexes can therefore be considered to impose 'checkpoint' functions that prevent spurious gene activation in the absence of a strong activating signal. PPARs and LXRs exert repressive effects on this subset of genes by inhibiting the signal-dependent clearance of NCoR/SMRT complexes. The second repression mechanism involves Co-REST/LSD1 corepressor complexes, which we recently found to function in an anti-inflammatory pathway in microglia, the main innate immune cells of the brain. In this pathway, the orphan nuclear receptor Nurr1 is induced in response to TLR signaling and recruits CoREST/LSD1 co-repressor complexes to p65 at NFkB-responsive promoters. This acts to facilitate p65 turnover and re-establish a basal state of gene expression. Several new questions have emerged from these findings that will be addressed in this proposal. Specific Aim 1 will be to define the molecular mechanisms that enable NCoR complexes to exert their checkpoint functions at TLR4 target genes. Specific Aim 2 will be to define mechanisms underlying signal dependent turnover of NCoR from TLR-responsive genes and the molecular basis for inhibition of this step by LXRs and PPAR3. Specific Aim 3 will be to define roles of the NR4/CoREST/LSD1 transrepression pathway in resolution of pro-inflammatory gene expression and the functional relationship of this pathway to the NCoR/SMRT checkpoint functions. Overall, these studies will provide new insights into molecular mechanisms that are utilized to integrate pro- and anti-inflammatory signaling pathways at the level of individual promoters and are likely to identify new points for intervention in transcriptional programs that contribute to cancer, insulin resistance and chronic inflammatory diseases.

描述（由申请人提供）：精确控制炎症对于有效免疫和维持正常组织稳态至关重要。在当前支持时期进行的工作导致发现了两个共抑制剂依赖机制，这些机制使核受体能够在上下文和基因特异性方式中抑制类似Toll样受体（TLR）依赖性基因表达。第一种机制涉及NCOR和SMRT共抑制配合物。这些复合物位于许多基础条件下许多TLR响应基因的启动子上，并响应TLR连接作为基因激活的先决条件而被清除。因此，这些复合物可以被认为施加“检查点”功能，以防止在没有强激活信号的情况下进行虚假基因激活。 PPAR和LXRS通过抑制NCOR/SMRT复合物的信号依赖性清除率对基因的这一子集发挥抑制作用。第二种抑制机制涉及共同/LSD1 COREPRESSOR复合物，我们最近发现在小胶质细胞（大脑的主要先天免疫细胞）的抗炎途径中起作用。在此途径中，孤儿核受体Nurr1是响应TLR信号传导而诱导的，并在NFKB响应启动子处招募Corest/LSD1共抑制络合物到P65。这可以促进p65周转率并重新建立基因表达的基础状态。这些发现将在本提案中解决的这些发现中提出了一些新问题。具体目标1将是定义能够在TLR4靶基因上发挥其检查点功能的分子机制。具体目的2将是定义来自TLR响应基因的NCOR信号依赖性周转的基础机制，以及通过LXRS和PPAR3抑制此步骤的分子基础。具体目标3将是定义NR4/Corest/LSD1反抑制途径在促炎基因表达的分辨率以及该途径与NCOR/SMRT检查点函数的功能关系中的作用。总体而言，这些研究将为分子机制提供新的见解，这些见解可用于整合单个启动子水平上的促和抗炎信号传导途径，并可能确定有助于癌症，胰岛素抵抗和慢性炎症疾病的转录程序的新点。