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Collagen Transcription and Lung Fibrosis

胶原蛋白转录和肺纤维化

基本信息

批准号：
7623960
负责人：
BARBARA Davis SMITH
金额：
$ 38.28万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-07-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7623960
关键词：
Affinity Animals Attenuated Binding Biological Assay Bleomycin Boxing C-terminal Cell Nucleus Cells Chromatin Chromatin Structure Clinical Trials Collagen Collagen Gene Collagen Type I Complex Connective Tissue Cytokine Signaling DNA DNA Polymerase II Data Development Dominant-Negative Mutation Enhancers Fibroblasts Fibrosis Funding GTP Binding Gene Expression Genetic Transcription Human Infection Inflammation Inflammatory Inflammatory Response Injury Interferon Type II Interferons Lentivirus Vector Lung MHC class II transactivator protein Major Histocompatibility Complex Measures Mediating Modeling Mus Mutation Post-Translational Protein Processing Process Production Protein Binding Protein Family Proteins Pulmonary Fibrosis RFX regulatory factor RNA RNA Polymerase II Recruitment Activity Repression Research Personnel Role Site T-Cell Activation Testing Transactivation Transcription Initiation Site Transcriptional Regulation Transfection Transforming Growth Factor beta Transforming Growth Factors chromatin immunoprecipitation cytokine gene repression human CREB1 protein injury and repair interstitial lung injury mutant programs promoter protein complex protein function repaired response response to injury transforming growth factor beta3

项目摘要

DESCRIPTION (provided by applicant): Certain lung injuries induce large increases in connective tissue content, particularly collagen, resulting in pulmonary fibrosis. During injury, inflammation, and repair, cells are exposed to molecules such as interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta) that are released by inflammatory cells and regulate production of collagen. Collagen type I transcription is activated after inflammatory response to injury in order to repair damage. This process is followed by repression of transcription. Without transcriptional repression, progressive fibrosis results in the lung. We hypothesize that changes in transcription require multiple proteins interacting cooperatively to alter transcription and chromatin structure in response to cytokine signals. During the last funding period, we focused on the mechanism of IFN-gamma induced repression of collagen transcription. IFN-gamma increases expression of regulatory factor for X-box 5 (RFX5) complex proteins which localizes in the nucleus, interacts with the collagen gene transcriptional start site and represses collagen synthesis. Class II transactivator (CIITA) dramatically increases early during IFN-gamma treatment and interacts with RFX5 complex. IFN-gamma-induced CIITA protein is responsible for both activation of major histocompatibility complex (MHC) and repression of collagen gene expression. Clinical trials for interstitial pulmonary fibrosis with IFN-gamma have been unsuccessful due to increased inflammatory response. We hypothesize that RFX5/CIITA proteins may be responsible for activating inflammatory responses while repressing collagen through separate CIITA transactivation and repression domains. We have compelling evidence that many proteins including co-repressors bind to the collagen start site during repression. Activation by agents such as TGF-beta may recruit different proteins to the collagen gene. The specific aims are to; 1) Determine the proteins interacting with the collagen start site during IFN-gamma treatment. 2) Examine the functional interactions of activation proteins binding upstream in the promoter with RFX family of proteins with and without TGF-beta. 3) Examine bleomycin induced fibrosis in animals with CIITA mutations and/or deficiencies with and without collagen-promoter-CAT constructs to investigate inflammation and collagen transcriptional regulation during fibrosis.

描述（由申请人提供）：某些肺损伤引起结缔组织含量，特别是胶原蛋白含量的大量增加，导致肺纤维化。在损伤、炎症和修复过程中，细胞暴露于炎症细胞释放的干扰素- γ (ifn - γ)和转化生长因子- β (tgf - β)等分子中，并调节胶原蛋白的产生。I型胶原蛋白转录在炎症反应后被激活，以修复损伤。这个过程之后是转录抑制。没有转录抑制，进行性纤维化导致肺。我们假设转录的变化需要多种蛋白质协同作用来改变转录和染色质结构，以响应细胞因子信号。在上一个资助期间，我们专注于ifn - γ诱导胶原转录抑制的机制。ifn - γ增加X-box 5 （RFX5）复合物蛋白调控因子的表达，该蛋白定位于细胞核，与胶原基因转录起始位点相互作用，抑制胶原合成。II类transactivator （CIITA）在ifn - γ治疗早期显著增加，并与RFX5复合物相互作用。ifn - γ诱导的CIITA蛋白负责主要组织相容性复合体（MHC）的激活和胶原基因表达的抑制。ifn - γ治疗间质性肺纤维化的临床试验由于炎症反应增加而失败。我们假设RFX5/CIITA蛋白可能负责激活炎症反应，同时通过单独的CIITA转激活和抑制域抑制胶原蛋白。我们有令人信服的证据表明，在抑制期间，许多蛋白质包括共同抑制因子结合到胶原蛋白的起始位点。tgf - β等物质的激活可能会将不同的蛋白质招募到胶原蛋白基因中。具体目标是：1)确定ifn - γ治疗期间与胶原起始位点相互作用的蛋白。2)检查启动子上游结合的激活蛋白与RFX家族蛋白（含tgf - β和不含tgf - β）的功能相互作用。3)在CIITA突变和/或缺乏的动物中检测博来霉素诱导的纤维化，有无胶原蛋白启动子- cat结构，以研究纤维化期间的炎症和胶原转录调节。