Collagen Gene Expression and Atherosclerosis

胶原蛋白基因表达与动脉粥样硬化

• 批准号: 6599673
• 负责人: BARBARA Davis SMITH
• 金额: $ 9.39万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2003-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6599673
• 关键词: apolipoprotein E; atherosclerosis; binding sites; cell proliferation; collagen; gene expression; genetic regulation; genetically modified animals; immunoprecipitation; interferon gamma; laboratory mouse; methylation; muscle cells; pathologic process; protein biosynthesis; protein isoforms; protein protein interaction; protein structure function; simvastatin; smooth muscle; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Atherosclerotic lesions begin as fatty streaks that can develop into mature lesions consisting of monocytes/macrophages, T lymphocytes and smooth muscle cells (SMCs), a necrotic core and a fibrous cap containing extracellular matrix components. Plaque rupture at the shoulder region and at sites of thinning in the fibrous cap overlying the lipid-rich core is a likely cause of myocardial infarction. This process is the result of chronic inflammation and is accompanied by cytokines, including interferon-gamma (IFN-y). IFN-y activates major histocompatibility class II (MHC II) gene transcription by inducing transcription of the class II transcriptional activator (CIITA). Recently, we have demonstrated that the collagen type I genes have an RFX binding site at the collagen type I transcription start sites and that RFX5 interacts with CIITA only after IFN-7 stimulation. Collagen synthesis is down regulated by CIITA and IFN-7 decreases collagen gene transcription through CIITA. Our hypotheses are that collagen repression occurs at the RFX site through cooperative interactions with CIITA and that INF-y stimulation of SMCs leads to lowered fibrous cap stability. An HMG-CoA reductase inhibitor, simvastatin, blocks IFNy-induced activation of MHC-II by inhibiting synthesis of CIITA. In addition to their well-known role in reducing lipid synthesis, statins increase collagen gene expression, reduce inflammation, inhibit cell proliferation, and decrease MMP accumulation in atheromas. We propose that these processes occur through the blocking of CIITA induction. We hypothesize that the statins lead to increased collagen synthesis by blocking IFN-gamma induction of CIITA through a lipid intermediate. RFX1 binds with high affinity to the methylated collagen gene transcription start site and can repress collagen gene transcription when over-expressed. The collagen gene is methylated at the RFX site in proliferating SMCs. Therefore, we hypothesize that, during SMC proliferation accompanying the development of aterhosclerotic lesions, the collagen gene is methylated, increasing binding of RFXI. Our specific aims are to 1. Investigate CIITA-mediated regulation of collagen type I gene transcription by SMCs. 2. Examine whether statins increase collagen type I gene expression by blocking IFN-7 induction of CIITA and/or by blocking proliferation. 3. Study collagen type I expression and accumulation in vascular lesions in vivo using transgenic mice models.

描述（由申请人提供）：动脉粥样硬化病变开始于脂肪条纹开始，这些条纹可以发展成由单核细胞/巨噬细胞，T淋巴细胞和平滑肌细胞（SMC），坏死性核心和纤维帽组成的成熟病变。肩部区域和纤维帽中稀疏部位的斑块破裂可能是心肌梗塞的原因。该过程是慢性炎症的结果，并伴有细胞因子，包括干扰素 - γ（IFN-Y）。 IFN-Y通过诱导II类转录激活剂（CIITA）的转录来激活主要的组织相容性II类（MHC II）转录。最近，我们证明了I型胶原蛋白基因在胶原型I型转录起始位点具有RFX结合位点，并且RFX5仅在IFN-7刺激后才与CIITA相互作用。胶原蛋白合成受CIITA的调节，IFN-7通过CIITA降低胶原基因转录。我们的假设是，胶原蛋白抑制是通过与CIITA的合作相互作用在RFX部位发生的，而对SMC的INF-y刺激导致纤维帽稳定性降低。 HMG-COA还原酶抑制剂辛伐他汀通过抑制CIITA的合成来阻断IFNY诱导的MHC-II的激活。除了其在减少脂质合成中的众所周知的作用外，他汀类药物还会增加胶原蛋白基因的表达，减少炎症，抑制细胞增殖并减少动脉瘤中MMP的积累。我们建议这些过程通过阻止CIITA诱导发生。我们假设他汀类药物通过通过脂质中间体阻断CIITA的IFN-gamma诱导而导致胶原蛋白的合成增加。 RFX1与甲基化的胶原基因转录起始位点具有高亲和力结合，并在过表达时可以抑制胶原基因转录。在增殖的SMC中，胶原基因在RFX位点被甲基化。因此，我们假设，在伴随着牙本质病变发展的SMC增殖过程中，胶原基因是甲基化的，从而增加了RFXI的结合。我们的具体目的是1。研究CIITA介导的SMC对I型基因转录的调节。 2。汀类药物是否通过阻断CIITA和/或阻断增殖来阻止IFN-7诱导IFN-7来增加I型胶原蛋白的表达。 3。使用转基因小鼠模型研究胶原蛋白I型表达和体内血管病变的积累。