ENDOTHELIAL GENE EXPRESSION CONTROL OF PDGF PRODUCTION

PDGF 产生的内皮基因表达控制

• 批准号: 2217891
• 负责人: Tucker O Collins
• 金额: $ 23.66万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2217891
• 关键词: atherosclerosis; atherosclerotic plaque; cell growth regulation; complementary DNA; cytokine; gel electrophoresis; gene expression; gene induction /repression; genetic promoter element; genetic regulation; genetic regulatory element; genetic transcription; genetic translation; human tissue; mitogens; platelet derived growth factor; protein purification; tissue /cell culture; transcription factor; transfection; vascular endothelium

The initiating event in atherosclerosis is now thought to be a subtle process of endothelial dysfunction. Secretory products produced by dysfunctional endothelial might initiate the migration and proliferation of smooth muscle cells. This model for atherogenesis has been supported by observations that endothelial cells can produce a platelet-derived growth factor (PDGF)-like mitogen. The underlying assumption behind these studies has been that a crucial initial step in atherogenesis consists of increased production of PDGF-like mitogens by endothelium. If this model is correct, then understanding the structure and regulatory mechanisms used by the endothelial cell to control PDGF production would be important advances in the understanding of atherogenesis. PDGF is now know to be a dimer of two chains, designated A and B. Endothelial cDNAs for the A and B chains have been obtained and used to define both the A and B chain genes. This structural information forms the basis of this proposal in which the regulatory mechanisms used by the endothelial cell in controlling expression of these genes will be defined. Regulation of the expression of PDGF by endothelial cells may occur at both the transcriptional and translational levels. In the proposed studies, the transcriptional units of the A and B chain genes will be further defined by characterizing the functional elements in the promoters and defining novel transcriptional regulatory factors. By localizing the functional cis-acting elements in the PDGF A and B chain promoters, it may be possible to elucidate the normal transcriptional control of the gene, as well as mechanisms that may activate it in certain pathologic settings. Also, the identification of novel trans-acting factors interacting with the A and B chain genes may provide new insights into the process of endothelial dysfunction. It is clear that the translation of the PDGF B chain transcript is a relatively inefficient process and therefore a stage at which the expression of the gene could be regulated. The proposed studies will further characterize the translational control of PDGF expression by defining the elements in the 5'untranslated region of the A and B chain genes which inhibit translation and identifying novel putative RNA binding factors regulating this process. Understanding these regulatory events may provide important insights into the control of PDGF expression and may permit the development of new strategies for identifying patients at risk of forming atherosclerotic lesions.

现在认为动脉粥样硬化的起始事件被认为是微妙的 内皮功能障碍的过程。生产的分泌产品 功能失调的内皮可能会引发迁移和扩散 平滑肌细胞。这种动脉粥样形成的模型得到了 观察到内皮细胞可以产生血小板衍生的生长 因子（PDGF）类似丝分裂原。这些研究背后的基本假设 一直是动脉粥样硬化的关键初步步骤包括增加 由内皮产生类似PDGF的有丝分裂剂。如果此模型正确， 然后了解 控制PDGF生产的内皮细胞将是重要的进步 对动脉粥样硬化的理解。现在知道PDGF是两个二聚体 链条，指定为A和B. A和B链的内皮cDNA 已获得并用于定义A和B链基因。这 结构信息构成了该提议的基础 内皮细胞在控制中使用的调节机制 这些基因的表达将被定义。调节表达 内皮细胞的PDGF可能在转录和 翻译水平。在拟议的研究中， 通过表征A和B链基因将进一步定义 启动子中的功能元素并定义新的转录 监管因素。通过将功能性顺式作用元素定位在 PDGF A和B链启动子，有可能阐明正常 基因的转录控制以及可能的机制 在某些病理设置中激活它。另外，识别 与A和B链基因相互作用的新型跨作用因子可能 提供有关内皮功能障碍过程的新见解。这是 清楚的是，PDGF B链转录本的翻译是相对的 效率低下的过程，因此是表达的阶段 可以调节基因。拟议的研究将进一步表征 通过定义PDGF表达的转化控制 抑制翻译的A和B链基因的5'untranslated区域 并确定调节此过程的新型假定RNA结合因子。 了解这些监管事件可能会提供重要的见解 PDGF表达的控制，可能允许开发新的 识别有风险形成动脉粥样硬化的患者的策略 病变。