"Investigating the Regulation of TNFα/IFNγ Synergy by Transcriptional Coativators in Endothelial Cells"

“研究内皮细胞转录共激活剂对 TNFα/IFNγ 协同作用的调节”

• 批准号: 9761007
• 负责人: Selma Zaki Elsarrag
• 金额: $ 4.54万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761007
• 关键词: Affect; Antigen Presentation; Antigen Presentation Pathway; Arterial Fatty Streak; Atherosclerosis; Binding; Biology; Cell Adhesion Molecules; Cells; ChIP-seq; Chemicals; Chronic; Complex; Cytokine Signaling; DNA Polymerase II; DNA-Directed RNA Polymerase; Dose; Elements; Endothelial Cells; Endothelium; Enhancers; Epigenetic Process; Exhibits; Exposure to; Family; Gene Expression; Genes; Genetic Transcription; Histones; Human; Individual; Inflammatory; Inflammatory Response; Interferon Type II; Interleukins; Kinetics; Leukocytes; Link; Lysine; Measurement; Measures; Mediating; Mediator of activation protein; Process; Proteins; RNA; Reader; Regulation; Regulatory Element; Research; Signaling Molecule; Smooth Muscle Myocytes; Stimulus; TNF gene; Techniques; Transcription Coactivator; Transcriptional Regulation; Variant; Vascular Smooth Muscle; cell injury; chemokine; chromatin modification; cofactor; cytokine; gene induction; genome-wide; inhibitor/antagonist; member; novel therapeutics; programs; promoter; protein complex; recruit; response; small molecule inhibitor; synergism; targeted treatment; transcription factor; transcription factor TFIIH; transcriptome sequencing

Project Summary Atherosclerosis is the culmination of a chronic inflammatory response to endothelial cell injury. Central to the initiation and progression of atherosclerotic plaques are cytokines, signaling molecules which are secreted by and act on leukocytes, endothelial cells, and vascular smooth muscle cells. In particular, human atherosclerotic plaques exhibit an increase in several members of the interleukin family, TNFα, and IFNγ. TNFα and IFNγ have been shown to induce a greater than additive level of expression of key mediators of atherosclerosis, including adhesion molecules, chemokines, and components of antigen presentation pathways. While transcriptional synergy is traditionally viewed as the product of cooperative transcription factor binding at cis-regulatory elements, it is possible for synergism to be induced via control of rate limiting steps in the transcription cycle. These steps, primarily RNA polymerase recruitment and pause release, are controlled by transcriptional coactivators which are emerging as critical links between transcription factor binding and target gene control. We hypothesize that TNFα/IFNγ induced synergistic gene expression is mediated via kinetic regulation of the transcriptional cycle, that this involves increased recruitment of multiple coactivators, and that synergistic gene induction can be selectively perturbed via combination treatment with small molecule inhibitors of these coactivators. If true, we believe this represents a promising target and therapeutic strategy in the treatment of atherosclerosis. We plan to utilize high-throughout sequencing techniques including RNA-sequencing and Chip- sequencing to characterize the transcriptional and epigenetic mechanisms involved in synergistic gene induction along with a chemical biology approach to perturb likely protein mediators of this process.

项目摘要 动脉粥样硬化是对内皮细胞损伤的慢性炎症反应的顶点。中央 与动脉粥样硬化斑块的发生和发展有关的是细胞因子， 由白细胞、内皮细胞和血管平滑肌细胞分泌并作用于它们。在 特别地，人动脉粥样硬化斑块表现出白细胞介素 家族、TNFα和IFNγ。TNFα和IFNγ已被证明可诱导高于相加水平的 动脉粥样硬化的关键介质的表达，包括粘附分子，趋化因子， 抗原呈递途径的组分。虽然转录协同作用传统上被视为 协同转录因子在顺式调节元件上结合的产物， 通过控制转录循环中的限速步骤来诱导协同作用。这些步骤， 主要是RNA聚合酶的募集和暂停释放，是由转录控制的。 作为转录因子结合和靶基因之间的关键环节出现的辅激活因子 控制我们假设TNFα/IFNγ诱导的协同基因表达是通过以下途径介导的： 转录周期的动力学调节，这涉及增加招募 多个共激活因子，并且协同基因诱导可以通过以下方式选择性地干扰： 与这些共活化剂的小分子抑制剂的组合治疗。如果是真的，我们相信 这代表了动脉粥样硬化治疗中有希望的靶点和治疗策略。我们 计划利用高通量测序技术，包括RNA测序和芯片， 测序以表征协同基因中涉及的转录和表观遗传机制 诱导沿着化学生物学方法以干扰该过程可能蛋白质介体。