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

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高潮。中环 对动脉粥样硬化斑块的启动和发展起作用的是细胞因子，信号分子 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……里面 具体地说，人类动脉粥样硬化斑块中的几个白介素类成员增加。 家族、肿瘤坏死因子α和干扰素γ。肿瘤坏死因子α和干扰素γ已被证明诱导了比相加水平更大的 动脉粥样硬化的关键介质，包括黏附分子、趋化因子和 抗原提呈途径的组成部分。而转录协同作用传统上被视为 协同转录因子结合在顺式调控元件上的产物，有可能 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，由转录调控 共激活因子--转录因子结合与靶基因之间的重要联系 控制力。我们推测，肿瘤坏死因子α/干扰素γ诱导的协同基因表达是通过 转录周期的动力学调节，这涉及到增加对 多个共激活子，并且这种协同基因诱导可以选择性地通过 用小分子抑制剂联合治疗这些共激活剂。如果是真的，我们相信 这为动脉粥样硬化的治疗提供了一个很有前景的靶点和治疗策略。我们 计划利用高通量测序技术，包括RNA测序和芯片测序 对协同基因涉及的转录和表观遗传机制进行测序 诱导与化学生物学方法一起扰乱这一过程中可能的蛋白质介体。

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.