SNORNAS ARE ESSENTIAL MEDIATORS OF ROS SIGNALING IN CARDIOVASCULAR CELLS

描述（由申请人提供）：本提案描述了一项为期五年的研究和培训计划，该计划将使克里斯托弗霍利博士能够独立成为心血管研究人员和医生科学家。霍利博士在科学研究和医学方面接受过广泛的培训，拥有医学博士和博士学位。他完成了内科的研究生住院医师培训以及心脏病学的临床研究员培训，特别强调心力衰竭的管理。这项研究提案的主要目标是让霍利博士发展心血管疾病基础科学研究的新技能，这将促进向专注于热衰竭的独立科学研究的过渡。 这项研究将在华盛顿大学医学院（圣路易斯，密苏里州）的Jean Schaffer博士的实验室进行。华盛顿大学在基础科学研究方面有着悠久的历史，其中包括17位与医学院有关的诺贝尔奖获得者。心血管科学是华盛顿大学的一个特别优势领域，有60多名教职员工积极参与研究。该项目的导师Schaffer博士是糖尿病心血管并发症领域的国际领导者，并拥有成功的指导记录。还成立了一个专家咨询委员会，提供专门的科学投入和额外的职业指导。已经提出了一个详细的职业发展计划，其中包括定期参加地方研讨会和国家会议，以及手稿和最终R01申请的时间轴。 拟议的研究将集中在心力衰竭和病理性心脏重塑的分子和细胞方面。特别是，这项研究旨在更好地了解活性氧（ROS）和氧化应激如何影响心脏成纤维细胞的增殖和激活，并扩展到心力衰竭和纤维化的体内模型。Schaffer实验室最近发表的工作已经确定了三种小核仁RNA（snoRNA），它们是氧化应激的重要介质。该提案中提出的初步数据表明，这些snoRNA影响心脏中的ROS水平，并且它们特别影响心脏成纤维细胞ROS水平和增殖。这些snoRNA、ROS和心脏成纤维细胞生物学之间的关系将在三个目标中进行检查。目的1研究snoRNA在正常心脏成纤维细胞增殖过程中对ROS的调控作用。目的2将研究snoRNA如何影响病理性心脏成纤维细胞增殖和血管紧张素II下游的激活，这是已知的涉及ROS依赖性信号传导。最后的目标将评估这些snoRNA如何调节ROS和心脏成纤维细胞生物学在血管紧张素II输注导致心血管氧化应激和纤维化的小鼠模型中。

DESCRIPTION (provided by applicant): This proposal describes a five-year research and training program that will allow Dr. Christopher Holley to achieve independence as a cardiovascular researcher and physician-scientist. Dr. Holley has broad training in scientific research and medicine, with both MD and PhD degrees. He has completed post-graduate residency training in Internal Medicine as well as clinical fellowship training in Cardiology, witha special emphasis on the management of heart failure. The primary objective of this research proposal is to allow Dr. Holley to develop new skills for basic science research in cardiovascular disease, which will facilitate a transition to independent scientific investigations focused on heat failure. The research will take place at the Washington University School of Medicine (St. Louis, MO), in the laboratory of Dr. Jean Schaffer, MD. Washington University has a strong history of basic science research, including 17 Nobel Laureates that have been associated with the School of Medicine. Cardiovascular science is an area of particular strength at Washington University, with over 60 faculty members actively engaged in research. The mentor for this project, Dr. Schaffer, is an international leader in the area of diabetic cardiovascular complications and has a successful track record of mentoring. An expert advisory committee has also been formed to provide specialized scientific input and additional career guidance. A detailed career development plan has been proposed that includes regular participation in local seminars and national meetings, as well as a timeline for manuscripts and an eventual R01 application. The proposed research will focus on molecular and cellular aspects of heart failure and pathologic cardiac remodeling. In particular, this research seeks to better understand how reactive oxygen species (ROS) and oxidative stress influence the proliferation and activation of cardiac fibroblasts, with extension to an in vivo model of heart failure and fibrosis. Work that wa recently published by the Schaffer laboratory has identified three small nucleolar RNAs (snoRNAs) that are essential mediators of oxidative stress. Preliminary data presented in this proposal suggests that these snoRNAs influence ROS levels in the heart, and that they specifically influence cardiac fibroblast ROS levels and proliferation. The relationship between these snoRNAs, ROS, and cardiac fibroblast biology will be examined in three Aims. Aim 1 will characterize the role of snoRNAs in the regulation of ROS during normal cardiac fibroblast proliferation. Aim 2 will examine how the snoRNAs influence pathologic cardiac fibroblast proliferation and activation downstream of angiotensin II, which is known to involve ROS-dependent signaling. The final Aim will assess how these snoRNAs regulate ROS and cardiac fibroblast biology in a mouse model of angiotensin II infusion that results in cardiovascular oxidative stress and fibrosis.