SNORNAS ARE ESSENTIAL MEDIATORS OF ROS SIGNALING IN CARDIOVASCULAR CELLS

描述（由申请人提供）：该提案描述了一个为期五年的研究和培训计划，该计划将使Christopher Holley博士成为一名独立的心血管研究员和内科科学家。Holley博士拥有医学博士和医学博士学位，在科学研究和医学方面受过广泛的训练。他完成了内科研究生住院医师培训以及心脏病学临床奖学金培训，特别强调心力衰竭的管理。这项研究计划的主要目标是让Holley博士开发心血管疾病基础科学研究的新技能，这将有助于过渡到专注于热衰竭的独立科学调查。这项研究将在华盛顿大学医学院（St. Louis， MO）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，包括17位诺贝尔奖获得者与医学院有关。心血管科学是华盛顿大学的一个特别强大的领域，有60多名教职员工积极从事研究。这个项目的导师，Dr. Schaffer，是糖尿病心血管并发症领域的国际领导者，有着成功的指导记录。还成立了一个专家咨询委员会，以提供专门的科学投入和额外的职业指导。已提出一项详细的职业发展计划，其中包括经常参加当地讨论会和全国会议，以及提交手稿和最终申请R01的时间表。建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，本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实验室最近发表的一项研究已经确定了三种小核核rna (snorna)，它们是氧化应激的基本介质。本提案提出的初步数据表明，这些snorna影响心脏中的ROS水平，并且它们特异性地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方面进行研究。目的1将描述snoRNAs在正常心脏成纤维细胞增殖过程中调控ROS的作用。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，已知血管紧张素II涉及ros依赖性信号传导。最后的目的是评估这些snorna如何在血管紧张素II输注导致心血管氧化应激和纤维化的小鼠模型中调节ROS和心脏成纤维细胞生物学。

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. PUBLIC HEALTH RELEVANCE: Heart disease is the leading cause of death in the United States, with heart failure affecting three million Americans and leading to 300,000 deaths each year. One important aspect of heart failure is that the heart becomes excessively stiff due to a process known as cardiac fibrosis. The research proposed here will add to our understanding of heart disease by studying how heart cells are activated to produce cardiac fibrosis.