SNORNAS ARE ESSENTIAL MEDIATORS OF ROS SIGNALING IN CARDIOVASCULAR CELLS

SNORNAS 是心血管细胞中 ROS 信号传导的重要介质

基本信息

批准号：
8706952
负责人：
Christopher Lee Holley
金额：
$ 11.32万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8706952
关键词：
Advisory Committees Affect American Angiotensin II Area Basic Science Biological Models Biology Cardiac Cardiology Cardiovascular Diseases Cardiovascular system Cause of Death Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Cycle Proteins Cell Death Cell Proliferation Cells Cessation of life Chronic Clinical Cyclin-Dependent Kinase Inhibitor Cyclins Cytoplasm Data Deposition Development Plans Disease Doctor of Philosophy Event Exposure to Extracellular Matrix Faculty Failure Fellowship Fibroblasts Fibrosis Functional RNA G2/M Arrest Genes Genetic Heart Heart Diseases Heart failure Heating Histone H3 Histopathology Hydrogen Peroxide Hypertension Hypertrophy Inflammatory Infusion procedures Internal Medicine International Investigation Laboratories Link Lipopolysaccharides Manuscripts Mediator of activation protein Medicine Mentors Metabolic Molecular Myocardial Myocardial Infarction Myocardium Nature Neonatal Oxidative Stress Pathologic Physicians Process Production Proteins Publishing Rattus Reactive Oxygen Species Recording of previous events Regulation Research Research Personnel Research Proposals Research Training Residencies Role Saturated Fatty Acids Science Scientist Signal Pathway Signal Transduction Small Nucleolar RNA Source Structure Testing TimeLine Training Training Programs United States Universities Ventricular Remodeling Washington Work base career career development diabetic gain of function heart cell in vivo in vivo Model loss of function medical schools meetings member mouse model overexpression research study response skills

项目摘要

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.

描述（由申请人提供）：该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（Christopher Holley）博士成为心血管研究人员和医师科学家的独立性。 Holley博士在MD和PHD学位的科学研究和医学方面都接受了广泛的培训。他已经完成了内科医学研究生的居住培训以及心脏病学临床奖学金培训，并特别强调了心力衰竭的管理。这项研究建议的主要目的是允许Holley博士为心血管疾病的基础科学研究提供新的技能，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（密苏里州圣路易斯）的医学博士实验室。华盛顿大学拥有基础科学研究的悠久历史，其中包括与医学院相关的17项诺贝尔奖获得者。心血管科学是华盛顿大学特殊力量的领域，有60多名教职员工积极从事研究。该项目的指导者Schaffer博士是糖尿病心血管并发症领域的国际领导者，并成功地指导了指导记录。还成立了一个专家咨询委员会，以提供专业的科学意见和其他职业指导。已经提出了一项详细的职业发展计划，其中包括定期参加当地研讨会和国家会议，以及手稿的时间表和最终的R01申请。拟议的研究将着重于心力衰竭和病理心脏重塑的分子和细胞方面。特别是，这项研究试图更好地了解活性氧（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体内模型。 Schaffer实验室最近发表的WA的工作确定了三个小核RNA（SNORNA），它们是氧化应激的必不可少的介体。该提案中介绍的初步数据表明，这些snornas会影响心脏中的ROS水平，并且特别影响心脏成纤维细胞ROS水平和增殖。这些snornas，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。 AIM 1将表征SNORNA在正常心脏成纤维细胞增殖过程中ROS调节中的作用。 AIM 2将检查SNORNA如何影响血管紧张素II下游的病理心脏成纤维细胞增殖和激活，这涉及ROS依赖性信号传导。最终目标将评估这些snoRAS在血管紧张素II输注的小鼠模型中如何调节ROS和心脏成纤维细胞生物学，从而导致心血管氧化应激和纤维化。