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

• 批准号: 8345261
• 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
• 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/8345261
• 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

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.

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 Christopher Holley 博士能够实现作为心血管研究人员和医师科学家的独立。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。他完成了内科住院医师研究生培训以及心脏病学临床进修培训，特别侧重于心力衰竭的治疗。这项研究计划的主要目标是让霍利博士能够开发心血管疾病基础科学研究的新技能，这将有助于向专注于热衰竭的独立科学研究过渡。 该研究将在华盛顿大学医学院（密苏里州圣路易斯）Jean Schaffer 博士的实验室进行。华盛顿大学拥有悠久的基础科学研究历史，其中包括 17 名诺贝尔奖获得者与医学院有联系。心血管科学是华盛顿大学的优势领域，有 60 多名教职员工积​​极从事研究。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，拥有成功的指导记录。还成立了一个专家咨询委员会，以提供专业的科学投入和额外的职业指导。已提出详细的职业发展计划，包括定期参加当地研讨会和全国会议，以及稿件和最终 R01 申请的时间表。 拟议的研究将重点关注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活化，并扩展到心力衰竭和纤维化的体内模型。 Schaffer 实验室最近发表的研究成果鉴定出三种小核仁 RNA (snoRNA)，它们是氧化应激的重要介质。该提案中提供的初步数据表明，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研究。目标 1 将描述 snoRNA 在正常心脏成纤维细胞增殖过程中 ROS 调节中的作用。目标 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。最终目标将评估这些 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。 公共卫生相关性：心脏病是美国的首要死因，心力衰竭影响 300 万美国人，每年导致 30 万人死亡。心力衰竭的一个重要方面是心脏由于心脏纤维化的过程而变得过度僵硬。这里提出的研究将通过研究心脏细胞如何被激活以产生心脏纤维化来增加我们对心脏病的理解。