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: 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
• 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

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)：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·霍利博士作为一名心血管研究员和内科科学家实现独立。霍利博士在科学研究和医学方面受过广泛的培训，拥有医学和博士学位。他已经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开发心血管疾病基础科学研究的新技能，这将促进向以热衰竭为重点的独立科学研究的过渡。这项研究将在华盛顿大学医学院(密苏里州圣路易斯市)马里兰州让·谢弗博士的实验室进行。华盛顿大学在基础科学研究方面有着深厚的历史，其中包括与医学院有联系的17位诺贝尔奖获得者。心血管科学在华盛顿大学是一个特别有优势的领域，有60多名教职员工积极从事研究。该项目的导师谢弗博士是糖尿病心血管并发症领域的国际领导者，在指导方面有着成功的记录。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。提出了一项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，以及手稿和最终的R01申请的时间表。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的体内模型。Schaffer实验室最近发表的工作已经确定了三个小核仁RNA(SnoRNAs)，它们是氧化应激的基本介质。这项研究提供的初步数据表明，这些snoRNAs影响心脏中的ROS水平，并特异性地影响心脏成纤维细胞的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从三个方面进行研究。目的1研究snoRNAs在正常心脏成纤维细胞增殖过程中调节ROS的作用。目的2将研究snoRNAs如何影响血管紧张素II下游的病理性心脏成纤维细胞的增殖和激活，这是已知涉及ROS依赖的信号转导。最终目标将评估这些snoRNAs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。