Coronary Regulation in Dystrophic Cardiomyopathy

营养不良性心肌病的冠状动脉调节

• 批准号: 7870613
• 负责人: DeWayne Townsend
• 金额: $ 12.86万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7870613
• 关键词: Academia; Address; Animal Model; Award; Biology; Blood Vessels; Blood flow; Bradykinin; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Case Study; Clinical; Clinical Research; Complex; Contracts; Coronary; Coronary artery; Cytoskeletal Proteins; Development Plans; Disease; Duchenne muscular dystrophy; Dystrophin; Endothelium; Environment; Exhibits; Foundations; Functional disorder; Funding; Gene Transfer; Goals; Heart; Heart Diseases; Heart failure; Hereditary Disease; Hormonal; Hypoxia; Institutes; Investigation; Knowledge; Laboratories; Lead; Limb-Girdle Muscular Dystrophies; Link; Location; Lung diseases; Mediating; Mediator of activation protein; Mentors; Minnesota; Modeling; Muscle; Muscle Cells; Muscle Contraction; Muscular Dystrophies; Myocardial; Nitric Oxide; Nitric Oxide Synthase Type I; Oxygen Consumption; Patients; Physiology; Postdoctoral Fellow; Process; Proteins; Regulation; Research; Research Personnel; Resources; Role; Sarcoglycans; Signal Transduction; Signaling Protein; Skeletal Muscle; Smooth Muscle; Stimulus; Technology; Troponin I; United States National Institutes of Health; Universities; Vascular Smooth Muscle; Vasodilation; Vasospasm; Work; Workload; authority; career; career development; coronary perfusion; graduate student; insight; micro-dystrophin; mouse model; novel; novel therapeutic intervention; programs; public health relevance; release factor; research study; response; restoration; shear stress; skills; vasoconstriction

DESCRIPTION (provided by applicant): This proposal describes a five year career development plan focused on providing the principle investigator (PI) a strong foundation on which to build a successful academic research program. The long-term goal of the PI is to lead a strong NIH funded research program. In the short term this proposal will allow the PI to develop independent lines of research that are both scientifically important and generate a clear change in direction from his current mentor. Work funded by this award will take place at the University of Minnesota in the laboratory of Dr. Joseph Metzger. Dr. Metzger is a noted authority on the utilization of gene transfer technologies to understand cardiac physiology and disease. He is the chair of the department of Integrative Biology and Physiology and has a long track record of successful post-doctoral fellows and graduate students, many of which have gone on to successful careers in academia. In addition to the skills and mentoring of Dr. Metzger, the PI has cultivated a strong network of collaborators and advisors to provide scientific and career advice. The research will focus on the control of coronary artery blood flow in dystrophic cardiomyopathy. Both clinical studies and animal models of muscular dystrophy provide evidence that the regulation of coronary flow is abnormal in muscular dystrophies. The experiments proposed here focus on models of Duchenne muscular dystrophy and limb girdle muscular dystrophy (2C and 2F). The specific aims are: 1) To evaluate the role of dystrophin and sarcoglycan complex in the modulation of coronary flow in response to changes in endothelial shear stress and hormonal mediated vasoconstriction and vasodilation. 2) To determine the mechanistic link between neuronal nitric oxide synthase (nNOS) and dystrophin in the auto-regulatory control of blood flow in the heart. This work will represent the first detailed examination of coronary blood flow regulation in dystrophic cardiomyopathy. The University of Minnesota provides an excellent environment for basic cardiovascular research. The Lillihei Heart Institute provides excellent core resources and a strong collaborative environment. In short, this environment provides all of the resources required for the PI to develop strong independent lines of investigation. PUBLIC HEALTH RELEVANCE: This project focuses on abnormal regulation of coronary perfusion as a potentially novel pathogenic mechanism underlying the heart disease associated with muscular dystrophy. Duchenne muscular dystrophy is the most common fatal genetic disease and heart failure is an emerging threat to these patients. This project will provide insights into the role of coronary blood flow regulation in the pathophysiology of this disease. Such an understanding could lead to novel therapeutic approaches to redress this progressive and fatal disease.

描述（由申请人提供）：该提案描述了一个五年职业发展计划，重点是为首席研究员（PI）提供建立成功的学术研究项目的坚实基础。 PI 的长期目标是领导 NIH 资助的强大研究项目。在短期内，该提案将使 PI 能够开发独立的研究领域，这些研究领域既具有科学重要性，又会使其现任导师的方向发生明显变化。该奖项资助的工作将在明尼苏达大学 Joseph Metzger 博士的实验室进行。 Metzger 博士是利用基因转移技术了解心脏生理学和疾病方面的著名权威。他是综合生物学和生理学系的系主任，拥有长期成功的博士后研究员和研究生记录，其中许多人在学术界取得了成功的职业生涯。除了 Metzger 博士的技能和指导外，PI 还培养了一个强大的合作者和顾问网络，以提供科学和职业建议。该研究将重点关注营养不良性心肌病中冠状动脉血流的控制。肌营养不良症的临床研究和动物模型都提供了肌营养不良症中冠状动脉血流调节异常的证据。这里提出的实验重点关注杜氏肌营养不良症和肢带型肌营养不良症（2C 和 2F）模型。具体目标是： 1) 评估肌营养不良蛋白和肌聚糖复合物在响应内皮剪切应力和激素介导的血管收缩和舒张变化而调节冠状动脉血流中的作用。 2) 确定神经元一氧化氮合酶（nNOS）和抗肌营养不良蛋白在心脏血流自动调节控制中的机制联系。这项工作将代表对营养不良性心肌病冠状动脉血流调节的首次详细检查。明尼苏达大学为基础心血管研究提供了良好的环境。 Lillihei 心脏研究所提供优秀的核心资源和强大的协作环境。简而言之，这种环境为 PI 提供了开发强大的独立调查路线所需的所有资源。 公共健康相关性：该项目重点关注冠状动脉灌注的异常调节，作为与肌营养不良症相关的心脏病的潜在新致病机制。杜氏肌营养不良症是最常见的致命性遗传病，心力衰竭是这些患者面临的新威胁。该项目将深入了解冠状动脉血流调节在该疾病的病理生理学中的作用。这种理解可能会带来新的治疗方法来治疗这种进行性和致命的疾病。