Coronary Regulation in Dystrophic Cardiomyopathy

描述（由申请人提供）：该提案描述了一个五年的职业发展计划，重点是为主要研究者（PI）提供一个强大的基础，以建立一个成功的学术研究计划。PI的长期目标是领导一个强大的NIH资助的研究计划。在短期内，这一提议将允许PI开发独立的研究路线，这些研究路线既具有科学重要性，又能从他目前的导师那里产生明确的方向变化。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的著名权威。他是综合生物学和生理学系的主任，并拥有成功的博士后研究员和研究生的长期记录，其中许多人已经在学术界取得了成功。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。这项研究将集中在营养不良性心肌病的冠状动脉血流控制。肌营养不良症的临床研究和动物模型都提供了证据，表明肌营养不良症中冠状动脉血流的调节是异常的。本文提出的实验集中于Duchenne肌营养不良和肢带型肌营养不良的模型（2C和2F）。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切应力变化和激素介导的血管收缩和血管舒张而调节冠状动脉血流中的作用。2)确定神经元型一氧化氮合酶（nNOS）和肌营养不良蛋白在心脏血流自动调节控制中的机制联系。这项工作将代表第一次详细检查冠状动脉血流调节营养不良性心肌病。明尼苏达大学为基础心血管研究提供了良好的环境。Lillihei心脏研究所提供了优秀的核心资源和强大的合作环境。简而言之，这种环境提供了PI开发强大的独立调查线所需的所有资源。 公共卫生相关性：该项目的重点是冠状动脉灌注的异常调节作为一种潜在的新的致病机制与肌营养不良症相关的心脏病。杜氏肌营养不良症是最常见的致命性遗传疾病，心力衰竭是这些患者的一个新的威胁。该项目将提供深入了解冠状动脉血流调节在这种疾病的病理生理学中的作用。这种理解可能导致新的治疗方法来纠正这种进行性和致命的疾病。

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.