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）建立一个成功的学术研究计划奠定坚实的基础。PI的长期目标是领导一个强大的NIH资助的研究项目。在短期内，这项提议将使PI能够发展独立的研究路线，这些研究路线在科学上具有重要意义，并且可以明确改变他当前导师的方向。由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来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主任，长期以来培养了一批成功的博士后和研究生，其中许多人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。本研究将聚焦于营养不良型心肌病的冠状动脉血流控制。肌营养不良的临床研究和动物模型均表明，肌营养不良患者的冠状动脉血流调节异常。本文提出的实验重点是杜氏肌营养不良和肢带肌营养不良模型（2C和2F）。具体目的是：1)评估肌营养不良蛋白和肌糖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血管舒张变化的冠状动脉血流调节中的作用。2)探讨神经元一氧化氮合酶（nNOS）与肌营养不良蛋白（dystrophin）在心脏血流自动调节中的作用机制。这项工作将代表在营养不良型心肌病冠状动脉血流调节的第一个详细检查。明尼苏达大学为基础心血管研究提供了良好的环境。利利黑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，这种环境提供了PI开发强大的独立调查线所需的所有资源。

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.