Coronary Regulation in Dystrophic Cardiomyopathy

描述(由申请人提供)：本提案描述了一个五年的职业发展计划，重点是为首席调查员(PI)提供一个坚实的基础，在此基础上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资助的研究项目。在短期内，这项建议将允许PI开发具有科学重要性的独立研究路线，并从他目前的导师那里产生明显的方向变化。由该奖项资助的工作将在明尼苏达大学约瑟夫·梅茨格博士的实验室进行。梅茨格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主任，拥有成功的博士后研究员和研究生的长期记录，其中许多人在学术界取得了成功的职业生涯。除了梅茨格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，提供科学和职业建议。这项研究将重点放在营养不良心肌病的冠状动脉血流控制上。肌营养不良症的临床研究和动物模型均证明，肌营养不良症患者的冠脉血流调节异常。这里提出的实验重点是Duchenne肌营养不良症和肢体带状肌营养不良症模型(2C和2F)。其具体目的是：1)评价肌营养不良蛋白和肌聚糖复合体在血管内皮细胞切应力和激素介导的血管收缩和血管扩张的变化中对冠状动脉血流的调节作用。2)探讨神经元型一氧化氮合酶(NNOS)与dystrophin在心脏血流自动调节中的机制联系。这项工作将是第一次详细检查营养不良心肌病的冠脉血流调节。明尼苏达大学为基础心血管研究提供了极好的环境。礼来黑心脏研究所提供了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制定强有力的独立调查路线所需的所有资源。

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.