Mentored training in comprehensive mouse phenotyping (K26)

描述（由申请人提供）：肌肉萎缩症是一种遗传性进行性肌肉疾病，可导致严重的肌肉无力、心肌病、行动能力丧失和早期死亡。心肌病是20-30%患者死亡的原因。超过30种不同的基因导致肌肉营养不良，其中一些最常见的基因突变影响肌营养不良蛋白糖蛋白复合物（DGC）蛋白的表达或功能。像许多遗传疾病一样，由此产生的疾病表型代表了主要基因突变对肌肉和心脏的直接影响，以及影响整体肌肉和心脏功能的次要表型和环境影响的组合。虽然运动等环境影响对健康个体的肌肉和心脏是有益的，因为营养不良动物的骨骼肌和心肌对肌肉损伤都很敏感，但运动对疾病结局的影响以及营养不良患者的活动建议尚不清楚。我们对肌肉萎缩症和许多其他遗传和获得性疾病的机制的理解已经大大增加，这是由于可获得的靶向小鼠品系概括了疾病的许多重要方面。研究小鼠心血管功能的最先进的方法现在可以与许多可以在人类身上进行的成像和侵入性导管置入方法相媲美。该提案的指导部分是通过开发和执行一系列模块化的实践短期课程和讲习班来培训研究员，研究生和独立科学家，指导下一代研究人员进行最先进的综合心血管表型分析。本提案的研究项目部分将利用最先进的无线电遥测和心脏表型方法，1)从遗传学上剖析DGC功能丧失对心脏的直接影响与营养不良骨骼肌周围血管功能障碍对整体心血管功能的假设之间的相互作用；2)确定急性和慢性运动如何影响渐进式发展的分子和生理机制营养不良动物的心肌病。

DESCRIPTION (provided by applicant): Muscular dystrophies are inherited, progressive muscle disorders that result in severe muscle weakness, cardiomyopathy, loss of ambulation and early death. Cardiomyopathy is the cause of death in 20-30% of patients. More than 30 different genes cause muscular dystrophy with some of the most common gene mutations affecting the expression or function of the proteins of the dystrophin glycoprotein complex (DGC). Like many genetic diseases, the resulting disease phenotypes represent a combination of direct effects of the primary gene mutation on muscle and the heart, and secondary phenotypes and environmental influences that impact overall muscle and heart function. While environmental influences such as exercise are beneficial for muscle and hearts of healthy individuals, because both skeletal and cardiac muscles in dystrophic animals are sensitive to muscle injury, the impact of exercise on disease outcome and recommendations for activity in dystrophic patients are not clear. Our understanding of the mechanisms of muscular dystrophy, and many other genetic and acquired diseases, has grown considerably due to the availability of targeted mouse strains that recapitulate many important aspects of disease. State of the art approaches to study cardiovascular function in mice now rival many of the imaging and invasive catheterization methods that can be performed in humans. A mentoring portion of this proposal is to mentor the next generation of investigators in state of the art comprehensive cardiovascular phenotyping though development and execution of a series of modular, hands-on short courses and workshops to train fellows, graduate students and independent scientists. The research project portion of this proposal will take advantage state of the art radiotelemetry and cardiac phenotyping approaches to 1) genetically dissect the interplay between direct effects of loss of DGC function on the heart and the hypothesized dysfunction of the peripheral vasculature in dystrophic skeletal muscle on overall cardiovascular function and 2) Determine the molecular and physiological mechanisms of how acute and chronic exercise impact the progressive development of cardiomyopathy in dystrophic animals.