Mentored training in comprehensive mouse phenotyping (K26)

全面小鼠表型分析的指导培训（K26）

基本信息

批准号：
8487847
负责人：
Daniel E Michele
金额：
$ 7.83万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-15 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8487847
关键词：
Acute Affect Animals Blood Vessels Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Physiology Cardiovascular system Catheterization Cause of Death Cell Survival Cessation of life Chronic Complex Data Development Disease Disease Outcome Disease Progression Dystroglycan Dystrophin ECM receptor Early Ambulation Educational workshop Exercise Fatigue Fibrosis Functional disorder Gene Mutation Gene Targeting Generations Genes Genetic Glycoproteins Goals Health Heart Heart Diseases Hereditary Disease Human Image Individual Inherited Injury Lead Mechanics Mentors Methods Molecular Mouse Strains Mus Muscle Muscle Cells Muscle Weakness Muscle function Muscular Dystrophies Mutant Strains Mice Myocardial Myocardium Myopathy Nitric Oxide Other Genetics Pathogenesis Patients Peripheral Peripheral Resistance Phenotype Physiological Predisposition Proteins Recommendation Research Research Personnel Research Project Grants Role Running Scientist Series Signal Transduction Skeletal Muscle Stress Stretching Telemetry Testing Tissues Training Vasodilation Work cell injury clinically significant disease phenotype glycosylation graduate student heart function in vivo mouse model muscular dystrophy mouse model next generation null mutation protein complex protein function public health relevance response

项目摘要

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.

描述（由申请人提供）：肌营养不良症是一种遗传性进行性肌肉疾病，会导致严重的肌肉无力、心肌病、丧失行走能力和过早死亡。心肌病是 20-30% 患者的死亡原因。超过 30 种不同的基因会导致肌营养不良，其中一些最常见的基因突变会影响肌营养不良蛋白糖蛋白复合物 (DGC) 的表达或功能。与许多遗传疾病一样，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有益，但由于营养不良动物的骨骼肌和心肌对肌肉损伤都很敏感，因此运动对疾病结果的影响以及营养不良患者的活动建议尚不清楚。由于能够概括疾病许多重要方面的目标小鼠品系的出现，我们对肌营养不良症以及许多其他遗传性和获得性疾病的机制的了解有了很大的提高。研究小鼠心血管功能的最先进方法现在可以与许多可在人类身上进行的成像和侵入性导管插入方法相媲美。该提案的指导部分是通过开发和执行一系列模块化、实践短期课程和研讨会来培训研究员、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。该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来：1）从基因角度剖析 DGC 功能丧失对心脏的直接影响与营养不良骨骼肌中假设的外周脉管系统功能障碍之间的相互作用。整体心血管功能；2) 确定急性和慢性运动如何影响营养不良动物心肌病逐渐发展的分子和生理机制。