Mentored training in comprehensive mouse phenotyping (K26)

全面小鼠表型分析的指导培训（K26）

• 批准号: 8681572
• 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
• 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/8681572
• 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

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）：肌营养不良是一种遗传性、进行性肌肉疾病，可导致严重肌无力、心肌病、截肢和早逝。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营养不良症，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）的蛋白质的表达或功能。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有益，但由于营养不良动物的骨骼肌和心肌对肌肉损伤敏感，因此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。我们对肌营养不良症以及许多其他遗传和获得性疾病的机制的理解已经大大增长，这是由于目标小鼠品系的可用性，这些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新方法现在可以与许多可以在人类中进行的成像和侵入性导管插入术方法相媲美。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研讨会来指导下一代研究人员进行最先进的综合心血管表型分析，以培训研究员，研究生和独立科学家。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分析方法，1）从遗传学角度剖析DGC功能丧失对心脏的直接影响与营养不良骨骼肌中外周血管系统功能障碍对整体心血管功能的假设之间的相互作用，以及2）确定急性和慢性运动如何影响营养不良动物心肌病进展的分子和生理机制。