GENETIC MODIFICATION OF STRIATED MUSCLES DURING AGING

本计划项目申请旨在探索 影响横纹肌的遗传性疾病，这些疾病是如何 受正常衰老过程的影响，它还寻求开发基因 治疗这些疾病的治疗方法。申请者是 对老龄问题感兴趣的不同和基础广泛的研究人员群体， 肌肉结构-功能关系、遗传性肌肉疾病和基因 心理治疗。附属项目的重点是心肌和骨骼肌。 并汇集了老年学、生理学、 分子生物学和遗传学。项目1寻求开发一种新的 缺乏所有病毒基因的腺病毒载体，可以将 将基因转化为幼年和老年动物的横纹肌。项目2旨在 更好地理解肌营养不良相关蛋白的作用 横纹肌中的蛋白质复合体，编码该蛋白的基因突变如何 这种复合体的蛋白质导致肌营养不良症(CDS)，以及它是如何 正常衰老是MDS的病理机制之一。项目3探索 肥厚性心肌病，旨在开发腺病毒载体 将基因转移到心脏作为纠正遗传的一种机制 心脏疾病在疾病发展的不同阶段。这些 项目将得到四个核心实验室的支持。核心1是一个 行政核心以协调单独的项目。核心2是一种病毒 载体核心提供腺病毒载体的大规模生长和 帮助他们使用它们。核心3是动物模型/免疫学核心 将为这些研究安置动物，提供兽医护理和 协议方面的帮助，它还将提供详细的 免疫学方法研究腺病毒载体的免疫应答 调职。核心45我们将衡量变化的可伸缩性核心 正常和病变肌肉老化过程中的肌肉收缩特性 以腺病毒为基础的基因转移到横纹肌之后。这些 这些项目将使人们更好地了解肌肉疾病和 老龄化，并将有助于开发遗传疗法 骨骼肌和心肌疾病。

This program project application is designed to explore mechanisms of genetic diseases that affect striated muscle, how these diseases are affected by the normal aging process, and it also seeks to develop gene therapy approaches for treating these diseases. The applicants are a diverse and broad based group of researchers with interests in ageing, muscle structure-function relationships, genetic muscle diseases, and gene therapy. The affiliated projects focus on cardiac and skeletal muscle disease and bring together the fields of gerontology, physiology, molecular biology, and genetics. Project 1 seeks to develop a new class of adenoviral vectors that lacks all viral genes and that can transfer large genes into striated muscle of young and old animals. Project 2 aims to develop a better understanding of the role of the dystrophin associated protein complex in striated muscle, how mutations in genes that encode the proteins of this complex lead to muscular dystrophies (CDs), and how normal ageing contributes to the pathology of the MDs. Project 3 explores hypertrophic cardiomyopathies, and aims to develop adenoviral vector mediated gene transfer to the heart as a mechanism to correct inherited cardiac diseases at different stages of disease progression. These projects will be supported by four Core Laboratories. Core 1 is an administrative core to coordinate the separate projects. Core 2 is a Viral Vector Core to provide large scale growth of adenoviral vectors and assistance with their use. Core 3 is an Animal Models/Immunology Core that will house the animals for these studies, provide veterinary care and assistance with protocols, and which will also provide detailed immunological assays to study immune responses to adenoviral vector transfer. Core 45 us a Contractility Core that will measure changes in muscle contractile properties during ageing of normal and diseased muscle and following adenoviral based gene transfer to striated muscles. These projects will lead to a greater understanding of muscle diseases and ageing, and will contribute to the development of therapies for inherited diseases of skeletal and cardiac muscle.