GENETIC MODIFICATION OF STRIATED MUSCLES DURING AGING

衰老过程中横纹肌的基因修饰

• 批准号: 6169149
• 负责人: JOSEPH Mark METZGER
• 金额: $ 94.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6169149
• 关键词: aging; dystrophin; gene therapy; muscular dystrophy; striated muscles; transfection /expression vector

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.

本计划项目应用程序旨在探索机制， 影响横纹肌的遗传疾病，这些疾病是如何 受正常衰老过程的影响，并且还寻求发展基因 治疗这些疾病的方法。申请人是A 对老龄问题感兴趣的多样化和基础广泛的研究人员群体， 肌肉结构与功能关系、遗传性肌肉疾病和基因 疗法附属项目集中在心脏和骨骼肌 疾病，并汇集了老年学，生理学， 分子生物学和遗传学。项目1旨在开发一种新的 腺病毒载体缺乏所有的病毒基因，可以转移大的 基因植入年轻和年老动物的横纹肌。项目2旨在 更好地了解肌营养不良蛋白相关的作用， 横纹肌中的蛋白质复合物，编码蛋白质复合物的基因突变是如何发生的？ 这种复合物的蛋白质导致肌肉萎缩症（CD），以及如何 正常的衰老会导致MD的病理学改变。项目3探索 肥大性心肌病，目的是开发腺病毒载体 介导的基因转移到心脏作为一种机制，以纠正遗传 心脏病在不同阶段的疾病进展。这些 项目将由四个核心实验室提供支持。核心1是一个 行政核心，以协调单独的项目。核心2是病毒 载体核心提供腺病毒载体的大规模生长， 协助其使用。核心3是动物模型/免疫学核心， 将为这些研究饲养动物，提供兽医护理， 协助议定书，并将提供详细的 研究对腺病毒载体免疫应答的免疫学测定 转移核心45是一个收缩核心，它将测量 正常和患病肌肉老化过程中的肌肉收缩特性 并随后将基于腺病毒的基因转移至横纹肌。这些 项目将导致更好地了解肌肉疾病， 衰老，并将有助于开发遗传性疾病的治疗方法。 骨骼肌和心肌疾病。