Genetic modification of aging and diseased striated muscle

衰老和患病横纹肌的基因改造

基本信息

批准号：
7633019
负责人：
JEFFREY S CHAMBERLAIN
金额：
$ 38.81万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7633019
关键词：
Address Adipose tissue Adult Affect Age Aging Alleles Animals Backcrossings Becker Muscular Dystrophy Cachexia Capsid Disease Drug Formulations Duchenne muscular dystrophy Dystrophin Elasticity Elderly Exercise Follistatin Gene Delivery Gene Expression Gene Mutation Gene Targeting Gene Transfer Genes Genetic Genome Hereditary Disease Human Genetics Inborn Genetic Diseases Individual Injection of therapeutic agent Intervention Knock-out Length Life Malignant Neoplasms Mediating Methods Modeling Modification Mus Muscle Muscle function Muscle satellite cell Muscular Atrophy Muscular Dystrophies Mutation Patients Phenotype Physiological Play Reporter Genes Role Serotyping Site Striated Muscles Tamoxifen Testing Tissues Transduction Gene Transgenic Mice Viral Viral Genome Work adeno-associated viral vector age related base cell type design disability embryonic stem cell flexibility gene therapy improved inhibitor/antagonist knockout gene mature animal mdx mouse method development micro-dystrophin middle age mini-dystrophin mouse model muscle aging muscle form muscular structure myostatin normal aging older patient public health relevance respiratory retinal rods sarcopenia therapeutic gene vector wasting young adult

项目摘要

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) and the allelic Becker MD is one of the most common human genetic disorders. DMD/BMD is caused by mutations in the dystrophin gene, and is characterized by progressive muscle wasting. BMD displays a later onset and slower progression, with many patients living well past middle age. Improved respiratory support is also helping many DMD patients live into their fourth decade, and both groups ultimately display a profound loss of muscle mass that is replaced by fibrotic and adipose tissues. Genetic therapies for these and other muscle wasting disorders would be facilitated by methods that allow efficient gene transfer to muscles of adult and old patients, yet virtually all studies of gene transfer to date have focused on young mice. This project explores the ability to deliver therapeutic genes to muscles of aging mice, with a focus on the interplay between muscular dystrophy and aging. Since many muscle wasting disorders typically manifest in older individuals, it is important to focus on age related phenomena that inhibit or otherwise impact the ability to improve the physiological state of the target muscles. The ability to genetically modify muscles of old animals would facilitate the use of similar approaches for other muscle wasting disorders, such as muscle loss during aging (sarcopenia) and muscle atrophy associated with cancer (cachexia). Our primary focus will be on aging normal and mdx mice, a model for DMD/BMD. We will evaluate the ability to target muscles of adult and old mice by systemic delivery of adeno-associated viral (AAV) vectors and will identify and circumvent barriers to gene delivery in elderly animals. We will use these optimized methods to generate new mouse models and methods for studying disorders and phenotypes that are exacerbated by, or associated with, advanced age. Finally, we will develop methods to modify muscle structure and function in elderly animals, with a focus on old WT and dystrophic mice by co-delivery of improved mini-dystrophins and modulators of muscle mass. PUBLIC HEALTH RELEVANCE: This work is highly relevant to developing genetic-based treatments for the muscular dystrophies, which are common inherited disorders that affect young, adult and elderly individuals. These same methods should also be broadly applicable to developing interventions to slow or halt muscle wasting associated with normal aging.

描述（由申请人提供）：Duchenne肌肉营养不良（DMD）和等位基因Becker MD是最常见的人类遗传疾病之一。 DMD/BMD是由肌营养不良蛋白基因突变引起的，其特征是进行性肌肉浪费。 BMD表现出以后的发作和较慢的进展，许多患者生活在中年。改善的呼吸支持也有助于许多DMD患者进入第四个十年，两组最终都表现出肌肉质量的严重丧失，并由纤维化和脂肪组织取代。这些和其他肌肉浪费障碍的基因疗法将通过允许有效的基因转移到成人和老年患者的肌肉的方法来促进，但实际上所有的基因转移研究都集中在年轻小鼠上。该项目探讨了将治疗基因传递给衰老小鼠的肌肉的能力，重点是肌肉营养不良和衰老之间的相互作用。由于许多肌肉浪费障碍通常在老年人中表现出来，因此重要的是要关注抑制或以其他方式影响改善靶肌生理状态的年龄相关现象。遗传修饰老动物肌肉的能力将促进使用类似的方法来用于其他肌肉浪费障碍，例如衰老期间的肌肉损失（肌肉减少症）和与癌症相关的肌肉萎缩（Cachexia）。我们的主要重点将放在衰老正常和MDX小鼠上，这是DMD/BMD的模型。我们将通过系统地递送腺相关病毒（AAV）向量来评估靶向成年和老鼠的肌肉的能力，并将识别和规避老年动物基因递送的障碍。我们将使用这些优化的方法来生成新的小鼠模型和方法来研究因高龄而加剧或相关的疾病和表型。最后，我们将开发用于改变老年动物的肌肉结构和功能的方法，重点是通过改善的迷你疾病和肌肉质量调节剂的共同分娩来介绍旧的WT和营养不良小鼠。公共卫生相关性：这项工作与为肌肉营养不良的基于遗传的疗法高度相关，肌肉营养不良是影响年轻，成年和老年人的常见遗传性疾病。这些相同的方法也应广泛地适用于制定与正常衰老相关的减慢或停止肌肉浪费的干预措施。