Modulation of Muscle Growth for the Muscular Dystrophies

描述(申请人提供)：肌营养不良症的特征是随着时间的推移逐渐失去力量。刺激肌肉生长可能会延缓严重残疾和死亡之前的时间。该中心的总体主题是研究调节肌肉生长和分解的机制，以治疗各种肌肉营养不良。IGF-1是一种强有力的刺激物，而肌肉生长抑制素是一种特定的肌肉生长抑制物。这两条通路的调节已经被证明可以改善肌营养不良症的MDX模型。最近，用Bowman Birk抑制剂浓缩物(BBIC)抑制蛋白酶也有类似的效果。该中心由约翰·霍普金斯大学、宾夕法尼亚大学和INTERNAL NINDS三个网站组成，包括肌肉抑制素和IGF-1领域的领军人物以及肌肉营养不良症的临床专家。这些调查人员在一起有过卓有成效的历史。在项目1中，李世真博士将阐明肌肉生长抑素活性的调节机制，目标是开发针对肌肉生长抑素活性的治疗药物。在项目2中，Lee Sweeney博士将在小鼠和犬类模型中研究抑制蛋白质分解同时刺激肌肉生长的效果。在项目3中，Kathryn Wagner博士将探索调节IGF-1和肌肉生长抑制素途径的潜在协同作用。在项目4中，Kenneth Fischbeck博士将指导一项使用蛋白酶抑制剂BBIC治疗Duchenne肌营养不良症的临床试验。有两个核心设施：行政核心A将为整个中心提供行政和科学支持，并促进在肌肉营养不良领域培训新的调查人员。生理评估核心B是基因工程小鼠的来源。用IGF-1，一种肌肉生长抑制因子和已经在临床试验中的蛋白酶抑制剂，调节肌肉生长是一种直接适用于各种肌营养不良症的方法。该MDCRC将提供关于该方法的安全性和有效性所需的基础、转换和临床数据。

Description (provided by applicant): The muscular dystrophies are characterized by progressive loss of strength over time. Stimulating muscle growth may delay the time before significant disability and death. The overall theme of this center is to study mechanisms to modulate muscle growth and breakdown for treatment of a variety of muscular dystrophies. IGF-1 is a potent stimulator and myostatin a specific inhibitor of muscle growth. Modulation of both pathways has been shown to ameliorate the mdx model of muscular dystrophy. Recently, protease inhibition with Bowman Birk Inhibitor Concentrate (BBIC) has been found to have similar effects. The center is composed of three sites, Johns Hopkins, University of Pennsylvania and intramural NINDS and includes investigators who are leaders in the field of myostatin and IGF-1 as well as clinical experts in muscular dystrophy. These investigators have a productive history together. In Project 1, Dr. Se-Jin Lee will elucidate the mechanisms by which myostatin activity is regulated with the goal of developing therapeutic agents targeting myostatin activity. In Project 2, Dr. Lee Sweeney will study the effects of inhibiting protein breakdown while stimulating muscle growth in mouse and canine models. In Project 3, Dr. Kathryn Wagner will explore the potential synergistic actions of modulating both IGF-1 and myostatin pathways. In Project 4, Dr. Kenneth Fischbeck will direct a clinical trial with the protease inhibitor, BBIC in Duchenne muscular dystrophy. There are two core facilities: Administrative Core A will provide administrative and scientific support for the entire center as well as facilitate training of new investigators in the area of muscular dystrophy. Physiological assesment Core B is a resource of genetically engineered mice. Modulating muscle growth is an immediately applicable approach to a variety of muscular dystrophies with IGF-1, a myostatin inhibitor, and protease inhibitors already in clinical trials. This MDCRC will provide needed basic, translational and clinical data on the safety and effectiveness of this approach.