Modulation of Muscle Growth for the Muscular Dystrophies

描述（由申请人提供）：肌营养不良症的特征是随着时间的推移逐渐丧失力量。刺激肌肉生长可能会延迟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，以治疗各种肌营养不良症。IGF-1是一种有效的刺激剂，而肌肉生长抑制素是肌肉生长的特异性抑制剂。两种途径的调节已显示改善肌营养不良症的mdx模型。最近，发现Bowman比尔克Inhibitor Concentrate（BBIC）的蛋白酶抑制作用具有类似的效果。该中心由三个地点组成，约翰霍普金斯，宾夕法尼亚大学和内部NINDS，包括肌生长抑制素和IGF-1领域的领导者以及肌营养不良症的临床专家。这些调查人员在一起有着富有成效的历史。在项目1中，Se-Jin Lee博士将阐明肌肉生长抑制素活性调节的机制，目的是开发针对肌肉生长抑制素活性的治疗药物。在项目2中，Lee Sweeney博士将研究在小鼠和犬模型中抑制蛋白质分解同时刺激肌肉生长的效果。在项目3中，Kathryn瓦格纳博士将探索调节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博士将指导蛋白酶抑制剂BBIC在杜氏肌营养不良症中的临床试验。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，并促进肌营养不良领域新研究人员的培训。生理学评价核心B是基因工程小鼠的来源。调节肌肉生长是一种立即适用于各种肌营养不良症的方法，IGF-1是一种肌生长抑制素抑制剂，蛋白酶抑制剂已经在临床试验中。本MDCRC将提供关于该方法安全性和有效性的所需基础、转化和临床数据。

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.