The Sarcolemma in FSHD and in the myd Mouse

描述(申请人提供)：面部肩周型肌营养不良症 在这个国家，每20,000名成年人中就有1人受到FSHD的影响。FSHD已链接 4号染色体端粒区域(4q35-4q35ter)的缺失，是 遗传的作为显性特征遗传的虽然我们已经学到了很多关于 导致FSHD的基因缺陷，我们仍然对其影响知之甚少 这些缺陷发生在单个肌肉纤维的水平上。事实上，细胞 导致肌肉无力和肌纤维变性的生物变化 从未被研究过。在这里，我们建议通过检查以下内容来解决此问题 使用超微结构技术的人体活检材料和 免疫荧光与激光扫描共聚焦显微镜联用。我们 假设，像其他人类营养不良症，如杜兴，贝克斯，和 部分肢体环状肌营养不良，FHSD肌肌膜改变 会导致肌肉无力，最终导致肌肉退化。在……里面 支持这一假说，我们的初步研究表明，肌膜 FSHD肌肉在其膜骨架中频繁中断，被分离 与最近的肌原纤维有相当大的差距，并且是有组织的 不规则，最类似于慢抽动肌肉的肌膜 纤维，尽管肌浆中含有丰富的快速抽动肌球蛋白。我们建议 在我们对FSHD肌肉的探索性研究中追求三个目标：(I)测试 这些观察结果的有效性，并在可能的情况下加以扩展；(Ii) 将它们与其他人类肌肉营养不良症进行比较；以及(Iii)研究 肌膜的生物力学特性，以了解它们是否受到 FSHD。我们的最终目标是：(4)研究MyD小鼠的肌膜，这是 已被提出作为FSHD的一种可能的动物模型。我们的实验室有 开发了一套独特的方法和抗体，使我们能够检查 肌膜的整体组织及其与周围组织的关系 收缩装置。在过去的一年里，我们已经调整了这些方法以用于 人类骨骼肌的快速冰冻活组织检查。因此，我们预计 在理解细胞生物学变化方面取得重大进展 发生在FSHD骨骼肌中，并确定其中哪一个，如果有的话， 这些变化与FSHD的病理生理机制有关。

DESCRIPTION (provided by applicant): Facioscapulohumeral Muscular Dystrophy (FSHD) affects 1 of every 20,000 adults in this country. FSHD has been linked to deletions at the telomeric region of chromosome 4 (4q35-4q35ter), and is inherited as a dominant trait. Although we have learned a great deal about the genetic defects that lead to FSHD, we still know very little about the effects these defects have at the level of individual muscle fibers. Indeed, the cell biological changes that result in muscle weakness and myofiber degeneration have never been studied. Here we propose to address this issue by examining human biopsied materials using ultrastructural techniques and immunofluorescence coupled with confocal laser scanning microscopy. We postulate that, like other human dystrophies, such as Duchennes, Beckers, and some limb girdle muscular dystrophies, the sarcolemma of FHSD muscle is altered in ways that lead to muscle weakness and ultimately to muscle degeneration. In support of this hypothesis, our preliminary studies show that the sarcolemma of FSHD muscle has frequent interruptions in its membrane skeleton, is separated from the nearest myofibrils by a considerable gap, and is organized irregularly, and most closely resembles the sarcolemma of slow twitch muscle fibers although the myoplasm is rich in fast twitch myosin. We propose to pursue three aims in our exploratory studies of FSHD muscle that will: (i) test the validity of these observations and to extend them, if possible; (ii) compare them to other human muscular dystrophies; and (iii) study the biomechanical properties of the sarcolemma, to learn if they are compromised by FSHD. Our final aim will: (iv) examine the sarcolemma of the myd mouse, which has been proposed as a possible animal model of FSHD. Our laboratory has developed an unique set of methods and antibodies that permit us to examine the overall organization of the sarcolemma and its relationship to the nearby contractile apparatus. In the past year, we have adapted these methods for use with snap frozen biopsies of human skeletal muscle. We therefore anticipate making significant progress in understanding the cell biological changes that occur in FSHD skeletal muscle, and in determining which, if any, of these changes are related to the pathophysiology of FSHD.