Sarcolemma in FSHD

描述（由申请人提供）：面肩肱肌营养不良症 （FSHD）影响该国每20，000名成年人中的1人。FSHD已与 4号染色体端粒区（4 q35 - 4 q35 ter）缺失， 作为显性特征遗传的。虽然我们已经了解了很多关于 遗传缺陷导致FSHD，我们仍然对它的影响知之甚少。 这些缺陷在单个肌肉纤维的水平上存在。事实上，细胞 导致肌肉无力和肌纤维变性的生物学变化 从未被研究过。在这里，我们建议通过检查来解决这个问题 使用超微结构技术的人类活组织检查材料， 免疫荧光结合共聚焦激光扫描显微镜。我们 假设，像其他人类营养不良，如杜兴，贝克尔，和 某些肢带型肌营养不良，FHSD肌的肌膜改变 导致肌肉无力并最终导致肌肉退化。在 为了支持这一假设，我们的初步研究表明， FSHD肌肉的膜骨架经常中断， 离最近的肌原纤维有相当大的间隙， 不规则的，最接近于慢颤肌的肌膜 纤维，虽然肌浆中富含快缩肌球蛋白。我们建议 追求三个目标，在我们的探索性研究FSHD肌肉，将：（i）测试 这些意见的有效性，并在可能的情况下予以扩大; ㈡ 将其与其他人类肌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：（iv）检查myd小鼠的肌膜， 已被提议作为FSHD的可能的动物模型。本实验室 开发了一套独特的方法和抗体，使我们能够检查 肌膜的整体组织结构及其与附近 收缩器在过去的一年里，我们对这些方法进行了调整， 快速冷冻的人体骨骼肌活组织检查。因此，我们预计 在理解细胞生物学变化方面取得了重大进展， 发生在FSHD骨骼肌，并确定其中，如果有的话， 这些变化与FSHD的病理生理学有关。

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.