Structure and function of muscle

描述（由申请人提供）：肌肉对循环、泌尿生殖、呼吸和消化系统的功能至关重要。虽然对肌动球蛋白的力量产生能力了解很多，但对肌肉细胞内的收缩机制如何组织以及它在收缩周期中如何稳定知之甚少。肌动蛋白丝的锚定位点代表了收缩器的组织、整合和束缚的关键位点。肌动蛋白交联蛋白，α-辅肌动蛋白，集中在肌肉中的肌动蛋白锚定位点。我们已经鉴定了LIM结构域蛋白的两个家族的成员，富半胱氨酸蛋白（CRP）家族和ALP-Enigma家族作为α-辅肌动蛋白结合伴侣。我们已经证明，这些蛋白质富集在肌肉中，它们与α-辅肌动蛋白共同定位在肌动蛋白丝锚定位点。在这里，我们建议定义这些蛋白质有助于肌肉细胞结构和功能的机制。通过分析我们产生的功能丧失突变，我们将确定这些蛋白质对正常肌肉结构和功能的贡献。我们将研究这些遗传改变的后果，在肌肉中的肌动蛋白锚定位点的超微结构组织和分子结构，包括Z-光盘，致密体，和细胞粘附区域。我们将鉴定与CRP和ALPEnigma复合的蛋白质，以获得对其分子作用机制的更全面的认识。肌动蛋白丝在肌肉中的锚定区域被认为在肌肉稳定性中起关键作用，并且这些区域可以作为监测收缩机制的完整性和功能的结构传感器。在人类中，肌动蛋白锚定位点组分的缺陷与心肌病有关。因此，我们的研究结果将有助于了解正常肌肉功能以及肌肉病理学方面。

DESCRIPTION (provided by applicant): Muscle is essential for the function of the circulatory, urogenital, respiratory, and digestive systems. Although much is understood about the force-generating capacity of acto-myosin, little is known about how the contractile machinery is organized within muscle cells and about how it is stabilized during contraction cycles. Sites of actin filament anchorage represent key sites for organization, integration, and tethering of the contractile apparatus. The actin crosslinking protein, a-actinin, is concentrated at actin anchorage sites in muscle. We have identified members of two families of LIM domain proteins, the Cysteine-Rich Protein (CRP) family and the ALP-Enigma family as a-actinin binding partners. We have demonstrated that these proteins are enriched in muscle where they co-localize with a-actinin at actin filament anchorage sites. Here we propose to define the mechanisms by which these proteins contribute to muscle cytoarchitecture and function. By analysis of lossof-function mutations that we have generated, we will defme the contributions of these proteins to normal muscle structure and function. We will examine the consequences of these genetic alterations for the ultrastructural organization and molecular architecture of actin anchorage sites in muscle, including Z-discs, dense bodies, and regions of cell adhesion. We will identify the proteins that complex with CRP and ALPEnigma in order to gain a more comprehensive view of their molecular mechanisms of action. Regions of actin filament anchorage in muscle are proposed to play a critical role in muscle stability, and these areas may serve as architectural sensors that monitor the integrity and function of the contractile machinery. In humans, deficiencies in components of actin-anchorage sites are associated with cardiomyopathies. Therefore, our results will contribute to an understanding of both normal muscle function as well as aspects of muscle pathology.