Structure and function of muscle

描述（由申请人提供）：肌肉对循环系统、泌尿生殖系统、呼吸系统和消化系统的功能至关重要。尽管人们对肌动蛋白产生力量的能力了解很多，但对肌肉细胞内的收缩机制是如何组织的以及它在收缩周期中是如何稳定的却知之甚少。肌动蛋白丝锚定位点是组织、整合和栓系收缩装置的关键位点。肌动蛋白交联蛋白，a-肌动蛋白，集中在肌动蛋白锚定位点。我们已经确定了两个LIM结构域蛋白家族的成员，半胱氨酸富蛋白（CRP）家族和ALP-Enigma家族作为a-肌动蛋白结合伙伴。我们已经证明，这些蛋白质在肌肉中富集，它们在肌动蛋白丝锚定位点与a-肌动蛋白共定位。在这里，我们建议确定这些蛋白质对肌肉细胞结构和功能的作用机制。通过分析我们已经产生的丧失功能突变，我们将定义这些蛋白质对正常肌肉结构和功能的贡献。我们将研究这些基因改变对肌肉中肌动蛋白锚定位点的超微结构组织和分子结构的影响，包括z型椎间盘、致密体和细胞粘附区域。我们将确定与CRP和ALPEnigma复合物的蛋白质，以便更全面地了解它们的分子作用机制。肌动蛋白丝锚定区域被认为在肌肉稳定性中起关键作用，这些区域可以作为监测收缩机械完整性和功能的建筑传感器。在人类中，肌动蛋白锚定位点成分的缺乏与心肌病有关。因此，我们的结果将有助于理解正常肌肉功能以及肌肉病理方面。

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.