Cellular and molecular biology of plakin crosslinking proteins in myogenic cells

多细胞生物由多种具有独特形状的细胞类型组成，这些形状主要由位于细胞内部的支架分子决定。细胞维持或改变其构象的能力对其在生物体中的功能具有深远而直接的影响。了解支架蛋白如何影响细胞的形状和功能是本资助申请的主要目标。拟议的研究特别侧重于了解一个被称为plakins的支架蛋白家族的功能。在经受重大机械压力的组织中，如皮肤和肌肉中，白蛋白尤其丰富，并且被认为在拉伸或压缩时保持这些组织的组织。在人类中，与某些plakin家族成员相关的遗传病变会导致皮肤起疱性疾病和肌肉营养不良。申请人对确定骨骼肌斑块的重要性特别感兴趣。为了实现这一目标，研究人员将评估大疱性类天疱疮抗原1 （Bpag1）在肌肉组织中的定位，并研究确定Bpag1相互作用蛋白。Bpag1是一种特异性斑块家族成员。此外，还提出了确定不同plakin家族成员在肌肉细胞增殖和分化过程中的相对贡献的研究。总的来说，这些研究有望为肌纤维的基本结构和功能提供新的见解，并将增强我们对与肌纤维结构破坏相关的肌病的理解。

Multicellular organisms are comprised of a variety of cell types with unique shapes that are dictated primarily by scaffolding molecules located inside the cells. The ability of cells to either maintain or change their conformation has profound and direct implications on their function within an organism. Understanding how scaffolding proteins influence cell shape and function is the primary objective of the present grant application. The proposed studies are particularly focused on understanding the functions of one family of scaffolding proteins known as plakins. Plakins are particularly enriched in tissues that undergo significant mechanical stress such as skin and muscle and are thought to preserve the organization of these tissues when they are stretched or compressed. In humans, genetic lesions associated with certain plakin family members result in skin blistering disorders and muscular dystrophies. The applicant is particularly interested in determining the importance of plakins in skeletal muscle. To achieve this objective, studies to assess the localization of bullous pemphigoid antigen 1 (Bpag1), one specific plakin family member, in muscle tissue and studies to identify Bpag1-interacting proteins are envisioned. Furthermore, studies to determine the relative contributions of different plakin family members during the proliferation and differentiation of muscle cells are proposed. Collectively, these studies are expected to provide new insights into the fundamental structure and function of muscle fibers and will enhance our understanding of myopathies that are related to disruptions of the muscle fiber architecture.