Role of Beta 1 containing Integrins in Cutaneous Basement Membrane Organization

描述（申请人提供）：在皮肤表皮中，细胞迁移和基底膜的组装和组织是许多生物和病理过程的核心，包括毛囊形态发生，伤口愈合和癌症转移。基底膜（BM）由细胞外基质蛋白的有序排列组成，表皮和真皮层都参与基底膜成分的合成。虽然基膜在发育过程中的重要作用，如建立细胞极性，促进细胞粘附和细胞存活，最近被阐明，但对正常组织稳态中基膜组装的动力学知之甚少。最近的遗传学和细胞生物学研究强调了整合素细胞粘附受体在基底膜组装和组织结构中的重要性，有助于表皮生长和分化的适当平衡和空间安排。到目前为止，我们的研究已经清楚地证明了含有整合素的a¿1在基膜组装中的作用。这项拟议的研究解决了已经出现的有趣问题，包括：“什么是整合素介导的信号，对维持体内BM完整性很重要？”和“整合素分子的哪些结构域对这种信号至关重要？”在本提案中，我们概述了具体的实验，以开始了解整合素及其下游信号效应物如何调节基膜组装/组织过程。了解单个整合素对的分子机制不仅在正常组织稳态的背景下很重要，而且可能在理解肿瘤细胞如何能够破坏基底细胞和转移方面发挥作用。哺乳动物的表皮需要一个完整的“基底膜”，这对正常的生理功能和发育至关重要。基底膜完整性的丧失与破坏性皮肤病和转移性皮肤癌有关。这项研究旨在提高我们对整合素（在上皮细胞细胞膜中发现的特殊蛋白质）在调节和维持动态但完整的基底膜中发挥关键作用的认识，将有助于识别可能与疾病及其治疗相关的特定分子实体。

DESCRIPTION (provided by applicant): In skin epidermis, cell migration and basement membrane assembly and organization are central to many biological and pathological processes, including hair follicle morphogenesis, wound healing and cancer metastasis. Basement membranes (BM) are composed of ordered arrays of characteristic extracellular matrix proteins and both the epidermis and the dermis contribute to the synthesis of basement membrane components. While important roles of basement membrane during development, such as establishing cellular polarity, promoting cell adhesion and cell survival have recently been elucidated, less is known about the dynamics of basement membrane assembly in normal tissue homeostasis. Recent genetic and cell-biological studies underscore the importance of the integrin cell adhesion receptors in basement membrane assembly and tissue architecture, contributing to the proper balance and spatial arrangement of growth and differentiation in the epidermis. Our research so far has clearly demonstrated a role for a¿1 containing integrins in basement membrane assembly. This proposed research addresses the interesting questions that have emerged, including: "What are the integrin-mediated signals that are important to maintain BM integrity in vivo?" and "What domains of the integrin molecule are critical for this signaling?" In this proposal we outline specific experiments to begin to understand how integrins, and their downstream signaling effectors regulate the process of basement membrane assembly/organization. Understanding the molecular mechanisms of individual integrin pairs is important not only in the context of normal tissue homeostasis but may also play a role in understanding how tumor cells are able to disrupt the BM and metastasize. Mammalian epidermis requires an intact "basement membrane" which is critical for normal physiological function and development. Loss of basement membrane integrity is associated with devastating skin diseases and metastatic skin cancers. This research, which seeks to advance our knowledge of the critical role that Integrins (special proteins found in the cell membranes of epithelial cells) play in regulating and maintaining a dynamic yet intact basement membrane, will help identify specific molecular entities that may be associated with diseases and their treatments.