Hevin Regulation of Cell Migration

描述(申请人提供)：细胞外基质(ECM)结构是细胞行为的已知决定因素，并反过来受来自相邻细胞的信号调节。Hevin等基质细胞蛋白作为接头在调节细胞/ECM通讯和ECM结构中发挥重要作用，因此是肿瘤生长及其相关血管生成等多种病理过程的关键调节因子。这一提议的假设是，Hevin通过诱导允许迁移的黏附状态来调节细胞迁移。旨在解决这一假设的具体目标集中在阐明Hevin发挥作用的一个或多个机制上。首先，我们将研究Hevin/I型胶原相互作用在死亡粘连中的作用，其次，我们将研究Hevin诱导的焦点粘连解体的机制。为了解决第一个特定目标，我们将评估Hevin/胶原I型结合及其对真皮成纤维细胞中胶原纤维的合成、结构以及与α2beta1整合素相互作用的影响。为了达到第二个特定目标，我们将研究Hevin调节牛主动脉内皮细胞和真皮成纤维细胞局部黏附分解和细胞迁移的信号通路。

DESCRIPTION (provided by applicant): Extracellular matrix (ECM) structure is a known determinant of cell behavior and is in turn regulated by signals from its adjacent cells. Matricellular proteins such as hevin play an important role in regulating cell/ECM communication and ECM structure by acting as adapters, and therefore are critical regulators of numerous pathologies such as tumor growth and its associated angiogenesis. The hypothesis of this proposal is that hevin functions as a regulator of cell migration by inducing a state of adhesion permissive for migration. The specific aims geared to address this hypothesis are focused on elucidating one or more of the mechanisms through which hevin functions. First, we will investigate the role of the hevin/collagen I interaction in deadhesion, and second, we will examine the mechanism of hevin-induced focal adhesion disassembly. To address the first specific aim, we will evaluate hevin/collagen I binding and its effect on collagen fibril synthesis, structure, and interaction with alpha2beta1-integrin in dermal fibroblasts. To address the second specific aim, we will investigate the signaling pathways involved in regulating focal adhesion disassembly and cell migration by hevin in bovine aortic endothelial cells and dermal fibroblasts.