THE ROLE OF AJUBA LIM PROTEIN IN EPITHELIA BIOGENESIS

描述(申请人提供)：上皮形成物理屏障，将身体内部环境与外部环境和病原体隔离并保护。上皮细胞的形成需要多种细胞过程的协调，包括一系列负责细胞间黏附的特殊细胞-细胞连接的组装，建立不渗透屏障，并为信号提供支架，以产生上皮极性，建立细胞蛋白质、脂类和顶端和基底外侧表面的不同分布。在正常发育和肿瘤转移等病理条件下，黏附连接翻转是上皮细胞运动所必需的。这一过程在形态和遗传学上被描述为上皮向间充质转化(EMT)。EMT不仅在胚胎发育期间，而且在成人机体的慢性炎症和纤维化、伤口愈合和癌症转移的状态下，都是一个中心的生物过程。虽然许多不同的环境信号诱导EMT，但它们都聚集在一起激活核转录因子，通过抑制上皮基因，特别是细胞-细胞黏附受体，上调间充质基因的表达，影响EMT基因程序。因此，一个基本的问题是确定细胞表面黏附事件和核过程是否以及如何相互联系，以协调动态的上皮细胞生物发生和形态发生。我们的实验室已经发现Ajuba Lim蛋白家族是黏附连接(AJ)的新成分，并被积极招募到新形成的E-钙粘附素依赖的连接中。因此，它们有助于连接络合物的形成、稳定性和功能。这些蛋白质也转移到细胞核，在那里它们的功能被证明是更难以捉摸的。我们现在已经确定Ajuba Lim蛋白与Snail转录抑制因子家族相互作用，并作为核辅助抑制因子发挥作用。蜗牛家族蛋白是EMT在发育和癌症进展过程中的中央调节因子。与蜗牛一样，Ajuba Lim蛋白在体内被发现对神经脊衍生物的发育具有重要作用。因此，Ajuba Lim蛋白类似于Wnt信号转导过程中的2-catenin，在上皮细胞生物发生/形态发生过程中具有协调细胞表面黏附事件和核反应的潜力。这项建议的总体目标是首先确定Ajuba Lim蛋白家族如何影响上皮细胞连接的形成、稳定性和功能，并确定核Ajuba Lim蛋白的生物学和功能含义。上皮覆盖所有身体表面(内外)，保护我们免受环境毒素和病原体的伤害。因此，了解上皮细胞是如何发育的，以及它们是如何维持的，对人类的健康和福祉至关重要。此外，上皮细胞的发育方式与上皮性癌症(如乳腺癌、结肠癌、肺癌)在成人中的扩散或转移非常相似。我们已经确定了一系列有助于上皮形成的蛋白质。这项提议的目标是了解这一蛋白质家族是如何做到这一点的。这些知识应该会增加我们治疗皮肤上皮疾病的能力，如皮肤病、癌症扩散和因损伤而造成的组织创伤。

DESCRIPTION (provided by applicant): Epithelia form physical barriers that separate and protect the internal milieu of the body from its external environment and pathogens. The formation of epithelia requires the coordination of multiple cellular processes that include the assembly of a series of specialized cell-cell junctions responsible for cell to cell adhesion, the establishment of an impermeable barrier, and provide a scaffold for signals to generate epithelial polarity that establish the differential distribution of cell proteins, lipids, and functions to apical and basolateral surfaces. Adhesive junction turnover are required for the movement of epithelia as occurs during normal development and in pathologic conditions such as cancer metastasis. This process has been morphologically and genetically described as an epithelial to mesenchymal transition (EMT). EMT has emerged as a central biologic process not only during embryonic development but also in states of chronic inflammation and fibrosis, wound healing, and cancer metastasis in the adult organism. While many different environmental signals induce EMT they all converge to activate nuclear transcription factors that effect an EMT gene program through repression of epithelial genes, particularly cell-cell adhesive receptors, and up-regulation of mesenchymal genes. A fundamental question then is to determine whether and how cell surface adhesive events and nuclear processes communicate with one another to coordinate dynamic epithelia biogenesis and morphogenesis. Our laboratory has identified the Ajuba LIM protein family as novel components of Adherens Junctions (AJ) and that are actively recruited to newly forming E-cadherin-dependent junctions. As such they contribute to the formation, stability, and function of junctional complexes. These proteins also translocate to the nucleus, where their function has proved to be more elusive. We have now identified the Ajuba LIM proteins as interacting with the Snail family of transcriptional repressors and act as nuclear co-repressors. Snail family proteins are central regulators of EMT during development and cancer progression. Like Snail, Ajuba LIM proteins were found to be important for the development of neural crest derivatives, in vivo. Thus, Ajuba LIM proteins, analogous to 2-catenin during Wnt signaling, have the potential to coordinate cell surface adhesive events with nuclear responses during epithelia biogenesis/morphogenesis. The general aims of this proposal then are to first determine how the Ajuba LIM protein family influences epithelial cell junction formation, stability, and function and to determine the biologic and functional implications of the nuclear Ajuba LIM protein. Epithelium cover all body surfaces (outside and inside) and protect us from environmental toxins and pathogens. Therefore understanding how epithelium develop, and how they are maintained is critical to human health and welfare. Moreover how epithelium develops is very similar to how epithelial cancers (e.g., breast, colon, lung) spread, or metastasis, in adults. We have identified a family of proteins that contribute to the formation of epithelium. The goal of this proposal is to understand how this family of protein does so. This knowledge should increase our capacity to treat disorders of the epithelium such as skin disorders, cancer spread, and tissue scaring in response to injury.