THE ROLE OF AJUBA LIM PROTEIN IN EPITHELIA BIOGENESIS

描述（由申请人提供）：上皮形成物理屏障，将身体的内部环境与外部环境和病原体隔离和保护。上皮的形成需要多个细胞过程的协调，包括一系列负责细胞间粘附的特化细胞-细胞连接的组装，建立一个不可渗透的屏障，并为产生上皮极性的信号提供支架，从而建立细胞蛋白、脂质和细胞顶侧和底侧表面功能的差异分布。在正常发育和癌症转移等病理条件下，黏附结的转换是上皮细胞运动所必需的。这一过程在形态学和遗传学上被描述为上皮到间充质转化（EMT）。EMT不仅在胚胎发育过程中，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状态中都是一个重要的生物学过程。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-细胞粘附受体和上调间充质基因来影响EMT基因程序。因此，一个基本问题是确定细胞表面粘附事件和核过程是否以及如何相互沟通以协调动态上皮生物发生和形态发生。我们的实验室已经确定了Ajuba LIM蛋白家族作为粘附连接（AJ）的新成分，并积极招募到新形成的e -钙粘蛋白依赖性连接。因此，它们有助于连接复合物的形成、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加难以捉摸的。我们现在已经确定了Ajuba LIM蛋白与蜗牛家族的转录抑制因子相互作用，并作为核共抑制因子。蜗牛家族蛋白是发育和癌症进展过程中EMT的中心调节因子。与Snail一样，Ajuba LIM蛋白在体内被发现对神经嵴衍生物的发育很重要。因此，Ajuba LIM蛋白类似于Wnt信号传导过程中的2-catenin，在上皮生物发生/形态发生过程中具有协调细胞表面粘附事件和核反应的潜力。本提案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意义。上皮覆盖身体的所有表面（内外），保护我们免受环境毒素和病原体的侵害。因此，了解上皮如何发育和维持对人类健康和福祉至关重要。此外，上皮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方式非常相似。我们已经确定了一个家族的蛋白质，有助于上皮的形成。这项提议的目标是了解这个蛋白质家族是如何做到这一点的。这一知识将提高我们治疗上皮疾病的能力，如皮肤疾病、癌症扩散和损伤后的组织瘢痕。

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.