Alpha-Catenin in Regulation of Tissue Homeostasis and Cancer

描述（由申请人提供）：相互粘附的能力是所有后生动物形成所必需的最基本的细胞功能之一。上皮性肿瘤最显着的组织学表现是正常组织结构的局灶性丧失。维持正常组织组织是细胞间粘附结构的主要功能之一，在上皮癌中细胞间粘附常常异常。我们实验室致力于了解细胞间粘附蛋白αE（上皮）-连环蛋白的正常和病理功能。 αE-连环蛋白在多种人类上皮肿瘤中经常下调：然而，这种下调的意义以及 α-连环蛋白在组织稳态和癌症中的总体机制尚不清楚。为了了解 α-连环蛋白下调在人类癌症中的重要性，我们使用条件基因敲除技术在小鼠中模拟这些事件。这些和其他方法导致认识到α-连环蛋白在干细胞的自我更新和分化调节中发挥重要作用，并且干细胞区室中α-连环蛋白的遗传丢失可能导致组织稳态和癌症发展的显着缺陷。在本提案中，我们将研究α-连环蛋白在信号转导中的分子机制，并利用遗传功能丧失和药理抑制实验来探索治疗α-连环蛋白减少或缺失的上皮性肿瘤的新治疗干预措施 表达。

DESCRIPTION (provided by applicant): The ability to adhere to each other is one of the most fundamental cellular functions necessary for the formation of all metazoans. The most significant histological manifestation of epithelial tumor is the focal loss of normal tissue architecture. Maintenance of normal tissue organization is one of the primary functions of cell-cell adhesion structures and intercellular adhesion is often abnormal in epithelial cancer. Our laboratory is concentrating on understanding the normal and pathological function of cell-cell adhesion protein alphaE(epithelial)-catenin. AlphaE-catenin is often downregulated in a variety of human epithelial tumors: however, the significance of this downregulation and overall mechanisms of alpha-catenin in tissue homeostasis and cancer is not well understood. To understand the significance of alpha-catenin downregulation in human cancer, we model these events in mice using conditional gene knockout technology. These and other approaches resulted in realization that alpha-catenin plays an important role in regulation of self-renewal an differentiation of stem cells and the genetic loss of alpha-catenin in stem cell compartment can result in prominent defects in tissue homeostasis and development of cancer. In this proposal we will study the molecular mechanisms of alpha-catenin in signal transduction and use genetic loss-of-function and pharmacological inhibition experiments to explore the novel therapeutic interventions for the treatment of epithelial tumors displaying a decrease or loss of alpha-catenin expression.