Cell adhesion mediated self-recognition

描述（由申请人提供）：细胞-细胞粘附是多细胞系统的基本特征。本提案的目的是分析单个上皮细胞如何识别邻近细胞形成相互细胞-细胞粘附而拒绝自我接触。两个对立细胞上的亲同性粘附受体迅速结合形成细胞-细胞粘附，而来自同一细胞表面的两个薄突起上的相同受体则不会。单个细胞的这种自我意识表明，细胞可以区分邻近细胞和自己细胞的化学成分相同的表面。我们假设自我识别机制是机械调节的，钙粘蛋白复合体是一种机械感应复合体，可以检测到外力，从而为细胞相互粘附提供信号提示。在没有外力的情况下，机械信号是关闭的，并导致自接触的消除。使用创新的微制造衬底来控制自接触事件，我们将分析自接触的形成和随后的自接触点的消除。此外，我们开发了微型力传感器来检测粘合剂接触处的力，并直接测试我们的假设。我们的发现还将强调相邻细胞之间如何形成相互的细胞-细胞粘附。一旦我们了解了细胞自我和他人识别的基本过程，我们的目标是开发出改变细胞间粘附的治疗药物，并可用于防止癌细胞入侵或病原体感染。

DESCRIPTION (provided by applicant): Cell-cell adhesion is a fundamental feature of multi-cellular systems. The goal of this proposal is to analyze how individual epithelial cells recognize neighboring cells to form mutual cell-cell adhesion while rejecting self-contact. Homophilic adhesive receptors on two opposing cells rapidly bind to form a cell-cell adhesion, yet the same receptors on two thin protrusions originating from the same cell surface do not. This self-awareness of individual cells suggests that cells can distinguish the chemically identical surface of neighboring cells from their own. We hypothesize that the self-recognition mechanism is mechanically regulated, and that the cadherin complex is a mechano-sensing complex that detects external forces, thereby providing a signaling cue for mutual cell adhesion. In the absence of external forces, the mechano-signal is off, and leads to the elimination of self-contacts. Using innovative micro-fabricated substrates to control self-contacting events, we will analyze the formation of self-contacts and the subsequent elimination of self-contacting sites. Furthermore, we have developed miniature force sensors to detect forces at the adhesive contacts and directly test our hypothesis. Our findings will also highlight how mutual cell-cell adhesion forms between neighboring cells. Once we understand the fundamental processes of self and other recognition by cells, our goal is to develop therapeutic agents that alter cell- cell adhesion and can be used to prevent cancer cell invasion or pathogen infection. PUBLIC HEALTH RELEVANCE: Regulation of cell-cell adhesion plays critical roles in development and homeostasis of multi-cellular organisms. The goal of this proposal is to analyze how individual epithelial cells recognize neighboring cells to form mutual cell-cell adhesions while rejecting self-contact. One potential outcome of the proposed research will be the development of advanced therapeutic agents that prevent cancer cell invasion or pathogen infection.