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。该提案的目标是分析单个上皮细胞如何识别相邻细胞以形成相互的细胞-细胞粘附，同时拒绝自我接触。在两个相对的细胞上的嗜同性粘附受体迅速结合以形成细胞-细胞粘附，而在源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，细胞可以区分相邻细胞的化学性质相同的表面。我们假设自我识别机制是机械调节的，钙粘蛋白复合物是一种机械感应复合物，可以检测外力，从而为相互的细胞粘附提供信号线索。在没有外力的情况下，机械信号关闭，并导致自接触的消除。使用创新的微加工基板来控制自接触事件，我们将分析自接触的形成和随后的自接触位点的消除。此外，我们还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。我们的发现也将突出相邻细胞之间相互细胞间粘附的形成。一旦我们理解了细胞自我和其他识别的基本过程，我们的目标是开发改变细胞-细胞粘附的治疗剂，并可用于预防癌细胞入侵或病原体感染。 公共卫生相关性：细胞间粘附的调节在多细胞生物体的发育和稳态中起着关键作用。该提案的目标是分析单个上皮细胞如何识别相邻细胞以形成相互的细胞-细胞粘附，同时拒绝自我接触。拟议研究的一个潜在成果将是开发预防癌细胞入侵或病原体感染的先进治疗药物。

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.