对基膜在果蝇组织内的组装和机械作用的基因分析

基膜（basement membrane）是对组织起支持作用的高度保守的胞外基质蛋白的层状多聚体。目前几乎没有在体内条件下的证据来揭示基膜成分间的相互作用对基膜的形成和再生的重要性。因为基膜和其组成成分对组织支持的必要的作用，很大范围内的人类疾病都是由于基膜装配或组成的缺陷导致的。这些疾病包括由细胞外基质激增引起的异常纤维化综合症和由基膜元件及其修饰酶突变引起的许多先天性疾病。大量的研究表明基膜对果蝇组织产生机械拉伸的作用。我们推测由受基膜集合和位置调控的基膜张力的变化将会影响组织的发育和生长。我们拟利用果蝇的遗传学工具和转基因技术，确定体内基膜元件体内集合的顺序，探讨单独基膜元件在保持机械拉伸力的功能，分析机械拉伸力在发育、再生和肿瘤上的作用。这一研究将填补基膜的基础生物学知识中长期存在的断层，为力学生物学提供合适的基因模型。最终，此项目的结果将有利于细胞外基质的突增类疾病的理解和治疗。

Basement membranes (BMs) are polymers of highly conserved extracellular matrix (ECM) proteins that provide mechanical support to tissues. Multiple interactions among BM components have been mapped in vitro, but little evidence exists in vivo to show which of these interactions are crucial for BM assembly and regeneration. Due to their essential tissue support role, BMs and their components are important regulators of morphogenesis, cell signaling, wound healing, immune responses and tumor progression. Indeed, a wide array of human disorders results from defects in BM assembly or composition. Furthermore, my research and that of others has proved the role of the BM in exerting mechanical tension on Drosophila tissues. I hypothesize that changes in BM tension dictated by BM assembly and composition affect tissue development and growth. To test this main hypothesis, the research I propose here intends to ascertain the hierarchy of assembly of basement membrane components in vivo, determine the function of individual basement membrane components in maintaining mechanical tension and analyze the effects of mechanical tension in development, regeneration and tumors. This work will also explore the effects of mechanical tension in tissue development and growth, providing suitable genetic models in mechanobiology. Finally, results from this project may have broad implications for the understanding and treatment of diseases involving abnormal ECM accumulation.