整合素信号通路在肠上皮损伤修复中的作用及机制

Organ function and homeostasis is commonly maintained by local stem cells self-renewal and differentiation. From Drosophila to human,the developmental process, cellualr makeup and regulatory mechanisms of the digestive system are highly conserved. This has raised hopes that fly could be used as a powerful genetic model to study intestinal regeneration. Integrin-mediated cell adhesion anchors intestinal stem cells in the basement membrane and facilitates stem cells to receive signals from the muscular niche to control maintenance and proliferation of intestinal stem cells. Our preliminary experimental results revealed that integrin is involved in Drosophila intestinal regeneration and integrin deletion inhibits injury-induced overexpression of signals from muscular niche. We speculate that the integrin-mediated anchorage of stem cells may be involved in upregulation of secretion signal caused by damage. On the basis of the preliminary work, this application study that under stress condition, integrin deletion impact on the relationship between stem cells and their niche, and on Wnt, JAK/STAT and EGFR signaling pathway, in order to clarify the function and mechanism of integrin signaling pathway in the regeneration of Drosophila intestine.

干细胞的不断自我更新和分化是维持器官功能和稳态的重要因素。从果蝇到人，肠道的发育过程、细胞组成以及调控机制的高度保守性，使得果蝇成为研究肠道再生机制的希望。整合素介导的细胞黏附帮助干细胞锚定在基底膜上，方便接收肌肉微环境分泌的信号，从而控制干细胞的维持和增殖。我们的初步实验结果发现整合素参与果蝇肠道的再生，整合素缺失抑制损伤情况下肌肉微环境分泌信号的增多。我们推测整合素介导的干细胞锚定可能参与上皮损伤导致的肌肉微环境分泌信号增多。因此，本申请将在前期工作的基础上，研究损伤情况下，整合素缺失对干细胞和微环境之间关系的影响，及对各个参与调控干细胞增殖的信号通路的影响，以期阐明整合素信号通路在果蝇肠道损伤修复中的作用及机制。

损伤情况下，干细胞通过过度增殖，产生更多的子细胞来修复损伤。本研究发现整合素参与果蝇肠道的再生。整合素mys突变抑制DSS和细菌ECC损伤导致的干细胞增殖。整合素信号通路上的胞内和胞外成员talin、laminin A突变同样抑制损伤导致的干细胞增殖。我们发现整合素缺失抑制损伤后肌肉微环境分泌信号vn和wg的增多，然而Wnt、JAK/STAT、EGFR信号通路激活不能补偿整合素缺失导致的干细胞增殖抑制。整合素缺失抑制损伤导致的硫酸乙酰肝素蛋白聚糖dally-like表达上调。而硫酸乙酰肝素蛋白聚糖dally和dally-like同时突变抑制损伤导致的干细胞增殖。我们的研究提示损伤情况下，整合素可能是通过调节硫酸乙酰肝素蛋白聚糖的表达，来影响微环境信号的表达，间接调控干细胞的增殖潜能，从而影响肠道再生。这对我们了解干细胞在损伤修复过程中的调控机制有着重要意义，并对未来治疗肠道疾病提供理论支持。