Role of processed peptides of the basement membrane component laminin in skin barrier function

层粘连蛋白在人体皮肤的基底膜结构和功能中起着重要作用。几条层粘连蛋白的C-末端LG模块可以通过蛋白水解法进行修饰，生成LG1-3和分泌的LG4-5模块。我们的初步数据显示，来自层粘连蛋白Ax3、Ax4和Ax5链LG4模块的合成肽具有有效的抗菌活性，并能够通过膜渗透杀灭细菌。此外，LG4衍生的多肽可促进角质形成细胞的迁移/增殖，并对单核细胞具有趋化活性。有趣的是，在细菌感染后，层粘连蛋白的表达会增加。基于这些数据，我们认为分泌层粘连蛋白LG4-5衍生多肽在生理条件下对皮肤提供了基础水平的保护，并且在组织损伤/皮肤创伤和/或细菌感染后，层粘连蛋白的表达和分泌以及导致加工的LG4-5多肽水平增加的蛋白酶活性被诱导。在该方案中，我们将鉴定正常生理和感染条件下人体皮肤以及创伤皮肤中自然加工的层粘连蛋白LG4-5多肽，并探讨LG4-5衍生加工多肽在皮肤天然防御中的功能作用。这些数据应该表明，来自层粘连蛋白LG4-5模块的加工多肽是否在保护皮肤免受感染的皮肤屏障功能中发挥重要作用。

Laminins play a fundamental role in basement membrane architecture and function in human skin. The C-terminal LG modules of several laminin ý chains can be modified by proteolysis generating a LG1-3 and secreted LG4-5 module. Our preliminary data show that synthetic peptides derived from laminin ý3, ý4 and ý5 chain LG4 modules have effective antimicrobial activity and are able to kill bacteria by membrane permeabilization. In addition, LG4-derived peptides promote migration/proliferation of keratinocytes and have chemotactic activity for monocytes. Interestingly, expression of laminin can be increased after bacterial infection. Based on these data, we propose that secreted laminin LG4-5-derived peptides provide a basal level of protection in skin under physiological conditions and that after tissue damage/skin wounding and/or bacterial infection laminin expression and secretion is induced as well as protease activity which results in increased levels of processed LG4-5 peptides. In the proposal we will identify the naturally processed laminin LG4-5 peptides under normal physiological and infectious conditions in human skin as well as in wounded skin and explore the functional role of the LG4-5 derived processed peptides in skin innate defense. The data should indicate whether processed peptides from the laminin LG4-5 modules play an important role in skin barrier function protecting human skin against infection.