Untersuchungen zur biologischen Rolle von neuen Kazal-typ Inhibitoren LEKTI-2 und LEKTI-3

新型 Kazal 型抑制剂 LEKTI-2 和 LEKTI-3 的生物学作用研究

• 批准号: 59922183
• 负责人: Professor Dr. Jens-Michael Schröder
• 金额: --
• 依托单位: Department of Transgenic Models of Diseases
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/59922183?language=en
• 关键词: Untersuchungen; zur; biologischen; Rolle; von

Analyses of healthy skin stratum corneum for antimicrobial peptides led to the discovery of two novel „lympho-epithelial Kazal-Type” protease inhibitors (LEKTI-2 and LEKTI-3). Whereas recombinant LEKTI-2 has antimicrobial properties and is a selective inhibitor of Kallikrein 5 (KLK-5), recombinant LEKTI-3 lacks antimicrobial activity, but exhibits potent inhibitory activities against both, tryptic KLK5 and chymotryptic KLK7. These two proteases have an essential role in the epidermal desquamation, which is disturbed in Netherton-Syndrome, an inflammatory skin disease with disrupted skin barrier due to a LEKTI-1 gene defect that causes LEKTI-1 deficiency. This was proven in LEKTI-1 k.o.- mice, which show a phenotype resembling Netherton syndrome patients.To study whether both novel LEKTIs are of similar importance in desquamation, LEKTI-2- und later also LEKTI-3 knock-out mice as well as transgenic mice overexpressing these LEKTIs will be generated. In this cooperation project in my laboratory murine LEKTI-2- and -3 orthologs will be cloned, its tissue expression in mice analysed and then recombinantly expressed for analyses of antimicrobial and protease-inhibiting properties, in particular for inhibition of desquamation-relevant kallikreins. We will further generate mLEKTI-2 and -3-antibodies for immunohistochemistry and ELISAs for LEKTI-2- and 3- to analyse its role in desquamation of various mouse models.

对健康皮肤角质层抗菌肽的分析发现了两种新型“淋巴上皮 Kazal 型”蛋白酶抑制剂（LEKTI-2 和 LEKTI-3），其中重组 LEKTI-2 具有抗菌特性，并且是一种选择性。激肽释放酶 5 (KLK-5) 抑制剂，重组 LEKTI-3 缺乏抗菌剂活性，但对胰蛋白酶 KLK5 和胰凝乳蛋白酶 KLK7 均表现出有效的抑制活性，这两种蛋白酶在表皮剥落中发挥重要作用，而内瑟顿综合征是一种因 LEKTI-1 导致皮肤屏障破坏的炎症性皮肤病。导致 LEKTI-1 缺陷的基因缺陷在 LEKTI-1 k.o.- 小鼠中得到证实，该小鼠表现出类似的表型。 Netherton 综合征患者。为了研究两种新型 LEKTI 在脱屑中是否具有相似的重要性，我实验室的这个合作项目将产生 LEKTI-2- 和后来的 LEKTI-3 敲除小鼠以及过度表达这些 LEKTI 的转基因小鼠。将克隆小鼠 LEKTI-2- 和 -3 直系同源物，分析其在小鼠中的组织表达，然后重组表达以进行分析抗菌和蛋白酶抑制特性，特别是抑制与脱屑相关的激肽释放酶我们将进一步生成 mLEKTI-2 和 -3-抗体，用于 LEKTI-2- 和 3- 的免疫组织化学和 ELISA，以分析其在各种小鼠脱屑中的作用。模型。