Role of astacin-like proteinases in physiological wound healing and scarring

虾红素样蛋白酶在生理性伤口愈合和疤痕形成中的作用

• 批准号: 282918683
• 负责人: Professor Dr. Christoph Becker-Pauly
• 金额: --
• 依托单位: Klinik für Dermatologie und Venerologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/282918683?language=en
• 关键词: Role; astacin; like; proteinases; physiological

Defective wound healing in skin, leading to chronic wounds or fibroproliferative disorders such as hypertrophic scarring, is a major healthcare challenge worldwide for which the market is estimated to be at least 10 billion euros and is destined to increase with the ageing population. The current lack of pathogenesis-specific therapies is largely due to the complexity of the multiple stages involved in wound healing and to the lack of information about the connectivity between the different players involved. This project aims to identify the roles of an emerging family of metalloproteinases, called astacin-like proteinases (ALPs), in normal and pathological wound healing.Unlike the matrix metalloproteinases, known largely for their roles in tissue degradation, the astacin-like proteinases, among which the bone morphogenetic protein-1/tolloid-like proteinases (BTPs) and meprin alpha and meprin beta are those found in skin, have recently been shown to orchestrate several aspects of tissue repair. Particularly important in this context are cytokine and growth factor activation, angiogenesis and extracellular matrix (ECM) assembly. Recent advances in quantitative proteomics to study proteolysis in complex samples and in the development of inhibitors directed against ALPs have made it possible to take an integrative approach to understanding the roles of these proteinases, which appear to have both overlapping and complementary substrate specificities, in tissue remodeling. The project will be multidisciplinary, including i) the characterization and application of new phosphinic peptide-type inhibitors specifically targeting individual ALPs, ii) the use of mouse models, human biopsies and skin primary cells to characterize the expression patterns of different ALPs in skin during the course of normal and fibroproliferative wound healing, iii) the application of quantitative proteomics (TAILS method) for the identification of ALP substrates, iv) the validation of these substrates in vitro and in vivo, and v) the use of the data (expression profiles, substrates) and tools (inhibitors) made available in the project to propose and test novel therapeutic strategies for scarring targeting either individual ALP members or subfamilies, using the above mouse models. The partners from Kiel and Freiburg have complementary expertise in ALPs, protease activity assays, quantitative proteomics, mouse models, fibrosis, and wound healing. The knowledge acquired during the course of the proposed project will form the basis for the development of new therapeutic strategies for the prevention and treatment of wound healing disorders.

皮肤伤口愈合不良，导致慢性伤口或纤维增生性疾病，如增生性瘢痕，是全球医疗保健的主要挑战，其市场估计至少为100亿欧元，并且注定会随着人口老龄化而增加。目前缺乏针对特定病因的治疗方法主要是由于伤口愈合涉及的多个阶段的复杂性以及缺乏有关所涉及的不同参与者之间的连接性的信息。本项目旨在确定一个新兴的金属蛋白酶家族，称为astacin样蛋白酶（ALP），在正常和病理性伤口愈合中的作用。与基质金属蛋白酶不同，基质金属蛋白酶主要是在组织降解中发挥作用，astacin样蛋白酶，其中骨形态发生蛋白-1/tolloid样蛋白酶（BTP）和meprin α和meprin β是在皮肤中发现的，最近已经显示出协调组织修复的几个方面。在这种情况下，特别重要的是细胞因子和生长因子活化，血管生成和细胞外基质（ECM）组装。定量蛋白质组学研究复杂样品中的蛋白水解和针对ALP的抑制剂的开发的最新进展使得有可能采取综合方法来理解这些蛋白酶的作用，这些蛋白酶似乎具有重叠和互补的底物特异性，在组织重塑中。该项目将是多学科的，包括i）特异性靶向个体ALP的新型膦肽型抑制剂的表征和应用，ii）使用小鼠模型、人类活检和皮肤原代细胞来表征正常和纤维增生性伤口愈合过程中皮肤中不同ALP的表达模式，3.定量蛋白质组学的应用（TAILS方法）用于鉴别ALP底物，iv）这些底物的体外和体内验证，以及v）数据的使用本项目中提供了一种新的治疗方法（表达谱、底物）和工具（抑制剂），以使用上述小鼠模型提出并测试靶向单个ALP成员或亚家族的瘢痕形成的新治疗策略。来自基尔和弗赖堡的合作伙伴在ALP、蛋白酶活性测定、定量蛋白质组学、小鼠模型、纤维化和伤口愈合方面具有互补的专业知识。在拟议项目的过程中获得的知识将形成新的治疗策略的基础，用于预防和治疗伤口愈合障碍的发展。

项目成果

STAT3 targeting in dystrophic epidermolysis bullosa

STAT3靶向治疗营养不良性大疱性表皮松解症

• DOI: 10.1111/bjd.18639
• 发表时间: 2020
• 期刊: British Journal of Dermatology
• 影响因子: 10.3
• 作者: Mittapalli VR;Kühl T;Kuzet SE;Gretzmeier C;Kiritsi D;Gaggioli C
• 通讯作者: Gaggioli C

Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration

• DOI: 10.1096/fj.201601113r
• 发表时间: 2017-03-01
• 期刊: FASEB JOURNAL
• 影响因子: 4.8
• 作者: Bedau, Tillmann;Peters, Florian;Becker-Pauly, Christoph
• 通讯作者: Becker-Pauly, Christoph

Inhibitors of BMP‐1/tolloid‐like proteinases: efficacy, selectivity and cellular toxicity

BMPâ1/tolloidâlike 蛋白酶抑制剂：功效、选择性和细胞毒性

• DOI: 10.1002/2211-5463.12540
• 发表时间: 2021
• 期刊: FEBS Open Bio
• 影响因子: 2.6
• 作者: Talantikite M;Lécorché P;Beau F;Damour O;Becker-Pauly C;Dive V;Vadon-Le Goff S;Moali C
• 通讯作者: Moali C