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Role of Integrin-linked kinase in skin homeostasis and carcinogenesis

整合素连接激酶在皮肤稳态和癌发生中的作用

基本信息

批准号：
262258314
负责人：
Professorin Dr. Sara A. Wickström, Ph.D.
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：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/262258314?language=en
关键词：
Role Integrin linked kinase skin

项目摘要

Epidermal (skin) tumors are the most common type of cancer in Europe. The epidermis is exposed to a wide range of environmental insults, including ultraviolet irradiation and chemical carcinogens. As a result, epidermal keratinocytes have a high risk of acquiring an oncogenic mutation. However, relatively few skin cancers develop because most cells that acquire mutations are either lost through the normal process of terminal differentiation or activation of a permanent state of cell cycle arrest termed senescence. Therefore, the analysis of factors that can co-operate with oncogenes is critical for understanding the mechanisms of cancer progression. We have previously analyzed mice lacking Integrin-linked kinase (ILK), a central effector of beta1 integrin adhesion receptor, in their skin. These mice display a profound defect in the balance between proliferation and terminal differentiation in the epidermis. Therefore it is clear that ILK regulates epidermal homeostasis and the proliferation-differentiation switch of the epidermal keratinocytes, but the molecular mechanisms of this regulation are still unclear. The aim of this project is to understand how the central adhesion signaling adaptor Integrin-linked kinase (ILK) regulates SC homeostasis in the skin, in particular through its effect on the matrix remodeling. We further aim to uncover how impairments in SC homeostasis and cell fate decisions contribute to skin carcinogenesis. The long-term goal of these studies is to precisely understand how cell-matrix interactions, through their ability to regulate growth factor bioavailability and activation, regulate cancer initiation and progression in humans.

表皮(皮肤)肿瘤是欧洲最常见的癌症类型。表皮暴露在广泛的环境侮辱中，包括紫外线照射和化学致癌物。因此，表皮角质形成细胞获得致癌突变的风险很高。然而，皮肤癌的发生相对较少，因为大多数获得突变的细胞要么在正常的末端分化过程中丢失，要么激活一种称为衰老的永久细胞周期停滞状态。因此，分析可以与癌基因协同作用的因素对于理解癌症进展的机制至关重要。我们之前已经分析了皮肤中缺乏整合素连接激酶(ILK)的小鼠，ILK是β1整合素黏附受体的中心效应器。这些小鼠在表皮的增殖和末端分化之间的平衡方面表现出严重的缺陷。由此可见，ILK对表皮的动态平衡和表皮角质形成细胞的增殖分化开关有明显的调节作用，但其分子机制尚不清楚。本项目的目的是了解中央黏附信号转接器整合素连接激酶(ILK)如何调节皮肤中SC的动态平衡，特别是通过其对基质重塑的影响。我们的进一步目标是揭示SC动态平衡和细胞命运决定的损害如何促进皮肤癌的发生。这些研究的长期目标是准确了解细胞-基质相互作用如何通过调节生长因子的生物可获得性和激活来调节人类癌症的启动和进展。