Role of endoglin in the regulation of extracellular matrix dynamics in the skin

内皮糖蛋白在皮肤细胞外基质动力学调节中的作用

• 批准号: RGPIN-2021-04077
• 负责人: Philip, Anie
• 金额: $ 2.33万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742855
• 关键词: Role; endoglin; regulation; extracellular; matrix

The extracellular matrix (ECM) homeostasis is essential for normal tissue function and is critical for fundamental cellular processes such as growth and differentiation. Among the factors that are known to regulate ECM homeostasis, TGF-beta is remarkable in its broad spectrum of effects, regulating the synthesis and breakdown almost all ECM components, and its action is tightly regulated. Our laboratory was among the first to show that endoglin, a TGF-beta co-receptor, differentially regulates distinct TGF-beta signaling pathways to regulate ECM synthesis. Our recent results show that endoglin deficiency in mice ameliorates basal and experimentally-induced ECM deposition. While our findings indicate that endoglin promotes ECM deposition in the mouse skin, the underlying mechanisms are unknown. Delineation of the mechanism of action of endoglin in regulating distinct TGF-beta-induced signaling to control ECM dynamics will provide key insights into how skin tissue homeostasis is maintained. We hypothesize that endoglin critically regulates TGF-beta receptor trafficking and orchestrates the balance of TGF-beta signaling by distinct intracellular signaling pathways to modulate ECM dynamics and cellular responses in the skin. The short term aims of the proposed research are: (1) To identify endoglin as a crucial regulator of TGF-beta receptor trafficking and of the balance of TGF-beta signaling via distinct intracellular signaling pathways in skin cells. (2) To determine whether endoglin regulates the expression of TGF-beta-induced ECM proteins and their interaction with integrins to regulate skin cell responses. (3) To establish endoglin as a critical regulator of TGF-beta signaling and ECM dynamics using cell type-specific deletion of endoglin in vivo in the skin. The long term goal of my research program is to delineate the molecular mechanisms by which TGF-beta co-receptors regulate TGF-beta signaling and ECM dynamics in the skin. The research proposed is an integral part of this long-term goal. The medium-term goal will be to elucidate the molecular mechanisms by which endoglin-integrin interaction and focal adhesion kinase activation regulate cytoskeleton remodeling, and cellular function, and mediate TGF-beta action. The overarching focus of the current research program is to unravel the mechanisms involved in the regulation of ECM homeostasis which is essential for several fundamental cellular processes. The findings from the proposed program will provide unique insights into the regulatory mechanism controlling the action of TGF-beta one of the most crucial regulators of ECM dynamics. The proposed strategy of determining the molecular pathways by which endoglin modulates TGF-beta-induced ECM deposition is innovative and will advance knowledge at the intersection of TGF-beta signaling and matrix biology. Furthermore, findings from these studies may lead to the development novel tools to manipulate tissue repair in animals and humans.

细胞外基质(ECM)的稳态对正常的组织功能至关重要，对生长和分化等基本细胞过程也是至关重要的。在已知的调节细胞外基质动态平衡的因素中，转化生长因子-β的作用范围广泛，调节几乎所有细胞外基质成分的合成和分解，其作用受到严格的调控。本实验室是最早发现转化生长因子-β共受体endoglin对不同的转化生长因子-β信号通路进行差异化调控以调节细胞外基质合成的实验室之一。我们最近的结果表明，小鼠缺乏endoglin可以改善基础和实验诱导的ECM沉积。虽然我们的发现表明endoglin促进了小鼠皮肤中ECM的沉积，但其潜在的机制尚不清楚。阐明endoglin在调节不同的转化生长因子-β诱导的信号以控制细胞外基质动态的作用机制将为如何维持皮肤组织的动态平衡提供关键的见解。我们假设，endoglin通过不同的细胞内信号通路来调节皮肤细胞外基质动力学和细胞反应，从而关键地调节转化生长因子-β受体的运输，并协调转化生长因子-β信号的平衡。这项研究的短期目标是：(1)确定endoglin是转化生长因子-β受体转运的重要调节因子，并通过不同的细胞内信号通路调节转化生长因子-β信号的平衡。(2)确定endoglin是否调节转化生长因子-β诱导的细胞外基质蛋白的表达及其与整合素的相互作用，从而调节皮肤细胞的反应。(3)通过体内细胞类型特异性删除皮肤中的endoglin，建立endoglin作为转化生长因子-β信号和细胞外基质动力学的关键调节因子。我的研究计划的长期目标是描述转化生长因子-β共受体调节转化生长因子-β信号和皮肤细胞外基质动力学的分子机制。拟议的研究是这一长期目标的组成部分。中期目标将是阐明内源性整合素相互作用和粘着斑激酶激活调节细胞骨架重塑和细胞功能的分子机制，并介导转化生长因子-β作用。当前研究计划的主要重点是解开参与ECM稳态调节的机制，这是几个基本细胞过程所必需的。拟议项目的发现将为控制转化生长因子-β的作用的调控机制提供独特的见解，转化生长因子-β是细胞外基质动力学最关键的调节因子之一。所提出的确定endoglin调节转化生长因子-β诱导的细胞外基质沉积的分子途径的策略是创新的，将促进转化生长因子-β信号转导和基质生物学的交叉领域的知识。此外，这些研究的发现可能会导致开发新的工具来操纵动物和人类的组织修复。