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

细胞外基质（ECM）稳态对于正常组织功能是必不可少的，并且对于基本细胞过程如生长和分化是至关重要的。在已知调节ECM稳态的因子中，TGF-β在其广谱作用方面是显著的，调节几乎所有ECM组分的合成和分解，并且其作用受到严格调节。我们的实验室是第一个表明内皮糖蛋白，TGF-β共受体，差异调节不同的TGF-β信号通路，以调节ECM的合成。我们最近的研究结果表明，小鼠内皮糖蛋白缺乏改善基础和实验诱导的ECM沉积。虽然我们的研究结果表明内皮糖蛋白促进小鼠皮肤中的ECM沉积，但其潜在机制尚不清楚。内皮糖蛋白在调节不同的TGF-β诱导的信号传导以控制ECM动力学中的作用机制的描述将提供对皮肤组织稳态如何维持的关键见解。我们假设内皮糖蛋白严格调节TGF-β受体运输，并通过不同的细胞内信号传导途径协调TGF-β信号传导的平衡，以调节皮肤中的ECM动力学和细胞反应。本研究的短期目标是：（1）鉴定内皮糖蛋白作为皮肤细胞中TGF-β受体运输和TGF-β信号通过不同细胞内信号通路平衡的关键调节剂。(2)确定内皮糖蛋白是否调节TGF-β诱导的ECM蛋白的表达及其与整合素的相互作用以调节皮肤细胞反应。(3)使用细胞类型特异性缺失内皮糖蛋白在皮肤中体内建立内皮糖蛋白作为TGF-β信号传导和ECM动力学的关键调节剂。 我的研究计划的长期目标是描绘TGF-β共受体调节皮肤中TGF-β信号传导和ECM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。中期目标是阐明内皮素-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以及介导TGF-β作用的分子机制。 目前的研究计划的首要重点是解开ECM稳态的调节机制，这是几个基本的细胞过程所必需的。该计划的研究结果将为控制TGF-β作用的调节机制提供独特的见解，TGF-β是ECM动力学最重要的调节因子之一。所提出的确定内皮糖蛋白调节TGF-β诱导的ECM沉积的分子途径的策略是创新的，并将推进TGF-β信号传导和基质生物学交叉点的知识。此外，这些研究的结果可能会导致开发新的工具来操纵动物和人类的组织修复。

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.