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

细胞外基质（ECM）稳态对正常组织功能至关重要，对细胞生长和分化等基本过程至关重要。在已知的调节ECM稳态的因素中，tgf - β具有广泛的作用，调节几乎所有ECM成分的合成和分解，其作用受到严格调节。我们的实验室是第一个证明内啡肽（一种tgf - β共受体）调节不同的tgf - β信号通路以调节ECM合成的实验室之一。我们最近的研究结果表明，小鼠内啡肽缺乏改善了基础和实验诱导的ECM沉积。虽然我们的研究结果表明内啡肽促进小鼠皮肤中的ECM沉积，但其潜在机制尚不清楚。描述内啡肽在调节tgf - β诱导的不同信号传导以控制ECM动力学中的作用机制将为了解皮肤组织如何维持稳态提供关键见解。我们假设内啡肽通过不同的细胞内信号通路调控tgf - β受体运输并协调tgf - β信号的平衡，从而调节皮肤中的ECM动力学和细胞反应。本研究的短期目标是：(1)确定内啡肽是皮肤细胞中tgf - β受体运输和tgf - β信号通路平衡的关键调节因子。(2)确定内啡肽是否调节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)在皮肤中，通过细胞类型特异性的内啡肽缺失，建立内啡肽作为tgf - β信号传导和ECM动力学的关键调节因子。我的研究计划的长期目标是描述tgf - β共受体调节tgf - β信号和皮肤ECM动力学的分子机制。提出的研究是这一长期目标的一个组成部分。中期目标将是阐明内啡肽-整合素相互作用和局灶黏附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。当前研究计划的首要重点是揭示参与ECM稳态调节的机制，这是几个基本细胞过程所必需的。该计划的研究结果将为控制tgf - β的调节机制提供独特的见解，tgf - β是ECM动力学中最重要的调节因子之一。提出的确定内啡肽调节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。

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.