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

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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.