YAP/TAZ Regulation of Extracellular Matrix Homeostasis

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ABSTRACT: The major goal of this grant application is to determine the molecular mechanisms by which YAP/TAZ regulate age-related skin dermal extracellular matrix (ECM) homeostasis. In human skin, dermal fibroblasts are responsible for the production, organization, and homeostasis of the collagen-rich dermal ECM, which comprises the bulk of the skin. In young skin, direct attachment to intact collagen fibrils allows fibroblasts to achieve a spread architecture, through mechanical forces generated by the assembly of the cytoskeleton. In this state, the YAP/TAZ pathway is active, which maintains a youthful anabolic phenotype with net ECM production. In aged skin, fragmented collagen fibrils do not support fibroblast attachment, resulting in reduced mechanical force/stretching and a decline in YAP/TAZ function. In this state, fibroblasts display an aged catabolic phenotype, with net ECM degradation, which is self-perpetuating and creates a dermal microenvironment milieu that promotes the pathogenesis of many age- related skin diseases. We propose to investigate the hypothesis that the YAP/TAZ mechano-sensing signaling pathway in dermal fibroblasts is a critical regulator of age-related dermal ECM homeostasis. This data-driven hypothesis encompasses the key concept that dermal ECM homeostasis is governed by the adaptation of fibroblasts to the surrounding ECM microenvironment, rather than cell‐autonomous factors. Thus, we view dermal ECM homeostasis as involving “outside‐in adaptation” of dermal fibroblasts to the age‐related state of the dermal ECM, in which fibroblasts are embedded, and that this adaptation is critically regulated by YAP/TAZ. To test the above hypothesis, we have recently generated two complementary genetically modified mouse models: 1) conditional knockout of Yap/Taz in dermal fibroblasts, which results in striking impairment of both neonatal dermal ECM maturation and significantly accelerated chronological dermal ECM aging; 2) humanized mouse model of dermal aging driven by expression of collage-degrading matrix metalloproteinase-1 in dermal fibroblasts. Importantly, this model displays physiological inactivation of YAP/TAZ in response to ECM degradation. Following Specific aims are proposed to test the stated hypothesis: AIM 1: DETERMINE THE MOLECULAR MECHANISMS BY WHICH YAP/TAZ MEDIATES DERMAL ECM HOMEOSTASIS DURING EARLY POSTNATAL LIFE AND CHRONOLOGICAL AGING AIM 2: DETERMINE THE IMPACT OF RESTORATION OF YAP/TAZ FUNCTION ON DERMAL ECM HOMEOSTASIS AIM 3: INVESTIGATE MECHANISMS BY WHICH AGE-RELATED FUNCTIONAL DECLINE OF YAP/TAZ IS MEDIATED BY FIBROBLASTS “OUTSIDE-IN ADAPTION”