Lymphatic ERG signaling in scleroderma fibrosis

SSc的特点是自身免疫，小血管病变和纤维化导致的损伤

SSc is characterized by autoimmunity, small blood vessel vasculopathy, and fibrosis causing damage in multiple organ systems. Current evidence posits that SSc originates from the endothelial injury, and if vascular neoangiogenic response fails to repair the damage, downstream pathological fibrosis ensues. Analogous to the blood vascular system, rarefaction of lymphatic vessels has also been documented in SSc patients. In contrast to the blood endothelium, the molecular mechanisms governing the lymphatic system defects remain largely unexplored. Our overarching goal is to delineate the molecular and cellular mechanisms that drive impairment of blood and lymphatic systems in SSc. To improve treatment options for SSc vascular disease, there is an urgent need in uncovering new molecular targets. The signaling molecules that selectively regulate deficiency of both blood and lymphatic endothelial cells would be desirable targets for therapeutic intervention. Furthermore, although there is increased evidence of impaired lymphatic circulation, there have been no studies that addressed the mechanisms responsible for the impairment of the lymphatic system in SSc. Based on published and our new preliminary data, we hypothesize that transcription factors ERG is required for regeneration of lymphatic vasculature and its deficiency leads to impaired wound healing and fibrosis. Furthermore, we hypothesize that deficiency of ERG is a shared pathological feature, yet with critical variations, between blood and lymphatic endothelial cells in SSc patients, which may contribute to impaired angiogenesis and lymphangiogenesis in these patients. We propose to use a comprehensive strategy, including analysis of gene expression in freshly isolated BEC and LEC from SSc and control skin biopsies, together with our newly developed mouse models of SSc vasculopathy based on the postnatal deletion of Erg in blood and lymphatic cells, and mechanistic in vitro studies to molecularly and functionally characterize the role of ERG deficiency in blood and lymphatic systems. We propose the following three aims: In Aim 1 we will investigate the role and functional significance of ERG deficiency in LEC focusing on the signaling pathways controlling proliferation; In Aim 2 we will use lineage tracing to determine the functional consequences of Erg endothelial deficiency during physiological neo-angiogenesis and neo-lymphangiogenesis; In Aim 3 we will determine if Erg lymphatic deficiency leads to increased susceptibility to fibrosis. If successful, the proposed study has the potential to establish new basic knowledge pertinent to lymphatic cell function and dissect novel mechanism(s) driving SSc lymphangiopathy.