Novel role of Foxc2 in regulating metabolic disease

Abstract The long-term goal of this proposal is developed to uncover the molecular mechanisms and identify critical regulators governing lymphatic vascular function in health and disease in hopes of offering potential new therapeutic targets to combat cardiovascular and metabolic disorders. At the third year of postdoctoral training, the PI has published his first postdoctoral project and presented his studies in several prestigious conferences that pave the way for his transition to an independent investigator. The lymphatic system is responsible for maintaining interstitial fluid homeostasis, immune cell trafficking and lipid absorption. Lymphatic function participates largely in the pathogenesis of metabolic and cardiovascular diseases such as obesity and atherosclerosis. How lymphatic dysfunction leads to abnormal lipid transport and fat deposition, and conversely, how these metabolic diseases impair lymphatic function are poorly understood but highly medically relevant questions. Embryonic mice lacking Foxc2, a key transcription factor, prevents the formation and maturation of collecting lymphatic vessels. Despite the crucial role of Foxc2 in lymphatic development and remodeling, little is known about the role of Foxc2 in adult physiological and pathological lymphatic function; limitation is largely due to a lack of appropriate animal models. In this proposed application, the PI recently has generated novel inducible lymphatic endothelial cell (LEC)-specific Foxc2 gain-of-function and Foxc2 loss-of- function mice. Utilizing these powerful genetic tools, the PI observed that deficiency of LEC Foxc2 in adult mice dramatically increased the lymphangiogensis, improves impaired lymphatic drainage and lipid absorption in metabolic disorders (unpublished data). In the K99 phase, the PI will continue the current project to determine the molecular mechanism by which Foxc2 regulates adult lymphangiogenesis and lymphatic function in obese model. While in R00 phase, the PI will investigate the role of Foxc2 in modulating macrophage cholesterol efflux and reverse cholesterol transport in atherosclerotic model, as well as how Foxc2 will affect atherogenesis, which is diverging from his mentor’s work on Epsin, a family of endocytic adaptor proteins. Moreover, other than the unique mouse models and cutting-edge techniques, the PI will develop a novel LEC-specific nanoparticle delivery system based on his recent published platform to specifically target LEC Foxc2, thus may halt inflammation and inhibit atheroma progression. This proposal will be valuable for restoring impaired lymphatics to treat cardiovascular and metabolic diseases.