Project Summary Lymphatic vessels control fluid homeostasis and immune cell circulation in all body tissues, and lipid absorption in the small intestine. Their dysfunction is implicated in cardiovascular, metabolic and neurodegenerative disease. Normal lymphatic function requires a division of labor between terminal lymphatic capillaries that uptake lymph via open button junctions, and collectors that transport lymph to the veins, which have tighter zipper junctions. We here address the role of LEC button and zipper junctions in health and disease, with the hypothesis that LEC junction manipulation offers novel opportunities in clinical settings. We have shown that zippering of intestinal lacteals prevents chylomicron absorption and renders mice resistant to diet-induced obesity, prompting us to investigate molecular mechanisms inducing formation of buttons and zippers and test their implication in lipid uptake, obesity and inflammation. Collectively, the proposed studies will elucidate an as yet understudied aspect of endothelial biology and identify molecular mechanisms and novel approaches based on this knowledge that could be useful to reduce obesity via zipper formation and may be effective in diseases associated with lymphatic dysfunction via buttons.