In healthy adult humans the lymphatic vasculature collects as much as 12 liters of lymph per day. Defects in lymphatic vascular function lead to lymphedema, which is characterized by the swelling of limbs. Additional health problems caused by lymphedema include fibrosis, hypertension, obesity and even cancer. While palliative treatments are available, they are never curative. Barriers to advancing new therapies include a remarkably limited present understanding of lymphatic functional anatomy and genetic controls. Lymph collected by lymphatic vessels is transported through collecting lymphatic vessels in which lymphatic valves prevent fluid stasis. Finally, lymph is returned to the blood circulation via four lymphovenous valves. Defects in lymphatic or lymphovenous valves are associated with lymphedema. The objective of this application is to better define the mechanisms of valve development, which remain poorly understood and is a critical barrier for treating lymphedema. We have determined that Wnt/?-catenin signaling pathway is necessary for the development of lymphatic and lymphovenous valves. Building on key preliminary data we will attempt to identify the upstream activators and downstream targets of Wnt/?-catenin signaling pathway. Numerous agonists and antagonists of Wnt/?-catenin signaling pathway are available. Therefore, our findings could translate into innovative approaches to treat human lymphedema patients.
We will determine how Wnt/?-catenin signaling pathway regulates lymphatic and lymphovenous valve development. This knowledge will enable new approaches to treat primary lymphedema. Thus, our work is relevant to NIH's mission to develop fundamental knowledge that will reduce the burdens of human disease.
| Cha, Boksik; Geng, Xin; Mahamud, Md Riaj et al. (2018) Complementary Wnt Sources Regulate Lymphatic Vascular Development via PROX1-Dependent Wnt/?-Catenin Signaling. Cell Rep 25:571-584.e5 |
| Geng, Xin; Cha, Boksik; Mahamud, Md Riaj et al. (2017) Intraluminal valves: development, function and disease. Dis Model Mech 10:1273-1287 |
| Cha, Boksik; Srinivasan, R Sathish (2016) Mechanosensitive ?-catenin signaling regulates lymphatic vascular development. BMB Rep 49:403-4 |
| Cha, Boksik; Geng, Xin; Mahamud, Md Riaj et al. (2016) Mechanotransduction activates canonical Wnt/?-catenin signaling to promote lymphatic vascular patterning and the development of lymphatic and lymphovenous valves. Genes Dev 30:1454-69 |
