Defining the mechanisms of lymphatic and lymphovenous valve development

项目总结/摘要 在健康的成年人中，淋巴管系统每天收集多达12升的淋巴液。缺陷 淋巴管功能的损害导致水肿，其特征在于肢体肿胀。额外 水肿引起的健康问题包括纤维化、高血压、肥胖症甚至癌症。而 姑息治疗是可行的，但它们永远无法治愈。推进新疗法的障碍包括 目前对淋巴功能解剖和遗传控制的认识非常有限。 由淋巴管收集的淋巴通过收集淋巴管运输， 淋巴瓣防止液体停滞。最后，淋巴液通过四个淋巴静脉回流到血液循环中。 阀门.淋巴管或淋巴静脉瓣膜的缺陷与水肿有关。的目的 应用是为了更好地定义瓣膜发育的机制，这仍然知之甚少， 治疗淋巴水肿的关键障碍。 我们已经确定，Wnt/β-catenin信号通路是必要的发展， 淋巴和淋巴静脉瓣。在关键的初步数据的基础上，我们将试图确定上游 Wnt/β-catenin信号通路的激活剂和下游靶点。许多激动剂和拮抗剂， Wnt/β-catenin信号通路是可用的。因此，我们的发现可以转化为创新 治疗人类水肿患者的方法。

PROJECT SUMMARY/ABSTRACT 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/β-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/β-catenin signaling pathway. Numerous agonists and antagonists of Wnt/β-catenin signaling pathway are available. Therefore, our findings could translate into innovative approaches to treat human lymphedema patients.