Role of Neuropilin receptors in lymphangiogenesis

描述（由申请人提供）：淋巴血管调节体液平衡、膳食脂质吸收和免疫系统功能。淋巴管缺失是致命的，淋巴管发育受损会引起间质中液体和蛋白质的积聚，导致淋巴水肿和持续的炎症反应。淋巴水肿和慢性炎症是心血管疾病的加重因素，是影响数百万无法获得治愈治疗的人的进行性和终身疾病。能促进淋巴管生成的治疗药物应能预防淋巴水肿，并对心血管疾病患者有益。这种药物的产生需要理解淋巴血管生成的细胞和分子介质。淋巴血管系统形成了一个固定的、分层的分支网络，覆盖了皮肤和身体的大多数内部器官。淋巴管通过发芽生长，随后成熟为包含保证流体输送的阀门的集管。淋巴内皮细胞（LECs）在发芽过程中如何相互作用形成一个定型网络，以及它们的成熟是如何被调节的，这在很大程度上仍然是未知的。我们将研究血管内皮生长因子（vegf）和III类信号蛋白（Sema3）的共受体Neuropilin 1和2 （Nrp1, 2）在淋巴管生成中的作用。我们已经证明，主要的淋巴管生成生长因子VEGF-C与Nrp2-VEGFR3复合物的结合对LEC的发芽至关重要。除了vegf - c - nrp2 - vegfr3诱导的LEC发芽外，我们的初步结果表明，Sema3A信号通过另一个Nrp受体Nrp1在淋巴管成熟中起选择性作用。我们建议分别通过Nrp2和1来研究VEGF-C和Sema3A在LEC发芽和成熟过程中的这些重要的、非冗余的功能。VEGF-C和Sema3A可能通过不同的细胞和分子机制刺激淋巴管生成和预防淋巴水肿。综上所述，这是一个全面的项目，旨在进一步了解关键的生物过程，淋巴管生成，这可能会导致新的治疗方法的发展，以防止淋巴水肿和心脏病。

DESCRIPTION (provided by applicant): The lymphatic vasculature regulates fluid homeostasis, absorption of dietary lipids and immune system function. The absence of lymphatic vessels is lethal, and impaired lymphatic vessel development causes fluid and protein accumulation in the interstitium, resulting in lymphedema and a persistent inflammatory response. Lymphedema and chronic inflammation are aggravating factors in cardiovascular disease, and are progressive and lifelong conditions affecting millions of people for which curative treatments are not available. Therapeutic agents that can promote lymphangiogenesis should prevent lymphedema and benefit individuals with cardiovascular pathologies. Generation of such agents requires understanding of the cellular and molecular mediators of lymphangiogenesis. The lymphatic vasculature forms a stereotyped, hierarchical branching network that covers the skin and most internal organs of the body. Lymphatic vessels grow by sprouting, and subsequently mature into collecting vessels containing valves that ensure fluid transport. How lymphatic endothelial cells (LECs) interact during sprouting to form a stereotyped network, and how their maturation is regulated remains largely unknown. We will investigate the role of Neuropilin 1 and 2 (Nrp1, 2), co-receptors for vascular endothelial growth factors (VEGFs) and class III Semaphorins (Sema3), in lymphangiogenesis. We have shown that binding of the major lymphangiogenic growth factor VEGF-C to a Nrp2-VEGFR3 complex is critical for LEC sprouting. In addition to VEGF-C-Nrp2-VEGFR3-induced LEC sprouting, our preliminary results show that Sema3A signaling via the other Nrp receptor Nrp1 plays a selective role in lymphatic vessel maturation. We propose to investigate these essential, non-redundant functions of VEGF-C and Sema3A via Nrp2 and 1 in LEC sprouting and maturation, respectively. VEGF-C and Sema3A might be useful to stimulate lymphangiogenesis and prevent lymphedema via distinct cellular and molecular mechanisms. Taken together, this is a comprehensive program aimed at further our understanding of a key biological process, lymphangiogenesis, that may result in development of new therapeutic approaches to prevent lymphedema and cardiac diseases.