Role of Neuropilin receptors in lymphangiogenesis

描述(申请人提供)：淋巴管系统调节体液平衡、饮食脂肪吸收和免疫系统功能。淋巴管的缺失是致命的，淋巴管发育受损会导致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，是影响数百万人的渐进性和终生疾病，无法获得根治性治疗。能够促进淋巴管生成的治疗药物应该可以防止淋巴水肿，并使患有心血管疾病的患者受益。这类药物的产生需要了解淋巴管生成的细胞和分子介质。淋巴管系统形成了一个老套的、层次分明的分支网络，覆盖了皮肤和身体的大部分内脏。淋巴管通过萌芽生长，然后成熟为含有确保液体运输的瓣膜的集合管。淋巴内皮细胞(LECs)在萌发过程中如何相互作用形成一个刻板的网络，以及它们的成熟是如何受到调控的，目前仍不清楚。我们将研究血管内皮生长因子(VEGFs)和III类信号素(Sema3)的共同受体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复合体的结合对LEC的萌发至关重要。除了VEGF-C-Nrp2-VEGFR3诱导的LEC萌发外，我们的初步结果表明，Sema3A信号通过另一个NRP受体Nrp1在淋巴管成熟过程中起着选择性的作用。我们建议分别通过Nrp2和1研究VEGF-C和Sema3A在LEC萌芽和成熟过程中的这些基本的、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，这是一项全面的计划，旨在加深我们对淋巴管生成这一关键生物学过程的理解，这可能会导致开发新的治疗方法来预防淋巴水肿和心脏疾病。 公共卫生相关性：控制淋巴管生成的新信号机制的发现将为开发治疗淋巴水肿和预防动脉粥样硬化性心血管疾病的新治疗策略提供新的见解和工具。

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. PUBLIC HEALTH RELEVANCE: The discovery of novel signaling mechanisms controlling lymphangiogenesis will provide new insights and tools into developing new therapeutic strategies for treatment of lymphedema and prevention of atherosclerotic cardiovascular diseases.