淋巴管收集并转运组织间液体到静脉循环和全身各处，对组织稳态、免疫监视及脂类转运至关重要。淋巴管生成不足会造成淋巴回流受阻，即淋巴水肿，目前还没有有效治疗措施。我们发现调控胆固醇代谢的一个新蛋白——载脂蛋白A1结合蛋白（AIBP）在淋巴水肿病人皮肤组织中表达量明显变化，Aibp-/-小鼠中表明AIBP促进真皮组织中淋巴管生成，体外实验提示AIBP可能通过质膜微囊中cav-1调控淋巴管生成。因此，本课题提出AIBP通过增强胆固醇流出影响质膜微囊，从而减少质膜微囊中cav-1对VEGFR3信号通路的抑制作用来促进淋巴管生成。首先，将进一步研究AIBP对淋巴管生成的作用；其次，研究AIBP调控淋巴管生成的确切机制；最后，研究AIBP作为分泌蛋白，在病理性淋巴管生成中的作用及治疗价值。本课题将率先把胆固醇代谢和淋巴管生成联系起来，帮助理解淋巴管生成的调控机制，同时为淋巴水肿提供新的治疗方案。

Lymphatic vessels collect and transport interstitial fluid to venous circulation throughout the body. Lyphangiogenesis generates lymphatic vessels that are essential for maintenance of tissue fluid homeostasis and for immune surveillance as well as for lipid transport. Insufficient lymphangiogenesis, resulting from congenital disorders or arising in the setting of acquired damage to the lymphatic system, may result in lymphatic dysfuction, which impairs fluid drainage from the interstitium. Clinically, this manifests as lymphedema, a disease presenting as an accumulation of protein-rich fluid in the interstitial space, followed by tissue changes, including accumulation of hypercellular adipose and fibrotic tissue. More than 100 million people are affected by lymphedema worldwide. Unfortunately, effective therapeutic strategies to treat lymphedema are still lacking. Our recent evidence suggests that apoA1 binding protein (AIBP) may be part of the mechanistic link between lipid metabolism and lymphagiogenesis. By studying human lymphedematous tissues, we found that AIBP expression is increased in the affected tissues of lymphedema patients, indicating a role of AIBP in lymphangiogenesis. We then generated AIBP knockout mice, which are viable and fertile, and found loss of AIBP in mice impeded lymphangiogenesis. In human lymphatic endothelia cells (HLEC), AIBP and apoA1 combination promote in vitro lymphangiogenesis, while cav1 prohibits lymphatic tube formation. We also found VEGFR3 binds cav1 and is located in caveolae of HLEC. Moreover, MβCD, which disrupts caveolae by sequestering cholesterol, reduces plasma membrane cav-1 levels and facilitates in vitro lymphangiogenesis. Because AIBP-targeted cholesterol efflux disrupts caveolae, we therefore hypothesize that AIBP enhances cholesterol removal to disrupt caveolae, which abolishes cav-1 inhibition of VEGFR3 and results in augmented VEGFR3 signaling and lymphangiogenesis. Herein, my specific aims are: (1) To further determine the role of AIBP in lymphangiogenesis and lymphatic development; (2) To determine the molecular mechanisms about AIBP enhances VEGFR3 signaling by increasing cholesterol efflux and reducing the inhibition of cav-1 within caveolae. (3) To determine the effect of AIBP administration on lymphatic regeneration in murine model. Our studies on AIBP-regulated lymphangiogenesis will help guide the design of novel therapy.