AIBP Mediates a Novel Interplay between Cholesterol Metabolism and Lymphangiogenesis

 描述（由申请方提供）：淋巴水肿是一种使人衰弱的疾病，可能由先天性疾病或后天淋巴管损伤引起。患有这种疾病的患者表现为受影响组织的水肿性肿胀，因为组织间隙中富含蛋白质和脂质的液体过多。进一步的组织重塑将导致脂肪积聚和患病组织的纤维化;迄今为止，对这种疾病的治疗是有限的。最近，新兴的研究表明，增加淋巴管生成，导致新的淋巴管的产生，可能代表一种新的治疗方法。淋巴管生成受VEGFC/VEGFR 3轴诱导的源自静脉前体的淋巴管内皮细胞的增殖和迁移控制。我们最近发现，apoA-I结合蛋白（AIBP）和小窝/脂筏调节血管生成。在这个提议中，我们试图阐明AIBP和小窝在淋巴管生成中的作用。我们的初步研究表明，AIBP和小窝调节VEGFR 3信号和淋巴管生成。我们将检验AIBP通过增加胆固醇流出和减少小窝内小窝蛋白-1的抑制来增强VEGFR 3信号传导的假设。为此，我们将利用体外淋巴管内皮细胞培养系统，对不同的转基因斑马鱼 品系和转基因小鼠模型。我们对AIBP的研究将有助于开发新的治疗方法，促进淋巴管生长，恢复由功能障碍性淋巴管疾病引起的淋巴功能。

 DESCRIPTION (provided by applicant): Lymphedema is a debilitating disease that may be caused by congenital disorder or acquired damage to lymphatic vessels. Patients with this disease manifest edematous swelling in the affected tissue because of excessive protein- and lipid-rich fluid in the interstitial space. Further tissue remodeling will result in adipose accumulation and fibrosis of the ailing tissue; treatment for this disease is so far limited. Recently, emerging studies have indicated that augmenting lymphangiogenesis, which results in generation of new lymphatic vessels, might represent a new therapeutic approach. Lymphangiogenesis is controlled by the VEGFC/VEGFR3 axis-induced proliferation and migration of lymphatic endothelial cells derived from the venous precursors. We recently demonstrated that apoA-I binding protein (AIBP) and caveolae/lipid rafts regulate angiogenesis. In this proposal, we sought to elucidate the role of AIBP and caveolae in lymphangiogenesis. Our preliminary studies suggest that AIBP and caveolae regulate VEGFR3 signaling and lymphangiogenesis. We will test the hypothesis that AIBP enhances VEGFR3 signaling by increasing cholesterol efflux and reducing the inhibition of caveolin-1 within caveolae. To this end, we will use in vitro lymphatic endothelial cell culture system, different transgenic zebrafish lines and genetically modified mouse models. Our studies on AIBP will contribute to the development of new therapies facilitating lymphatic vessel growth and restoring lymphatic functions in diseases caused by dysfunctional lymphatics.