AIBP-mediated Cholesterol Efflux and Angiogenesis

AIBP 介导的胆固醇流出和血管生成

• 批准号: 8353288
• 负责人: Longhou Fang
• 金额: $ 11.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353288
• 关键词: ATP-Binding Cassette Transporters; Adult; Animals; Aorta; Apolipoprotein A-I; Arteries; Attenuated; Binding Proteins; Cardiac; Cardiac Myocytes; Cholesterol; Cholesterol Homeostasis; Coronary; Dorsal; Ectopic Expression; Embryo; Embryonic Development; Endothelial Cells; Fishes; Goals; Heart; Heart Hypertrophy; High Density Lipoproteins; Human; In Vitro; Knockout Mice; Life; Mammals; Measures; Mediating; Mentors; Metabolism; Microcirculation; Microcirculatory Bed; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardium; Natural regeneration; Pathologic; Phase; Phenocopy; Phenotype; Play; Protein Deficiency; Protein Overexpression; Proteins; Recovery; Reperfusion Therapy; Research; Resected; Resources; Role; Site; Testing; Therapeutic; Therapeutic Intervention; Transgenic Organisms; Transplantation; United States; Veins; Zebrafish; angiogenesis; base; cholesterol transporters; constriction; embryo monitoring; improved; mortality; overexpression; prevent; protein expression; protein function; reconstitution; repaired; research study; restoration; tissue regeneration

DESCRIPTION (provided by applicant): Myocardial infarction is the leading cause of mortality and morbidity in the US. Following reperfusion, angiogenesis and restoration of microcirculation is a critical component in the recovery of normal cardiac function. Angiogenesis is also important for zebrafish heart regeneration. Much progress has been made towards understanding of the molecular mechanisms of angiogenesis, but the connection between metabolism and angiogenesis is less studied. My preliminary studies strongly suggest that cholesterol efflux from endothelial cells regulates angiogenesis. I found that angiogenesis in vitro and in embryonic zebrafish was regulated by ApoA-I binding protein (AIBP), a secreted protein identified in a screen of proteins that physically associate with ApoA-I. AIBP accelerated ABCG1-mediated cholesterol efflux from endothelial cells (EC) in vitro. Furthermore, AIBP controlled formation of segmental arteries (SeA) in embryonic zebrafish. Overexpression of AIBP inhibited SeA sprouting, while AIBP knockdown resulted in dysregulated SeA sprouting and branching. In my mentored K99 phase, I propose to test the hypothesis that secreted AIBP functions as a site-specific regulator of cholesterol efflux from EC and governs embryonic angiogenesis. First, I plan to demonstrate that AIBP-mediated, ABC transporters-dependent cholesterol efflux regulates embryonic angiogenesis in zebrafish. I found that the phenotype caused by the loss of AIBP was phenocopied by knockdown of cellular cholesterol transporters ABCA1 and ABCG1. My goal in this Aim is to prove that the effect of AIBP on embryonic angiogenesis relies on the AIBP function in cholesterol metabolism. These studies will establish a previously unrecognized mechanism connecting cholesterol efflux with embryonic angiogenesis. Then in my independent R00 phase, I will demonstrate that AIBP overexpression in adult zebrafish attenuates heart regeneration. Formation of coronary vasculature is believed to be important for heart regeneration because it conceivably provides resources necessary for robust proliferation of cardiomyocytes. I will make an AIBP conditional expression transgenic fish line, and investigate the impact of AIBP overexpression on angiogenesis that occurs during zebrafish heart regeneration. My second Aim in the independent R00 phase is to assess that AIBP expression modulates coronary angiogenesis in mice. Because my results suggest that AIBP limits angiogenesis, I propose that cardiomyocyte-specific loss of AIBP would promote angiogenesis under conditions of cardiac hypertrophy. These studies will elucidate a potential role for AIBP-governed angiogenesis in heart regeneration and in cardiac hypertrophy and suggest possible therapeutic interventions to stimulate the recovery of the microvasculature by promoting angiogenesis.

描述（由申请人提供）：心肌梗塞是美国死亡和发病的主要原因。再灌注后，血管生成和微循环恢复是恢复正常心脏功能的关键组成部分。血管生成对于斑马鱼心脏再生也很重要。在理解血管生成的分子机制方面已经取得了很大进展，但代谢与血管生成之间的联系的研究较少。我的初步研究强烈表明，内皮细胞的胆固醇流出调节血管生成。我发现体外和胚胎斑马鱼的血管生成受到 ApoA-I 结合蛋白 (AIBP) 的调节，AIBP 是在与 ApoA-I 物理相关的蛋白质筛选中发现的一种分泌蛋白。 AIBP 在体外加速了 ABCG1 介导的胆固醇从内皮细胞 (EC) 的流出。此外，AIBP 控制胚胎斑马鱼节段动脉 (SeA) 的形成。 AIBP 的过表达抑制 SeA 发芽，而 AIBP 敲低则导致 SeA 发芽和分支失调。在我指导的 K99 阶段，我建议检验以下假设：分泌型 AIBP 作为内皮细胞胆固醇流出的位点特异性调节剂，并控制胚胎血管生成。首先，我计划证明 AIBP 介导的 ABC 转运蛋白依赖性胆固醇流出调节斑马鱼的胚胎血管生成。我发现 AIBP 缺失引起的表型可以通过细胞胆固醇转运蛋白 ABCA1 和 ABCG1 的敲低来复制。我的目标是证明AIBP对胚胎血管生成的影响依赖于AIBP在胆固醇代谢中的功能。这些研究将建立一种以前未被认识的机制，将胆固醇流出与胚胎血管生成联系起来。然后在我的独立 R00 阶段，我将证明成年斑马鱼中 AIBP 的过度表达会减弱心脏再生。冠状脉管系统的形成被认为对于心脏再生很重要，因为它可以为心肌细胞的强劲增殖提供必需的资源。我将制作AIBP条件表达转基因鱼系，并研究AIBP过度表达对斑马鱼心脏再生过程中发生的血管生成的影响。我在独立 R00 阶段的第二个目标是评估 AIBP 表达调节小鼠冠状动脉血管生成。因为我的结果表明 AIBP 限制了血管生成，所以我提出心肌细胞特异性的 AIBP 损失将在心脏肥大的情况下促进血管生成。这些研究将阐明 AIBP 控制的血管生成在心脏再生和心脏肥大中的潜在作用，并提出可能的治疗干预措施，通过促进血管生成来刺激微脉管系统的恢复。