AIBP-Mediated Cholesterol Efflux and Angiogenesis

AIBP 介导的胆固醇流出和血管生成

• 批准号: 9178668
• 负责人: Longhou Fang
• 金额: $ 24.29万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-07 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178668
• 关键词: ATP binding cassette transporter 1; 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; 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; Supervision; Testing; Therapeutic; Therapeutic Intervention; Transgenic Organisms; Transplantation; United States; Veins; Zebrafish; angiogenesis; base; cardiac angiogenesis; cardiac regeneration; cholesterol transporters; constriction; embryo monitoring; experimental study; improved; knock-down; mortality; overexpression; prevent; protein expression; protein function; reconstitution; repaired; restoration; tissue regeneration

Project Summary 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.

项目概要 心肌梗塞是美国死亡和发病的主要原因。再灌注后， 血管生成和微循环的恢复是恢复正常心脏功能的关键组成部分 功能。血管生成对于斑马鱼心脏再生也很重要。已经取得了很大进展 有助于理解血管生成的分子机制，但代谢之间的联系 对血管生成的研究较少。我的初步研究强烈表明胆固醇从 内皮细胞调节血管生成。我发现体外和胚胎斑马鱼的血管生成是 受 ApoA-I 结合蛋白 (AIBP) 调节，AIBP 是一种在蛋白质筛选中鉴定出的分泌蛋白，该蛋白质在物理上 与 ApoA-I 相关。 AIBP 加速 ABCG1 介导的胆固醇从内皮细胞 (EC) 流出 体外。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 萌芽，而 AIBP 敲低则导致 SeA 失调 发芽和分枝。在我指导的 K99 阶段，我建议检验分泌 AIBP 的假设 作为从 EC 流出的胆固醇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胚胎 斑马鱼的血管生成。我发现 AIBP 缺失引起的表型是由 细胞胆固醇转运蛋白 ABCA1 和 ABCG1 的敲低。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 将建立一个以前未被认识的机制，将胆固醇流出与胚胎联系起来 血管生成。然后在我的独立 R00 阶段，我将证明 AIBP 在成人中过度表达 斑马鱼会减弱心脏再生。冠状动脉血管系统的形成被认为对于 心脏再生，因为它可以为心脏的强劲增殖提供必要的资源 心肌细胞。我将制作一个AIBP条件表达转基因鱼系，并研究其影响 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。我的第二个目标 独立R00阶段的目的是评估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，我认为心肌细胞特异性的 AIBP 损失会 在心脏肥大的情况下促进血管生成。这些研究将阐明其潜在作用 AIBP 控制心脏再生和心脏肥大中的血管生成，并表明可能 通过促进血管生成来刺激微脉管系统恢复的治疗干预措施。