AIBP and Endothelial Function

AIBP 和内皮功能

基本信息

批准号：
9039657
负责人：
Yury Miller
金额：
$ 51.96万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9039657
关键词：
Address Adhesions Animal Model Aorta Apolipoprotein A-I Apoptosis Arterial Fatty Streak Atherosclerosis Autophagocytosis Binding Proteins Blood Vessels Cardiovascular Diseases Cardiovascular system Cell Adhesion Molecules Cell membrane Cell model Cell physiology Cells Cholesterol Consensus Development Diet Disease Dyslipidemias Endothelial Cells Event Foam Cells Future Health High Density Lipoproteins Human Inflammation Inflammatory Inflammatory Response Infusion procedures Knockout Mice Lead Leukocytes Lipids Lipoproteins Low-Density Lipoproteins Measures Mediating Membrane Lipids Membrane Microdomains Modeling Modification Morbidity - disease rate Mus Myocardial Infarction Nature Pathology Patients Peptides Peripheral arterial disease Plasma Play Population Prevention Process Property Protein Deficiency Proteins Publishing Raisins Receptor Signaling Recombinants Recruitment Activity Role Sampling Signal Pathway Smooth Muscle Myocytes Stroke Surface Testing Therapeutic Therapeutic Effect Tissues United States Vascular Permeabilities Vascular Smooth Muscle Zebrafish atheroprotective base cardiovascular disorder risk chemokine cytokine endothelial dysfunction feeding improved in vivo macrophage monocyte mortality mouse model novel novel therapeutics oxidized low density lipoprotein paracrine prevent protein expression research study transcytosis vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Inflammation and lipid accumulation in the vascular wall constitute critical events in initiation and progression of cardiovascular disease, manifested in myocardial infarction and stroke in more than a half of the US population. Activated endothelial cells (EC) secrete chemokines and express adhesion molecules to recruit leukocytes to the vascular wall. Oxidized LDL and dysfunctional HDL play a major role in EC-mediated inflammation, whereas functional HDL preserves the EC integrity and prevents inflammatory responses. One of the major mechanisms by which HDL exerts its protective function is cholesterol efflux from the plasma membrane of EC. We discovered that apoA-I binding protein (AIBP) significantly improves HDL function by accelerating cholesterol efflux from EC. AIBP is a secreted protein and its effect on EC is paracrine and non-cell autonomous. These findings open the possibility of using AIBP or AIBP-derived peptides as a therapy to improve the cholesterol efflux function of HDL and thereby prevent and/or reverse vascular pathology. Here we propose to test the hypothesis that AIBP reduces EC inflammatory responses via modulation of cholesterol efflux and lipid rafts. We will test this hypothesis in cellular models as well as in aorta explants, by measuring expression of cytokines and adhesion molecules, probing relevant signaling pathways, detecting ROS, apoptosis and autophagy, and assessing LDL transcytosis and monocyte adhesion. Further, we will determine effects of systemic and tissue-specific AIBP deficiency on endothelial function. We have developed Aibp LoxP and Aibp knockout mice, which are viable and fertile. AIBP expression has been detected in macrophages and vascular smooth muscle cells (VSMC) of mouse atherosclerotic lesions. Thus, we propose that AIBP secreted by macrophages and/or VSMC protects aortic EC and that deletion of Aibp in these cells will lead to exacerbated EC inflammatory responses and increased atherosclerosis burden. We also hypothesize that, conversely, raising AIBP levels will improve endothelial function and reduce inflammation. The hypothesis will be tested in vivo with mouse and zebrafish animal models and ex vivo with human plasma samples obtained from patients with dyslipidemia and/or cardiovascular disease (CVD). In a hypercholesterolemic zebrafish model, we expect that conditional expression of Aibp will reduce vascular lipid accumulation, foam cell formation, membrane lipid order in EC, and vascular permeability. In a hypercholesterolemic mouse model, we expect that infusion of recombinant AIBP, alone or in combination with apoA-I, will reduce EC inflammation and atherosclerosis. In addition, human plasma and HDL isolated from CVD patients will be supplemented with recombinant AIBP and tested for their effect on monocyte adhesion to EC. We expect that AIBP will improve protective properties of dysfunctional HDL. Results of these experiments, if positive, will facilitate future development of AIBP-based therapeutic applications.

描述（应用程序提供）：血管壁中的炎症和脂质积累构成心血管疾病的启动和进展中的关键事件，表现为在超过一半的美国人口中，在心肌梗塞和中风中。活化的内皮细胞（EC）秘密趋化因子和表达粘附分子，以募集白细胞到血管壁。氧化的LDL和功能障碍的HDL在EC介导的炎症性中起主要作用，而功能性HDL可保留EC完整性并防止炎症反应。 HDL发挥其保护功能的主要机制之一是胆固醇从EC的质膜中排出。我们发现ApoA-I结合蛋白（AIBP）通过加速EC的胆固醇外排来显着提高HDL功能。 AIBP是一种分泌的蛋白质，其对EC的影响是旁分泌和非细胞自主。这些发现开辟了使用AIBP或AIBP衍生的Petides作为一种改善HDL胆固醇外排功能的疗法，从而预防和/或反向血管病理学的可能性。在这里，我们提出了测试AIBP通过调节胆固醇外排和脂质筏的炎症反应的假设。我们将通过测量细胞因子和粘附分子的表达，探测相关信号通路，检测ROS，凋亡和自噬来检验细胞模型以及主动脉外植体中的这一假设，并评估LDL跨囊病和单核细胞粘合剂。此外，我们将确定全身和组织特异性AIBP缺乏对内皮功能的影响。我们已经开发了AIBP LOXP和AIBP基因敲除小鼠，它们是可行且肥沃的。在小鼠动脉粥样硬化病变的巨噬细胞和血管平滑肌细胞（VSMC）中已检测到AIBP的表达。这就是我们建议，由巨噬细胞和/或VSMC分泌的AIBP保护主动脉EC，并且这些细胞中AIBP的删除将导致EC炎症反应加剧，并增加动脉粥样硬化伯恩。我们还假设，相反，提高AIBP水平将改善内皮功能并减少注射。该假设将用小鼠和斑马鱼动物模型在体内进行检验，并通过从血管症患者和/或心血管疾病（CVD）获得的人血浆样本进行体内测试。在高胆固醇血症模型中，我们期望AIBP的条件表达会减少血管脂质积累，泡沫细胞形成，EC中的膜脂质顺序和血管通透性。在高胆固醇小鼠模型中，我们预计单独或与APOA-I结合输注重组AIBP将减少EC炎症和动脉粥样硬化。此外，从CVD患者中分离出的人血浆和HDL将补充重组AIBP，并测试其对单核细胞粘合剂对EC的影响。我们预计AIBP将改善功能失调的HDL的保护特性。这些实验的结果（如果积极）将促进基于AIBP的治疗应用的未来开发。