AIBP therapy

AIBP治疗

基本信息

批准号：
9240927
负责人：
Yury Miller
金额：
$ 93万
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：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9240927
关键词：
Acute Acute myocardial infarction Adhesions Adult Respiratory Distress Syndrome Alveolar Animal Model Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein A-I Binding Proteins Blood Vessels Blood specimen Breathing Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell membrane Cells Cessation of life Cholesterol Chronic Data Development Edema Endothelial Cells Excision Foundations Genes Health Heart Diseases Heart Injuries High Density Lipoproteins Human Immunologic Receptors Inflammation Inflammatory Inflammatory Response Infusion procedures Injury Ischemia Lung Inflammation Lung diseases Mediating Membrane Microdomains Mus Myocardial Myocardial Infarction Nebulizer Neutrophil Infiltration Outcome Patients Physiological Proteins Recombinant Proteins Regulation Reperfusion Injury Reperfusion Therapy Research Rodent TLR4 gene Testing Therapeutic Tissues Zebrafish atheroprotective cytokine effective therapy extracellular lung injury macrophage monocyte mouse model novel pre-clinical preclinical study programs reconstitution

Acute Acute myocardial infarction Adhesions Adult Respiratory Distress Syndrome Alveolar Animal Model Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein A-I Binding Proteins Blood Vessels Blood specimen Breathing Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell membrane Cells Cessation of life Cholesterol Chronic Data Development Edema Endothelial Cells Excision Foundations Genes Health Heart Diseases Heart Injuries High Density Lipoproteins Human Immunologic Receptors Inflammation Inflammatory Inflammatory Response Infusion procedures Injury Ischemia Lung Inflammation Lung diseases Mediating Membrane Microdomains Mus Myocardial Myocardial Infarction Nebulizer Neutrophil Infiltration Outcome Patients Physiological Proteins Recombinant Proteins Regulation Reperfusion Injury Reperfusion Therapy Research Rodent TLR4 gene Testing Therapeutic Tissues Zebrafish atheroprotective cytokine effective therapy extracellular lung injury macrophage monocyte mouse model novel pre-clinical preclinical study programs reconstitution

展开

项目摘要

Project Summary This proposal describes a research program to establish mechanistic foundations and conduct preclinical studies toward AIBP therapy. We discovered that the secreted apoA-I binding protein (AIBP) accelerates cholesterol efflux from endothelial cells (EC) and macrophages and targets HDL to TLR4-occupied lipid rafts. Resulting targeted cholesterol removal from the plasma membrane and reduction of lipid rafts leads to reduced TLR4-mediated inflammatory responses. The significance of this discovery is in the widespread character of the AIBP/lipid rafts mechanism of anti-inflammatory regulation, which can be relevant to many inflammatory conditions. The translational importance of our findings arises from the extracellular mode of AIBP regulation and thus the possibility of recombinant protein infusion or inhalation. Considering an atheroprotective function of AIBP, the integrity and the normal physiological function of EC are critically important for maintaining a healthy vascular wall. We have strong preliminary data showing that AIBP facilitates HDL-mediated cholesterol efflux from EC, reduces EC expression of inflammatory genes and reduces monocyte adhesion to EC. These results suggest a strong impetus to pursue AIBP atheroprotective therapeutic applications. Cardiac reperfusion after an acute myocardial infarction (MI), or ischemia/reperfusion (I/R), contributes to myocardial injury, which generates subsequent inflammatory cascade, which in turn perpetuates cardiac damage. Innate immune receptors in general and TLR4 in particular critically contribute to I/R damage. Reducing inflammatory responses to I/R via increased removal of cholesterol from cardiomyocytes and vascular cells will be particularly important for post-MI patients. We posit that infusions of AIBP, alone or in combination with reconstituted HDL, will provide benefit to post-MI patients' health because AIBP specifically targets HDL to inflammatory cells. The extracellular mechanism of AIBP action also opens the possibility of its local administration in lung inflammation. Acute respiratory distress syndrome (ARDS) often results in death of those afflicted by its most severe subset due to the lack of effective therapies. Excessive inflammatory responses, including recruitment of neutrophils, secretion of cytokines and the development of alveolar edema, characterize ARDS in humans and rodents. We have shown in a mouse model of ARDS that nebulized AIBP significantly reduces lung inflammation. Our research program will focus on understanding basic anti- inflammatory mechanisms of AIBP and will use preclinical animal models, including mouse and zebrafish, and patients' blood samples to evaluate the potential of AIBP therapy in atheroprotection and in treatment of post- MI and ARDS patients.

项目摘要该建议描述了一个研究计划，以建立机械基础并进行临床前研究AIBP治疗。我们发现分泌的ApoA-I结合蛋白（AIBP）随着加速内皮细胞（EC）和巨噬细胞的胆固醇外排出，将HDL靶向TLR4占用的脂质筏。从质膜中去除靶向胆固醇和脂质筏的还原导致降低 TLR4介导的炎症反应。这一发现的意义在于抗炎调节的AIBP/脂质筏机制，可能与许多炎症有关状况。我们发现的翻译重要性来自AIBP调节的细胞外模式因此，重组蛋白输注或吸入的可能性。考虑动脉保护功能 AIBP，EC的完整性和正常生理功能对于维持A至关重要健康的血管壁。我们有强大的初步数据，表明AIBP促进了HDL介导的胆固醇 EC的外排减少EC的炎症基因的表达并将单核细胞粘附降低到EC。这些结果表明，追求AIBP动脉保护治疗应用的强大动力。心脏再灌注急性心肌梗塞（MI）或缺血/再灌注（I/R）后，会导致心肌损伤产生随后的炎症性级联反应，从而使心脏损伤永存。先天免疫通常，受体和TLR4特别严重造成了I/R损害。减少炎症通过从心肌细胞和血管细胞中除去胆固醇，对I/R的反应将是对于MI后患者特别重要。我们认为单独或与AIBP的注入重构的HDL将为MI后患者的健康提供好处，因为AIBP专门针对HDL 炎性细胞。 AIBP作用的细胞外机制也打开了其局部的可能性肺部炎症的给药。急性呼吸窘迫综合征（ARDS）通常导致那些死亡由于缺乏有效的疗法而受到其最严重的子集的困扰。过度炎症反应，包括中性粒细胞的募集，细胞因子的分泌和牙槽水肿的发展，描述了人类和啮齿动物中的ards。我们已经在ARDS的鼠标模型中显示了AIBP 显着减少肺部炎症。我们的研究计划将专注于理解基本的反 - AIBP的炎症机制，并将使用临床前动物模型，包括小鼠和斑马鱼，以及患者的血液样本评估AIBP治疗在动脉保护和治疗后的潜力 MI和ARDS患者。