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AIBP therapy

AIBP治疗

基本信息

批准号：
10551912
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/10551912
关键词：
Acceleration Acute Acute Respiratory Distress Syndrome Acute myocardial infarction Adhesions Alveolar Animal Model Anti-Inflammatory Agents Apolipoprotein A-I Binding Proteins Blood Vessels Blood specimen 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 Inhalation Ischemia Lung diseases Macrophage Mediating Membrane Microdomains Mus Myocardial Infarction Nebulizer Neutrophil Infiltration Outcome Patients Physiological Protein Secretion Pulmonary Inflammation Recombinant Proteins Regulation Reperfusion Injury Reperfusion Therapy Research Rodent TLR4 gene Testing Therapeutic Tissues Zebrafish atheroprotective cytokine effective therapy extracellular heart damage lung injury monocyte mouse model myocardial injury novel pre-clinical preclinical study programs reconstitution restraint

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.

项目摘要该提案描述了一项建立机械基础和进行临床前研究的计划对AIBP治疗的研究。我们发现，分泌的载脂蛋白A-I结合蛋白(AIBP)加速胆固醇从内皮细胞(EC)和巨噬细胞流出，并以高密度脂蛋白为靶点至TLR4占据的脂筏。由此产生的从质膜上有针对性地去除胆固醇和减少脂筏导致减少 TLR4介导的炎症反应。这一发现的意义在于广泛存在的 AIBP/脂筏的抗炎调节机制，可能与许多炎症有关条件。我们发现的翻译重要性来自于AIBP调节的细胞外模式从而使重组蛋白输注或吸入成为可能。考虑到动脉粥样硬化的保护作用在AIBP中，EC的完整性和正常的生理功能对于维持AIBP至关重要健康的血管壁。我们有强有力的初步数据表明，AIBP促进高密度脂蛋白介导的胆固醇从EC流出，减少EC炎症基因的表达，减少单核细胞与EC的黏附。这些结果表明，追求AIBP动脉粥样硬化保护治疗应用的动力很强。心脏再灌流在急性心肌梗死(MI)或缺血/再灌注(I/R)后，会导致心肌损伤，这产生随后的炎症级联反应，进而使心脏损害永久化。先天免疫受体，尤其是TLR4在I/R损伤中起关键作用。消炎消炎通过增加心肌细胞和血管细胞中胆固醇的清除，对I/R的反应将是对心肌梗死后患者尤其重要。我们假设AIBP单独或联合输注重组的高密度脂蛋白，将为心肌梗死后患者的健康提供好处，因为AIBP专门针对高密度脂蛋白炎性细胞。AIBP作用的细胞外机制也开启了其局部给药治疗肺部炎症。急性呼吸窘迫综合征(ARDS)通常会导致由于缺乏有效的治疗方法，受到其最严重的子集的困扰。过度的炎症反应，包括中性粒细胞重新聚集，细胞因子分泌和肺泡水肿，描述人类和啮齿动物的急性呼吸窘迫综合征。我们已经在ARDS的小鼠模型上展示了雾化AIBP 显著降低肺部炎症。我们的研究计划将集中在了解基本的反 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，以及以评估AIBP治疗在动脉粥样硬化保护和治疗中的潜力 MI和ARDS患者。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Context-Dependent Role of Oxidized Lipids and Lipoproteins in Inflammation.

氧化脂质和脂蛋白在炎症中的上下文依赖性作用。

DOI：
10.1016/j.tem.2016.11.002
发表时间：
2017-02
期刊：
Trends in endocrinology and metabolism: TEM
影响因子：
0
作者：
Miller YI;Shyy JY
通讯作者：
Shyy JY

Lipoprotein lipase regulates hematopoietic stem progenitor cell maintenance through DHA supply.

DOI：
10.1038/s41467-018-03775-y
发表时间：
2018-04-03
期刊：
Nature communications
影响因子：
16.6
作者：
Liu C;Han T;Stachura DL;Wang H;Vaisman BL;Kim J;Klemke RL;Remaley AT;Rana TM;Traver D;Miller YI
通讯作者：
Miller YI

From Inert Storage to Biological Activity-In Search of Identity for Oxidized Cholesteryl Esters.

DOI：
10.3389/fendo.2020.602252
发表时间：
2020
期刊：
Frontiers in endocrinology
影响因子：
5.2
作者：
Gonen A;Miller YI
通讯作者：
Miller YI

Palmitate and minimally-modified low-density lipoprotein cooperatively promote inflammatory responses in macrophages.

DOI：
10.1371/journal.pone.0193649
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Ann SJ;Kim KK;Cheon EJ;Noh HM;Hwang I;Yu JW;Park S;Kang SM;Manabe I;Miller YI;Kim S;Lee SH
通讯作者：
Lee SH

Biology of Lipid Rafts: Introduction to the Thematic Review Series.

脂筏生物学：专题评论系列简介。