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AIBP therapy

AIBP治疗

基本信息

批准号：
10331313
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/10331313
关键词：
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 Mediating Membrane Microdomains Mus Myocardial Infarction Nebulizer Neutrophil Infiltration Outcome Patients Physiological Proteins 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 macrophage monocyte mouse model myocardial injury novel pre-clinical preclinical study programs reconstitution

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.

项目总结