AIBP therapy

项目摘要 该提案描述了一项研究计划，以建立机制基础并进行临床前研究。 AIBP治疗的研究。我们发现分泌的apoA-I结合蛋白（AIBP）加速了 胆固醇从内皮细胞（EC）和巨噬细胞流出，并将HDL靶向TLR 4占据的脂筏。 由此产生的靶向胆固醇从质膜去除和脂筏减少导致降低的 TLR 4介导的炎症反应。这一发现的意义在于， AIBP/脂筏机制的抗炎调节，这可能与许多炎症 条件我们的研究结果的翻译重要性来自AIBP调节的细胞外模式 从而增加了重组蛋白输注或吸入的可能性。考虑到动脉粥样硬化保护功能 因此，EC的完整性和正常的生理功能对于维持AIBP的功能至关重要。 健康血管壁。我们有强有力的初步数据表明，AIBP促进HDL介导的胆固醇 从EC流出，减少炎性基因的EC表达，并减少单核细胞粘附EC。这些 结果显示了追求AIBP动脉粥样硬化保护治疗应用的强大动力。心脏再灌注 急性心肌梗死（MI）或缺血/再灌注（I/R）后会导致心肌损伤， 产生随后的炎症级联反应，这反过来又使心脏损伤永久化。先天免疫 受体，特别是TLR 4，对I/R损伤起关键作用。减少炎症 通过增加从心肌细胞和血管细胞中清除胆固醇对I/R的反应， 对心肌梗死后患者尤为重要。我们认为AIBP单独或与 重组HDL将为MI后患者的健康提供益处，因为AIBP特别针对HDL， 炎症细胞AIBP作用的细胞外机制也开启了其局部作用的可能性。 给药在肺部炎症。急性呼吸窘迫综合征（ARDS）常导致患者死亡， 由于缺乏有效的治疗方法，这些患者受到其最严重子集的折磨。过度的炎症反应， 包括中性粒细胞的募集、细胞因子的分泌和肺泡水肿的发展， 描述人类和啮齿类动物的ARDS。我们已经在小鼠ARDS模型中显示雾化AIBP 显著降低肺部炎症。我们的研究计划将侧重于了解基本的反- 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， 患者的血液样本，以评估AIBP治疗在动脉粥样硬化保护和治疗后 MI和ARDS患者。

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.