AIBP therapy

AIBP治疗

基本信息

  • 批准号:
    10551912
  • 负责人:
  • 金额:
    $ 93万
  • 依托单位:
  • 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

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。
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:
  • 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:
  • 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:
  • 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。
  • DOI:
    10.1194/jlr.in119000330
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    6.5
  • 作者:
    Sviridov,Dmitri;Miller,YuryI
  • 通讯作者:
    Miller,YuryI
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Yury Miller其他文献

Yury Miller的其他文献

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{{ truncateString('Yury Miller', 18)}}的其他基金

AIBP and regulation of neuropathic pain
AIBP 和神经性疼痛的调节
  • 批准号:
    9816541
  • 财政年份:
    2019
  • 资助金额:
    $ 93万
  • 项目类别:
Reversal of preexisting neuropathic pain by spinal delivery of AIBP
通过脊髓输送 AIBP 逆转先前存在的神经性疼痛
  • 批准号:
    9750836
  • 财政年份:
    2018
  • 资助金额:
    $ 93万
  • 项目类别:
Reversal of preexisting neuropathic pain by spinal delivery of AIBP
通过脊髓输送 AIBP 逆转先前存在的神经性疼痛
  • 批准号:
    10197482
  • 财政年份:
    2018
  • 资助金额:
    $ 93万
  • 项目类别:
Cholesterol Regulation of Inflammatory Macrophages in Atherosclerosis
动脉粥样硬化中炎症巨噬细胞的胆固醇调节
  • 批准号:
    10188606
  • 财政年份:
    2017
  • 资助金额:
    $ 93万
  • 项目类别:
AIBP therapy
AIBP治疗
  • 批准号:
    9240927
  • 财政年份:
    2017
  • 资助金额:
    $ 93万
  • 项目类别:
AIBP therapy
AIBP治疗
  • 批准号:
    10331313
  • 财政年份:
    2017
  • 资助金额:
    $ 93万
  • 项目类别:
Project 2: Cholesterol Regulation of Inflammatory Macrophages in Atherosclerosis
项目2:动脉粥样硬化中炎症巨噬细胞的胆固醇调节
  • 批准号:
    10334095
  • 财政年份:
    2017
  • 资助金额:
    $ 93万
  • 项目类别:
AIBP and Endothelial Function
AIBP 和内皮功能
  • 批准号:
    8885205
  • 财政年份:
    2015
  • 资助金额:
    $ 93万
  • 项目类别:
AIBP and Endothelial Function
AIBP 和内皮功能
  • 批准号:
    9039657
  • 财政年份:
    2015
  • 资助金额:
    $ 93万
  • 项目类别:
Early Forms of Oxidized LDL, TLRs and Atherosclerosis
氧化 LDL、TLR 和动脉粥样硬化的早期形式
  • 批准号:
    7839765
  • 财政年份:
    2009
  • 资助金额:
    $ 93万
  • 项目类别:

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