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
- 来源:
- 关键词:AccelerationAcuteAcute Respiratory Distress SyndromeAcute myocardial infarctionAdhesionsAlveolarAnimal ModelAnti-Inflammatory AgentsApolipoprotein A-IBinding ProteinsBlood VesselsBlood specimenCardiacCardiac MyocytesCardiovascular DiseasesCardiovascular systemCell membraneCellsCessation of lifeCholesterolChronicDataDevelopmentEdemaEndothelial CellsExcisionFoundationsGenesHealthHeart DiseasesHeart InjuriesHigh Density LipoproteinsHumanImmunologic ReceptorsInflammationInflammatoryInflammatory ResponseInfusion proceduresInhalationIschemiaLung diseasesMacrophageMediatingMembrane MicrodomainsMusMyocardial InfarctionNebulizerNeutrophil InfiltrationOutcomePatientsPhysiologicalProtein SecretionPulmonary InflammationRecombinant ProteinsRegulationReperfusion InjuryReperfusion TherapyResearchRodentTLR4 geneTestingTherapeuticTissuesZebrafishatheroprotectivecytokineeffective therapyextracellularheart damagelung injurymonocytemouse modelmyocardial injurynovelpre-clinicalpreclinical studyprogramsreconstitutionrestraint
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.
项目概要
该提案描述了一项建立机械基础并进行临床前研究的研究计划
AIBP 治疗的研究。我们发现分泌的 apoA-I 结合蛋白 (AIBP) 加速
胆固醇从内皮细胞 (EC) 和巨噬细胞流出,并将 HDL 靶向 TLR4 占据的脂筏。
由此产生的有针对性的胆固醇从质膜去除和脂筏的减少导致减少
TLR4 介导的炎症反应。这一发现的意义在于
AIBP/脂筏的抗炎调节机制,可能与许多炎症相关
状况。我们的研究结果的转化重要性源于 AIBP 调节的细胞外模式
因此重组蛋白输注或吸入的可能性。考虑动脉粥样硬化功能
AIBP 的完整性和正常生理功能对于维持 AIBP 的完整性和正常生理功能至关重要
健康的血管壁。我们有强有力的初步数据表明 AIBP 促进 HDL 介导的胆固醇
从 EC 流出,减少 EC 炎症基因的表达并减少单核细胞对 EC 的粘附。这些
结果表明,强烈推动 AIBP 动脉粥样硬化治疗应用的发展。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,进而使心脏损伤永久化。先天免疫
一般受体,尤其是 TLR4,对 I/R 损伤起着至关重要的作用。减少炎症
通过增加心肌细胞和血管细胞中胆固醇的清除来对 I/R 做出反应
对于心梗后患者尤其重要。我们认为 AIBP 的输注,单独或与
重组 HDL 将为心梗后患者的健康带来益处,因为 AIBP 专门针对 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
肺部炎症的给药。急性呼吸窘迫综合征(ARDS)常常导致患者死亡
由于缺乏有效的治疗方法,该病受到最严重的亚群的困扰。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 ARDS 的特征。我们已经在 ARDS 小鼠模型中展示了雾化 AIBP
显着减少肺部炎症。我们的研究计划将侧重于了解基本的抗
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,以评估 AIBP 疗法在动脉粥样硬化保护和治疗后动脉粥样硬化方面的潜力。
心肌梗塞和急性呼吸窘迫综合征患者。
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:
- 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:
- 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
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:
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:
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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