Ex vivo maintenance of endothelial cell barrier integrity via gap junction modification to prevent early ischemic injury in solid organ transplantation
通过间隙连接修饰离体维持内皮细胞屏障完整性以预防实体器官移植中的早期缺血性损伤
基本信息
- 批准号:10741452
- 负责人:
- 金额:$ 25.11万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-18 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAffectAllograftingAntigen PresentationAntigen-Presenting CellsBlood VesselsBrain DeathBrain Hypoxia-IschemiaCardiacCell Adhesion MoleculesCell CommunicationCell LineCellsCellular StructuresCommunicationConnexin 43ConnexinsCryopreservationDataEndothelial CellsEndotheliumFailureFundingGap JunctionsGeneticGraft RejectionGraft SurvivalHealthHeartHeart TransplantationHomeostasisImmuneImmunosuppressionIn VitroInflammatoryInjuryInnate Immune ResponseIntercellular JunctionsIschemiaLaboratoriesLongevityMainstreamingMaintenanceMediatingMessenger RNAModelingModificationMusNeutrophil InfiltrationOrganOrgan DonorOrgan PreservationOrgan TransplantationOutcomePatientsPenetrationPeptidesPerioperativePhasePhenotypePhosphorylationProteinsPublishingRegimenReperfusion InjuryReperfusion TherapyRoleSignal PathwaySignal TransductionSolidSurfaceT memory cellTestingTransplantationTreatment ProtocolsVascular Cell Adhesion Molecule-1Vascular Endothelial CellVascular Permeabilitiesadaptive immune responsecell injuryclinical translationclinically relevantcytokineend-stage organ failureexperimental studygraft failuregraft functionhigh rewardhigh riskimmune activationimmunogenicityimplantationimprovedin vitro Modelin vivoinjuredinnovationinsightintercellular cell adhesion moleculeischemic injuryisoimmunityknock-downmouse modelnovelnovel therapeutic interventionoverexpressionpharmacologicpre-clinicalpreservationpreventresponsestandard of caretherapeutic targettreatment strategy
项目摘要
Project Summary
Organ transplantation (Tx) is the mainstay therapy for patients with end-stage organ failure. Yet, barriers
exist that preclude long-term graft survival. It is well-established that early injury to the allograft, during the
donor organ preservation and reperfusion phases, set the organ up for late failure. Based on studies from
our laboratory, ischemia-reperfusion injury (IRI) and early alloimmunity, mediated by memory T cells, are
among the most prevalent and inevitable early injuries affecting endothelial cells (ECs) as the first point of
contact. Thus, our scientific premise revolves around the allograft's endothelium as central to these insults.
The endothelium contains an intact layer of aligned ECs that are joined by cell-to-cell junctions and enables
them to communicate and form a protective barrier. During IRI and early alloimmunity, the EC barrier is
disrupted, predisposing the ECs to inappropriate antigen presentation ultimately resulting in late graft failure.
Thus, the EC barrier is vital for graft protection. Endothelial cell-to-cell communication is dependent upon
gap junctions including connexin 43 (Cx43). Whether Cx43 gap junctions play a role in protecting the EC
barrier and dampening EC immunogenicity against early injuries allowing for a therapeutic target, forms the
central question of our proposal. Based on our preliminary data, we hypothesize that stabilizing and/or
overexpressing Cx43 gap junctions in ECs will mitigate early graft injury. To study this hypothesis, we
propose two Aims: Specific Aim 1 - Elucidate the role of Cx43 gap junction protein on EC
activation/immunogenicity during IRI in vitro. Specific Aim 2 - Demonstrate the preclinical ability to
downregulate the EC activation/immunogenicity in transplanted hearts in vivo by maintaining Cx43
protein levels via pre-treatment of donor hearts. Common to these aims, we will employ an in vitro model
of injury that simulates cold ischemia and warm reperfusion injury to study the role of Cx43 gap junctions on
EC health and immunogenicity. We will also employ clinically relevant in vivo brain-death mouse models of
IRI and alloimmune cardiac Tx and utilize a novel and unique donor organ pre-treatment strategy to deliver
Cx43 modulating agents. These innovative and high-risk high-reward studies will be the first to define the
specific and focused impact of Cx43 gap junction in ECs, associated with organ preservation and
reperfusion. Furthermore, it will provide a proof-of-concept to target the Cx43 gap junction in ECs prior to
transplantation using our unique pretreatment strategy which will set a stage for a paradigm shift in the
current standard of care during organ Tx.
项目摘要
器官移植(Tx)是终末期器官衰竭患者的主要治疗方法。然而,
存在妨碍移植物长期存活的因素。众所周知,在移植过程中,
供体器官保存和再灌注阶段,为器官晚期衰竭做准备。基于来自
我们的实验室,缺血再灌注损伤(IRI)和早期同种免疫,由记忆T细胞介导,
在影响内皮细胞(EC)的最普遍和不可避免的早期损伤中,
contact.因此,我们的科学前提围绕着同种异体移植物的内皮细胞作为这些损害的中心。
内皮细胞含有一层完整的排列整齐的内皮细胞,这些内皮细胞通过细胞间连接连接,
他们沟通,形成一个保护屏障。在IRI和早期同种异体免疫期间,EC屏障被破坏。
破坏,使EC倾向于不适当的抗原呈递,最终导致晚期移植物衰竭。
因此,EC屏障对于移植物保护至关重要。内皮细胞间的通讯依赖于
间隙连接包括连接蛋白43(Cx43)。Cx43缝隙连接是否在EC保护中发挥作用
屏障和抑制EC免疫原性对早期损伤允许治疗靶点,形成
我们提案的核心问题。根据我们的初步数据,我们假设稳定和/或
在内皮细胞中过度表达Cx43缝隙连接将减轻早期移植物损伤。为了研究这个假设,我们
具体目的1 -阐明缝隙连接蛋白Cx43在EC中的作用
体外IRI期间的活化/免疫原性。具体目标2 -证明临床前能力,
通过维持Cx43下调体内移植心脏中EC活化/免疫原性
通过对供体心脏的预处理来降低蛋白质水平。为了实现这些目标,我们将采用体外模型
模拟冷缺血和热再灌注损伤,研究Cx43缝隙连接在缺血再灌注损伤中的作用。
EC健康和免疫原性。我们还将采用临床相关的体内脑死亡小鼠模型,
IRI和同种免疫心脏Tx,并利用一种新颖独特的供体器官预处理策略,
Cx43调节剂。这些创新和高风险高回报的研究将是第一个定义
Cx43缝隙连接在EC中的特异性和集中性影响,与器官保存相关,
再灌注此外,它将提供一个概念验证,以靶向EC中的Cx43间隙连接,
移植使用我们独特的预处理策略,这将为移植的范式转变奠定基础。
在器官Tx期间的当前护理标准。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('SATISH N NADIG', 18)}}的其他基金
A Chicago Biomedical Consortium Hub of Innovative Technologies for Entrepreneurship and Science (CBC - HITES)
芝加哥生物医学联盟创业与科学创新技术中心 (CBC - HITES)
- 批准号:
10783500 - 财政年份:2023
- 资助金额:
$ 25.11万 - 项目类别:
Modulating endothelial cell immunometabolism and mitochondrial morphology- implications for organ transplantation
调节内皮细胞免疫代谢和线粒体形态——对器官移植的影响
- 批准号:
10170230 - 财政年份:2019
- 资助金额:
$ 25.11万 - 项目类别:
Modulating endothelial cell immunometabolism and mitochondrial morphologyimplications for organ transplantation
调节内皮细胞免疫代谢和线粒体形态对器官移植的影响
- 批准号:
10634543 - 财政年份:2019
- 资助金额:
$ 25.11万 - 项目类别:
Modulating endothelial cell immunometabolism and mitochondrial morphologyimplications for organ transplantation
调节内皮细胞免疫代谢和线粒体形态对器官移植的影响
- 批准号:
10402861 - 财政年份:2019
- 资助金额:
$ 25.11万 - 项目类别:
Modulating endothelial cell immunometabolism and mitochondrial morphologyimplications for organ transplantation
调节内皮细胞免疫代谢和线粒体形态对器官移植的影响
- 批准号:
10507521 - 财政年份:2019
- 资助金额:
$ 25.11万 - 项目类别:
Nanoparticle Therapy for Targeted Drug Delivery in Organ Transplantation
器官移植中靶向药物输送的纳米颗粒疗法
- 批准号:
9225201 - 财政年份:2016
- 资助金额:
$ 25.11万 - 项目类别:
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