Ischemic Reperfusion injury in Transplantation: Role of Sphingosine 1-phosphate receptors and dendritic cells
移植中的缺血再灌注损伤:1-磷酸鞘氨醇受体和树突状细胞的作用
基本信息
- 批准号:9337445
- 负责人:
- 金额:$ 7.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-25 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Renal Failure with Renal Papillary NecrosisAdverse effectsAffectAgonistAllograftingAnimal ModelApoptosisAttenuatedBone MarrowCadaverCell CountCell MaturationCell ProliferationCellsComplexComplicationDataDendritic CellsDendritic cell activationDevelopmentDialysis procedureDoseEmbryoEndothelial CellsEpithelial CellsEventFDA approvedFamilyFlow CytometryFutureG-Protein-Coupled ReceptorsHarvestHealthcare SystemsImageImmuneImmunohistochemistryImmunosuppressive AgentsIncidenceIndividualInfiltrationInflammationInjection of therapeutic agentInjuryInnate Immune ResponseIschemiaKidneyKidney TransplantationKnowledgeLeadLength of StayLymphocyteMalignant NeoplasmsMicroscopyModelingMusMyelogenousOliguriaOperative Surgical ProceduresOpportunistic InfectionsOrganOrgan DonorOrgan SurvivalOrgan TransplantationPathogenesisPatientsPharmaceutical PreparationsPharmacologyPhenotypePhysiologicalPlayPostoperative PeriodPredispositionProceduresProximal Kidney TubulesPublicationsReceptor ActivationReceptor CellRecoveryRegulatory T-LymphocyteReperfusion InjuryReperfusion TherapyRiskRodentRoleSeveritiesSpeedSphingolipidsSphingosine-1-Phosphate ReceptorSpleenSplenectomySupportive careSyndromeTestingTherapeuticTransgenic MiceTransplantationangiogenesiscell growthcostcytotoxicitydelayed graft functionedg-1 Proteineffective therapyend-stage organ failuregraft functionhemodynamicsimmunogenicityimmunoregulationmigrationneutrophilnovelnovel strategiesnovel therapeutic interventionnovel therapeuticspreventprotective effectpublic health relevancereceptorresponsesphingosine 1-phosphatetraffickingtreatment strategytwo-photon
项目摘要
Delayed graft function (DGF) is a form of acute kidney injury (AKI) resulting in post-
transplantation oliguria, increased allograft immunogenicity and risk of acute rejection episodes
resulting in decreased long-term survival. DGF necessitates dialysis in the first week after
surgery and occurs in 20% to 50% of patients receiving a cadaver graft. DGF is usually the
result of ischemic damage to the graft before or during harvesting and is further aggravated by
the reperfusion syndrome, a multifactorial event in which polymorphonuclear cells play a major
role. The pathogenesis of ischemic reperfusion injury (IRI) during transplantation involves a
complex interaction between altered microcirculatory hemodynamics, endothelial and epithelial
cells, and infiltration of immune cells. Dendritic cells (DCs) play a central role in activating or
inhibiting innate and adaptive effectors involved in AKI. In kidney IRI model, transfer of S1pr3-/-
bone marrow derived DCs (BMDCs) prior to ischemia protects mice kidneys from injury. The
majority of transferred S1pr3-/- BMDCs are found in the spleen as early as 30 minutes after
injection and prior splenectomy abrogates the S1pr3-/- BMDC dependent protection. In the
spleen, S1pr3-/- BMDCs induce an increase in Tregs to inhibit innate immune response
associated with IRI. Therefore, in transplantation, donor kidney DCs from S1pr3-/- mice will
migrate out of the transplanted kidney into the receipt spleen. In the spleen, donor derived
S1pr3-/- DCs will induce an increase in recipient Tregs to suppress the innate immune response
to attenuate IRI associated with transplantation. Accordingly, we hypothesize that: 1) donor DC
activation controls severity of AKI in kidney transplantation and 2) pharmacological modulation
of donor S1P1 can protect kidneys from IRI. In Specific aim 1 we will test the hypothesis that
S1P1 receptor activation of donor DCs regulates IRI in syngeneic mouse kidney transplant.
Specific Aim 2 will test the hypothesis that treatment of the donor with FTY720 reduces IRI in
syngeneic kidney transplant. This will be examined using a rodent kidney transplant model. The
results of these specific aims will yield important information about the role of S1P1 on donor
DCs to attenuate or prevent transplant associated DGF. These are previously unexplored
questions that may reveal novel targets to prevent DGF and possibly promote recovery due to
the DCs S1P1 dependent increase in recipient Tregs. The knowledge gained through this
project will form the basis of independent publications and an individual R01 application by the
PI.
移植肾功能延迟恢复(DGF)是急性肾损伤(阿基)的一种形式,导致移植后肾功能衰竭。
移植少尿、同种异体移植物免疫原性增加和急性排斥反应发作风险
导致长期存活率下降。DGF需要在术后第一周进行透析
在接受尸体移植的患者中,20%至50%的患者会发生这种情况。DGF通常是
在收获之前或收获期间对移植物造成缺血性损伤的结果,并且由于
再灌注综合征是一种多因素事件,其中多形细胞起主要作用,
作用移植过程中缺血再灌注损伤(IRI)的发病机制涉及一个新的机制。
改变的微循环血流动力学、内皮和上皮之间的复杂相互作用
细胞和免疫细胞的浸润。树突状细胞(DC)在活化或活化树突状细胞中起核心作用。
抑制参与阿基的先天和适应性效应物。在肾IRI模型中,S1 pr 3-/-
骨髓来源的DC(BMDCs)在缺血前保护小鼠肾脏免受损伤。的
大多数转移的S1 pr 3-/-BMDC早在接种后30分钟就在脾脏中发现。
注射和先前的脾切除消除了S1 pr 3-/- BMDC依赖性保护。在
脾,S1 pr 3-/- BMDCs诱导T细胞增加以抑制先天性免疫应答
与IRI有关。因此,在移植中,来自S1 pr 3-/-小鼠的供体肾DC将
从移植肾迁移到受体脾。在脾脏中,供体来源
S1 pr 3-/- DCs可诱导受体T淋巴细胞增加,从而抑制先天性免疫应答
减轻与移植相关的IRI。因此,我们假设:1)供体DC
活化控制肾移植中阿基的严重程度,以及2)药理学调节
供者S1 P1对IRI有保护作用。在具体目标1中,我们将检验以下假设:
供体DCs的S1 P1受体活化调节同基因小鼠肾移植中的IRI
具体目标2将检验用FTY 720治疗供体减少IRI的假设。
同基因肾移植这将使用啮齿动物肾移植模型进行检查。的
这些具体目标的结果将产生关于S1 P1对供体的作用的重要信息。
DC以减弱或预防移植相关的DGF。这些都是以前没有探索过的
这些问题可能揭示新的靶点,以预防DGF,并可能促进恢复,
DCs S1 P1依赖性增加受体T细胞增殖。通过这个过程获得的知识
该项目将形成独立出版物和个人R 01应用的基础,
Pi.
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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Amandeep Bajwa其他文献
Amandeep Bajwa的其他文献
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{{ truncateString('Amandeep Bajwa', 18)}}的其他基金
Off target mechanisms of kinase inhibitor toxicities
激酶抑制剂毒性的脱靶机制
- 批准号:
10584567 - 财政年份:2022
- 资助金额:
$ 7.9万 - 项目类别:
Sphingosine 1 phosphate receptors 1 and 3 as novel targets in transplantation
鞘氨醇 1 磷酸受体 1 和 3 作为移植新靶点
- 批准号:
8432025 - 财政年份:2012
- 资助金额:
$ 7.9万 - 项目类别:
Sphingosine 1 phosphate receptors 1 and 3 as novel targets in transplantation
鞘氨醇 1 磷酸受体 1 和 3 作为移植新靶点
- 批准号:
8803791 - 财政年份:2012
- 资助金额:
$ 7.9万 - 项目类别:
Sphingosine 1 phosphate receptors 1 and 3 as novel targets in transplantation
鞘氨醇 1 磷酸受体 1 和 3 作为移植新靶点
- 批准号:
8604390 - 财政年份:2012
- 资助金额:
$ 7.9万 - 项目类别:
Sphingosine 1 phosphate receptors 1 and 3 as novel targets in transplantation
鞘氨醇 1 磷酸受体 1 和 3 作为移植新靶点
- 批准号:
9000694 - 财政年份:2012
- 资助金额:
$ 7.9万 - 项目类别:
Sphingosine 1 phosphate receptors 1 and 3 as novel targets in transplantation
鞘氨醇 1 磷酸受体 1 和 3 作为移植新靶点
- 批准号:
8240822 - 财政年份:2012
- 资助金额:
$ 7.9万 - 项目类别:














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