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.
延迟移植功能(DGF)是急性肾损伤(AKI)的一种形式
项目成果
期刊论文数量(0)
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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: