The Role of the IL-1 Receptor in the AKI to CKD transition
IL-1 受体在 AKI 向 CKD 转变中的作用
基本信息
- 批准号:10370332
- 负责人:
- 金额:$ 17.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Renal Failure with Renal Papillary NecrosisAnimal ModelAnti-Inflammatory AgentsApplications GrantsAreaAttenuatedBehaviorBindingCD4 Positive T LymphocytesCell CommunicationCell DeathCell Surface ReceptorsCell physiologyCell surfaceCellsChronicChronic Kidney FailureCoculture TechniquesComplexComplicationCritical CareCritical IllnessCytometryDeath RateDendritic CellsDevelopmentFibrosisFoundationsFunctional disorderFutureGene ActivationGene ExpressionGoalsHealthHealth Care CostsHumanImmuneImmune signalingImmune systemIn VitroInflammatoryInjuryInjury to KidneyInnate Immune ResponseInterleukin-1 ReceptorsInterleukinsIschemiaKidneyKnowledgeLeukocytesLifeLymphocyteLymphocyte ActivationMeasuresMediatingMediator of activation proteinMedicineMethodsMissionModelingMorbidity - disease rateMultiple Organ FailureMusMyeloid CellsNatureOperative Surgical ProceduresOrgan failureOrganismPatientsPhenotypePlayPopulationProcessProductionPublic HealthQuality of lifeReceptor ActivationReceptor SignalingRecoveryRegulatory T-LymphocyteReperfusion TherapyResearchResearch PersonnelRoleSepsisSeveritiesSignal TransductionSpatial DistributionSyndromeT-Cell ActivationT-LymphocyteT-Lymphocyte SubsetsTNF geneTechniquesTestingTherapeuticTissuesToxinTrainingTubular formationUnited States National Institutes of HealthUreteral obstructionWorkadaptive immune responsebasebody systemcell injurycell motilitycytokinedisabilitydraining lymph nodeexperiencehealingimmunomodulatory therapiesimmunoregulationimprovedkidney cellkidney fibrosislymph nodesmacrophagemigrationmortalitynext generation sequencingnovelnovel imaging techniqueorgan repairpreventprogramsrenal damagerepairedsepticsingle-cell RNA sequencingtherapy designtissue injury
项目摘要
ABSTRACT
Multi-organ dysfunction syndrome (MODS) leads to significant morbidity and mortality in critically ill patients.
Acute kidney injury (AKI) is one of the most common components of MODS. Unresolved AKI leads to ongoing
renal injury, fibrosis, and subsequent chronic kidney disease (CKD). However, the mechanisms that direct renal
recovery and prevent the AKI to CKD transition are poorly understood. One novel and promising therapeutic
approach is to modulate the functions of macrophages and dendritic cells (DCs) that accumulate in the injured
kidney in order to prevent further injury and fibrosis. Interleukin (IL)-1α/β are canonical pro-inflammatory
cytokines that activate macrophages and DCs after binding to their cell surface receptor, IL-1R1. IL-1R1
activation plays a prominent role in renal healing. However, IL-1R1’s specific effects on macrophage and DC
function following AKI and on the AKI to CKD transition are poorly understood. Based on our preliminary studies,
our central hypothesis is that following AKI, macrophage IL-1R1 activation triggers TNFα (TNF)-dependent renal
cell necroptosis, which directs IL-1R1-dependent migration of DCs to lymph nodes to activate pro-inflammatory
T cells to drive the AKI to CKD transition. We will test our central hypothesis as follows:
Specific Aim 1: Determine effects of macrophage IL-1R1 activation on TNF-mediated renal cell
necroptosis following ischemic AKI. Mice with macrophage-specific deletion of IL-1R1 (IL-1R1 MKO) and
controls (IL-1R1 MWT) will undergo ischemia/reperfusion (I/R)- and septic AKI, and the severity of acute
kidney damage will be quantified. Renal cell necroptosis will be measured in injured kidneys and in
macrophage-renal tubular cell (RTC) co-culture. We will employ cell surface phenotyping and single cell
RNA-seq on sorted leukocytes from injured kidneys to precisely phenotype myeloid cells to determine how
IL-1R1 activation modulates macrophage polarization and renal injury.
Specific Aim 2: Elucidate the role of IL-1R1-mediated dendritic cell migration and T cell activation
during the AKI to CKD transition. Mice with deletion of IL-1R1 in DCs (IL-1R1 DCKO) and controls (IL-1R1
DCWT) will be subjected to I/R-induced AKI, and at multiple timepoints, the severity of renal damage and
fibrosis will be compared. We will examine IL-1R1-mediated accumulation of DC subsets in renal lymph
nodes following I/R and their consequent activation of effector lymphocytes. We will use novel tissue
cytometry to analyze spatial distribution of DC and T cells within fibrotic areas. Activated DC and T cells will
be co-cultured with RTC to determine their effect on pro-fibrotic gene expression programs.
The proposed studies will have a significant positive impact by promoting the development of future targeted
treatments for patients with life-threatening AKI. Together with my training plan, these studies will lay the
foundation for my development as an independent investigator in critical care medicine focused on identifying
treatments that promote renal healing after AKI to prevent CKD and remote organ failure.
摘要
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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Jamie R Privratsky其他文献
Jamie R Privratsky的其他文献
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{{ truncateString('Jamie R Privratsky', 18)}}的其他基金
Novel mitochondrial protective properties of annexin A1
膜联蛋白 A1 的新型线粒体保护特性
- 批准号:
10343330 - 财政年份:2021
- 资助金额:
$ 17.8万 - 项目类别:
Novel mitochondrial protective properties of annexin A1
膜联蛋白 A1 的新型线粒体保护特性
- 批准号:
10661073 - 财政年份:2021
- 资助金额:
$ 17.8万 - 项目类别:
The Role of the IL-1 Receptor in the AKI to CKD transition
IL-1 受体在 AKI 向 CKD 转变中的作用
- 批准号:
9895836 - 财政年份:2019
- 资助金额:
$ 17.8万 - 项目类别:
The Role of the IL-1 Receptor in the AKI to CKD transition
IL-1 受体在 AKI 向 CKD 转变中的作用
- 批准号:
10605321 - 财政年份:2019
- 资助金额:
$ 17.8万 - 项目类别:
The Role of the IL-1 Receptor in the AKI to CKD transition
IL-1 受体在 AKI 向 CKD 转变中的作用
- 批准号:
10132742 - 财政年份:2019
- 资助金额:
$ 17.8万 - 项目类别: