Protection of kidney from autoimmunity by modulating co-stimlatory signaling
通过调节共刺激信号来保护肾脏免受自身免疫的影响
基本信息
- 批准号:10614441
- 负责人:
- 金额:$ 16.84万
- 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:2019-07-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAnatomyAnimal ModelAntibodiesAntigen-Presenting CellsAntigensAutoantigensAutoimmuneAutoimmunityAutomobile DrivingBasic ScienceBiologyCD80 geneCTLA4 geneCellsChronicClinicalDataDendritic CellsDevelopmentDisciplineDisease modelEconomic BurdenElementsEnd stage renal failureFibrosisFundingGenetically Engineered MouseGoalsHealthImmune ToleranceImmune checkpoint inhibitorImmune responseImmunologyImmunosuppressionInfectionInfiltrationInflammationInjuryInjury to KidneyInterstitial NephritisIschemiaK-Series Research Career ProgramsKidneyKidney DiseasesKnowledgeLigandsLymphocyteMaintenanceMediatingModelingNephritisPD-1/PD-L1PathogenicityPathologic ProcessesPathway interactionsPatientsPeptide/MHC ComplexPersonsPhenotypePlayReagentResearchResearch MethodologyResearch Project GrantsRoleSamplingSignal PathwaySignal TransductionSourceSpecificityT cell infiltrationT cell therapyT-Cell ActivationT-Cell ReceptorT-LymphocyteTechniquesTechnologyTestingTissuesTransgenic MiceTransgenic OrganismsTranslational ResearchTubular formationTubulointerstitial NephritisUnited Statesadaptive immune responseadaptive immunityallograft rejectionanti-CTLA4anti-PD-1anti-PD-L1antigen-specific T cellsautoreactivitycancer immunotherapycancer transplantationcareer developmentchemokinegenetic approachimmune activationimmunoregulationin vivoinnovationischemic injurykidney allograftmouse modelnew therapeutic targetnovelpodocytepre-clinicalpreventprogrammed cell death ligand 1programmed cell death protein 1programsreceptorrenal damageresponsetargeted treatmenttherapeutic targettooltranscriptome sequencingtranscriptomics
项目摘要
Project Summary
Kidney inflammation occurs in response to ischemic injury, infections, and activation of autoreactive or
alloreactive lymphocytes and contributes to chronic kidney damage, fibrosis and end-stage kidney diseases.
Adaptive immune responses are tightly controlled in the kidney to prevent excessive inflammation and to
maintain tolerance against self-antigens. However, the fundamental understanding of the mechanisms
supporting immune regulation in the kidney is incomplete. Clinical observations suggest that the co-stimulatory
molecules such as PD-1 and CTLA4 play pivotal roles in regulating immune responses in the kidney, as
observed in acute interstitial nephritis or kidney allograft rejection in patients treated with immune checkpoint
inhibitors. Studies have elucidated the contribution of adaptive immunity in kidney inflammation. However, the
mechanistic study on the roles of antigen-specific T cells in kidney inflammation is far from complete due to the
lack of appropriate animal models to precisely track antigen specificity and this hinders development of specific
targeted therapy in autoimmune kidney diseases. To close this knowledge gap, we developed two new
transgenic mouse models in which the expression of self-antigens can be specifically induced in proximal
tubules or podocytes, the main target anatomical segments in the autoimmune kidney diseases. By combining
these animal models with a tetramer-based antigen-specific T cell tracking technique to detect endogenous T
cells that recognize specific peptide-MHC complexes, we are able to analyze their phenotype and function in
vivo. The overall goal of this project is to dissect the mechanisms of tolerance against kidney-restricted
antigens. Our preliminary data indicated that kidney-specific expression of self-antigens induced tolerance
against these antigens; however, administration of anti-PD-1 and anti-CTLA4 could overcome the tolerance,
manifested as infiltration of antigen-specific T cells into kidney interstitium. We hypothesize that the tolerance
in the kidney is regulated by the co-stimulatory molecules expressed in antigen-specific T cells and their
ligands found in kidney parenchymal cells or antigen presenting cells; and that disruption of the tolerance
would lead to maladaptive inflammation in the kidney. To test this hypothesis, we will investigate T cell
tolerance mechanism at steady state (Aim 1), characterize kidney-infiltrating pathogenic T cells (Aim 2), and
dissect the roles of antigen presenting cells in tolerance and autoimmunity (Aim 3).
These models provide a novel and innovative approach to study antigen-specific adaptive immune response in
autoimmune kidney disease and represent unique preclinical tools, which will lead to identification of novel
therapeutic targets. In addition, after completing this K award, I will establish my own translational research
project in the intersection of immunology and kidney biology. Developing this research project will be an
exceptional opportunity to become proficient in specific basic research methodologies (e.g. transcriptomics)
and in kidney biology research.
项目总结
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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Naoka Murakami其他文献
Naoka Murakami的其他文献
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{{ truncateString('Naoka Murakami', 18)}}的其他基金
Role of antigen-specific T cells in immunotherapy-associated acute interstitial nephritis and kidney allograft rejection
抗原特异性 T 细胞在免疫治疗相关急性间质性肾炎和肾同种异体移植排斥中的作用
- 批准号:
10351987 - 财政年份:2022
- 资助金额:
$ 16.84万 - 项目类别:
Role of antigen-specific T cells in immunotherapy-associated acute interstitial nephritis and kidney allograft rejection
抗原特异性 T 细胞在免疫治疗相关急性间质性肾炎和肾同种异体移植排斥中的作用
- 批准号:
10548204 - 财政年份:2022
- 资助金额:
$ 16.84万 - 项目类别:
Protection of kidney from autoimmunity by modulating co-stimlatory signaling
通过调节共刺激信号来保护肾脏免受自身免疫的影响
- 批准号:
9908074 - 财政年份:2019
- 资助金额:
$ 16.84万 - 项目类别:
Protection of kidney from autoimmunity by modulating co-stimlatory signaling
通过调节共刺激信号来保护肾脏免受自身免疫的影响
- 批准号:
10886997 - 财政年份:2019
- 资助金额:
$ 16.84万 - 项目类别:
Protection of kidney from autoimmunity by modulating co-stimlatory signaling
通过调节共刺激信号来保护肾脏免受自身免疫的影响
- 批准号:
10397065 - 财政年份:2019
- 资助金额:
$ 16.84万 - 项目类别:
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