lmmunomodulatory roles of renal lymphatic endothelial cells in Acute Kidney Injury
肾淋巴内皮细胞在急性肾损伤中的免疫调节作用
基本信息
- 批准号:10612171
- 负责人:
- 金额:$ 3.63万
- 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:2023-05-30 至 2025-05-29
- 项目状态:未结题
- 来源:
- 关键词:Acute Renal Failure with Renal Papillary NecrosisAddressAdmission activityAffectAgonistAntigen PresentationAttenuatedAutomobile DrivingBindingCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCardiorenal syndromeCell CommunicationCell Differentiation processCell SurvivalCell secretionCellsChronicChronic Kidney FailureCisplatinCulture TechniquesDataDevelopmentDisease modelEnd stage renal failureEnvironmentFibrosisFlow CytometryFutureGenetic ModelsGoalsHealthHeart InjuriesHomeostasisHospitalizationImmuneImmune responseInflammationInflammatoryInflammatory ResponseInjuryInjury to KidneyInterferon Type IIIschemiaKidneyKidney DiseasesLengthLipidsLiquid substanceLymphangiogenesisLymphaticLymphatic Endothelial CellsLymphatic ResearchLymphocyteMalignant NeoplasmsMedical Care CostsModelingMolecularMusOutcomePathway interactionsPatientsPhenotypePlayPopulationPositioning AttributePostdoctoral FellowProteinsQuality of lifeRNARecoveryRegulatory T-LymphocyteRenal functionReperfusion TherapyResearchResolutionResourcesRiskRoleSecureSignal PathwaySignal TransductionSkinSphingosine-1-Phosphate ReceptorSpleenT cell responseT memory cellT-LymphocyteTestingTherapeuticTissuesUnited StatesUnited States National Institutes of HealthVEGFC geneVascular Endothelial Growth Factor CVascular Endothelial Growth Factor DVascular Endothelial Growth Factorsadaptive immune responsecareer networkingchemokine receptordensityimmune activationimmunoregulationimprovedinflammatory milieuinjuredkidney fibrosislymph nodeslymphatic vasculaturelymphatic vessellymphocyte traffickingmacromoleculemelanomamortalitymouse modelnoveloverexpressionpreventprogrammed cell death ligand 1receptor expressionresponsesingle-cell RNA sequencingskillssphingosine 1-phosphatetargeted treatmenttraffickinguptake
项目摘要
PROJECT SUMMARY
In the United States an estimated 50% of ICU patients develop AKI and is associated with a 50% mortality rte.
A single occurrence of AKI predisposes a patient to develop chronic conditions such as Chronic Kidney Disease
(CKD) and End-Stage Renal Disease (ESRD), conditions which decrease quality of life and may be fatal.
Increasingly, research demonstrates that AKI induced injury promotes persistent renal inflammation and fibrosis
driving progression to CKD and ESRD. Understanding mechanisms by which renal inflammation may be
regulated would therefore allow development of targeted renal therapeutic environments. Inflammation
associated lymphangiogenesis is responsible for maintaining tissue homeostasis through uptake of fluids,
macromolecules, proteins, and immune cell trafficking. Upon AKI insult lymphatic growth factors Vascular
endothelial growth factor D (VEGF-D) and VEGF-C are increased within the kidney. Lymphatic research has
identified immunomodulatory roles of LECs such as expression of MHCs, chemokine receptors, and antigen
presentation. The lab has demonstrated increased renal lymphangiogenesis in models of AKI alters adaptive
immune cell presence and reduces renal fibrosis. However, how LECs regulate AKI associated inflammation
and recovery is still unknown. The long-term goal of this study is to identify how immunomodulatory roles of
LECs impact the renal immune response and recovery in AKI. The proposal’s overall objective is to identify how
the adaptive immune response is altered in AKI with increased renal lymphatic density and how these immune
cell populations are altered upon deletion of a known LEC immunomodulatory molecule. The central hypothesis
is that renal LECs regulate inflammation through direct lymphatic-immune cell interactions and regulate immune
cell clearance from the tissue, altering pathophysiological outcomes in AKI. Directed by strongly supportive
preliminary data the hypothesis will be tested by two specific aims: Aim 1 Identify how increased renal
lymphangiogenesis alters the adaptive immune response in AKI. Aim 2 Demonstrate LEC specific deletion of
sphingosine-1-phosphate (S1P) secretion alters the T cell response and inflammation resolution in AKI. In the
first aim cisplatin and ischemia-reperfusion (IR) models of AKI will assess if increased renal lymphatic density
prior to injury in a mouse model of kidney specific inducible overexpression of VEGF-D (KidVD) alters adaptive
immune cell populations and inflammatory progression. Preliminary data suggests increased renal lymphatic
density primes the adaptive immune response and attenuates renal fibrosis. For the second aim, determining
how a LEC specific deletion of S1P, a bioactive, alters renal immune cell clearance and the adaptive immune
response in AKI may provide a novel renal targeted therapeutic option. To address how LECs regulate AKI
associated inflammation and recovery a combination of lymphatic specific genetic models, renal injury models,
and immune cell phenotyping will identify alterations in the renal immune cell response to AKI.
项目概要
在美国,估计 50% 的 ICU 患者会出现 AKI,并导致 50% 的死亡率。
单次发生 AKI 会使患者容易患上慢性疾病,例如慢性肾病
(CKD)和终末期肾病(ESRD),这些疾病会降低生活质量并可能致命。
越来越多的研究表明 AKI 引起的损伤会促进持续性肾脏炎症和纤维化
推动进展为 CKD 和 ESRD。了解肾脏炎症可能的机制
因此,受到监管将允许开发有针对性的肾脏治疗环境。炎
相关的淋巴管生成负责通过吸收液体维持组织稳态,
大分子、蛋白质和免疫细胞运输。 AKI 损害淋巴生长因子 血管
肾脏内内皮生长因子 D (VEGF-D) 和 VEGF-C 增加。淋巴管研究有
确定了 LEC 的免疫调节作用,例如 MHC、趋化因子受体和抗原的表达
推介会。该实验室已证明 AKI 模型中肾淋巴管生成增加,改变了适应性
免疫细胞的存在并减少肾纤维化。然而,LECs 如何调节 AKI 相关炎症
并且恢复情况仍是未知数。这项研究的长期目标是确定免疫调节作用如何
LEC 影响 AKI 中的肾脏免疫反应和恢复。该提案的总体目标是确定如何
随着肾淋巴密度增加,AKI 中的适应性免疫反应发生改变,以及这些免疫反应如何改变
删除已知的 LEC 免疫调节分子后,细胞群就会发生改变。中心假设
肾 LEC 通过直接淋巴-免疫细胞相互作用调节炎症并调节免疫
细胞从组织中清除,改变 AKI 的病理生理结果。大力支持指导
初步数据 该假设将通过两个具体目标进行检验: 目标 1 确定肾功能如何增加
淋巴管生成改变 AKI 中的适应性免疫反应。目标 2 证明 LEC 特异性删除
1-磷酸鞘氨醇 (S1P) 的分泌会改变 AKI 中的 T 细胞反应和炎症消退。在
第一个目标 顺铂和 AKI 缺血再灌注 (IR) 模型将评估肾淋巴密度是否增加
在肾脏特异性诱导性过度表达 VEGF-D (KidVD) 的小鼠模型中,损伤前会改变适应性
免疫细胞群和炎症进展。初步数据表明肾淋巴管增加
密度可以启动适应性免疫反应并减轻肾纤维化。对于第二个目标,确定
LEC 特异性删除 S1P(一种生物活性物质)如何改变肾脏免疫细胞清除和适应性免疫
AKI 的反应可能提供一种新的肾脏靶向治疗选择。解决 LEC 如何调节 AKI
相关的炎症和恢复淋巴特异性遗传模型、肾损伤模型的组合,
免疫细胞表型分析将识别肾脏免疫细胞对 AKI 反应的变化。
项目成果
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