Lymphatics and lymphangiogenesis in kidney function and inflammation
肾功能和炎症中的淋巴管和淋巴管生成
基本信息
- 批准号:10087925
- 负责人:
- 金额:$ 44.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-01-23 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:Acute Renal Failure with Renal Papillary NecrosisAddressAffectAmericanAntigensBilateralBiological MarkersBiological ModelsBiologyCellsCharacteristicsChronicChronic Kidney FailureCisplatinClinicalClosure by clampDataDiabetes MellitusDiseaseDisease ProgressionEpidemicExcretory functionExhibitsFibrosisFunctional disorderFutureGeneticGenetic ModelsGenetic TechniquesGoalsHealthHealthcareHomeostasisHumanHypertensionImmuneImmune responseImpairmentInflammationInflammatoryInflammatory ResponseInjuryInjury to KidneyIschemiaKidneyKidney DiseasesKnowledgeLiquid substanceLymphangiogenesisLymphaticMedicareMetabolismMineralsMissionModelingMolecular GeneticsMorbidity - disease rateMusNational Institute of Diabetes and Digestive and Kidney DiseasesOsteoporosisOutcomePathogenesisPathologyPathway interactionsPatient-Focused OutcomesPatientsPharmacologyPhenotypePhysiologicalPhysiologyPositioning AttributePre-Clinical ModelProteinuriaPublic HealthPublishingRegulationRenal functionReperfusion InjuryReperfusion TherapyReportingResearchResistanceRiskRisk FactorsRoleRouteSeveritiesSodiumTestingTherapeuticTissuesUnited States National Institutes of HealthUp-RegulationVascular Endothelial Growth Factor CVascular Endothelial Growth Factor DVascular Endothelial Growth Factor Receptor-3Workanimal datachronic inflammatory diseasecytokinedensityhigh salt dietimprovedinjury recoveryinnovationinorganic phosphateinterstitialkidney preservationlymphatic vasculaturelymphatic vesselmacromoleculemortalitymouse modelnephrotoxicitynoveloverexpressionpressurepreventresponseresponse to injurysodium phosphatesolutestatisticssuccesstissue injury
项目摘要
PROJECT SUMMARY
Acute kidney injury (AKI) is a major cause of patient morbidity and mortality and appears to be a substantial risk
factor for future progression to chronic kidney disease (CKD). According to NIDDK statistics, roughly 14% of
Americans exhibit indications of CKD and 20% of all Medicare spending goes towards it management. Slowing
AKI-to-CKD progression, or identifying those patients most at risk for future CKD following AKI, is currently not
possible largely due to a fundamental gap in understanding of the pathogenesis of AKI-to-CKD transition.
Inflammation-associated lymphangiogenesis (LAG) is critical in regulating inflammation through fluid,
macromolecule (cytokines and antigens), and immune cell transport. While LAG has been identified in a host of
kidney diseases, reports have been mostly correlative. The long-term goal is to identify the mechanisms by
which lymphatics regulate tissue biology in chronic inflammatory disease. The overall objective in this
application is to identify the roles of the renal lymphatic vasculature during kidney injury and exploit the induction
of enhanced LAG as a potential therapy. The central hypothesis is that increasing renal lymphatics provides a
route of immune cell clearance while also potentially regulating solute transport. Guided by strong preliminary
data, this hypothesis will be tested by pursuing three specific aims: 1) Determine how renal LAG affects
inflammation and renal function in AKI; and 2) Determine the mechanisms by which renal LAG reduces AKI-to-
CKD progression; and 3) Determine the impact of enhancing renal lymphatic density on CKD. Under the first
aim, 3 models of AKI with diverse pathophysiologies will be used to identify how lymphatic density changes with
AKI and whether expanding lymphatics using KidVD mice, a genetic model of kidney-specific LAG, can limit the
AKI inflammatory response. Preliminary data suggest increased LAG protects against AKI. In the second aim,
how LAG alters the progression of AKI-to-CKD will be determined. Additionally, how changes in interstitial
pressures and mineral metabolism in the kidney with increased LAG during sodium and phosphate challenge
may provide a novel mechanism for AKI protection. For the third aim, therapeutic strategies to induce LAG once
CKD is established will be tested in each of the 3 renal pathologies. The proposed research is innovative, in the
applicant’s opinion, because it addresses and specifically targets the lymphatic vasculature of the kidney to
improve kidney function and inflammation upon AKI. New potential therapies and biomarkers are expected to
result from this work. The proposed research is significant because it is expected to identify previously unknown
mechanisms of kidney inflammatory regulation and transport functions. Ultimately, understanding the
mechanisms by which lymphatic vessels regulate kidney function and health has the potential to be
transformative to AKI response and treatment and in remediating the current epidemic of incurable chronic
kidney disease.
项目总结
急性肾损伤(AKI)是患者发病率和死亡率的主要原因,似乎是一种很大的风险。
未来发展为慢性肾脏疾病(CKD)的因素。根据NIDDK的统计,大约14%的
美国人表现出慢性肾脏病的迹象,所有医疗保险支出的20%用于IT管理。减速
AKI到CKD进展,或确定那些在AKI后最有可能患上未来CKD的患者,目前还不是
可能很大程度上是由于对AKI到CKD转变的发病机制的根本认识上的差距。
炎症相关淋巴管生成(LAG)是通过液体调节炎症的关键,
大分子(细胞因子和抗原)和免疫细胞运输。虽然LAG已经在许多
肾脏疾病方面的报道多为相关报道。长期目标是通过以下方式确定这些机制
在慢性炎症性疾病中,哪些淋巴管调节组织生物学。这个项目的总体目标是
其应用是确定肾淋巴管在肾脏损伤中的作用,并开发其诱导作用
增强滞后作为一种潜在的治疗方法。中心假设是肾脏淋巴管的增加提供了一个
免疫细胞清除的途径,同时也潜在地调节溶质运输。以强劲的前期工作为指导
数据,这一假设将通过追求三个具体目标来检验:1)确定肾滞后如何影响
AKI的炎症和肾功能;以及2)确定肾滞后降低AKI-TO-1的机制。
CKD进展;3)确定肾淋巴管密度增加对CKD的影响。在第一个下
目的:3种不同病理生理学的急性肾损伤模型将被用来识别淋巴密度的变化。
Aki以及使用KidVD小鼠扩张淋巴管是否可以限制
Aki炎症反应。初步数据显示,增加的滞后时间可以预防AKI。在第二个目标中,
滞后如何改变AKI到CKD的进程将得到确定。此外,间质中的变化
钠和磷酸盐刺激时肾脏的压力和矿物质代谢滞后增加
可能为AKI的保护提供一种新的机制。对于第三个目标,一次诱导滞后的治疗策略
慢性肾脏病的建立将分别在3种肾脏病理中进行检测。拟议的研究是创新的,在
申请人的意见,因为它涉及并特别针对肾脏的淋巴血管系统
改善肾功能,改善急性肾损伤的炎症反应。新的潜在疗法和生物标记物有望
这项工作的成果。这项拟议的研究意义重大,因为它有望发现以前未知的
肾脏炎症调节和转运功能的机制。最终,理解
淋巴管调节肾脏功能和健康的机制可能是
对AKI的反应和治疗以及对当前不治之症的治疗具有变革性作用
肾脏疾病。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Joseph Michael Rutkowski其他文献
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{{ truncateString('Joseph Michael Rutkowski', 18)}}的其他基金
Lymphatics and lymphangiogenesis in kidney function and inflammation
肾功能和炎症中的淋巴管和淋巴管生成
- 批准号:
10306392 - 财政年份:2020
- 资助金额:
$ 44.3万 - 项目类别:
Lymphatics and lymphangiogenesis in kidney function and inflammation
肾功能和炎症中的淋巴管和淋巴管生成
- 批准号:
10259635 - 财政年份:2020
- 资助金额:
$ 44.3万 - 项目类别:
Lymphatics and lymphangiogenesis in kidney function and inflammation
肾功能和炎症中的淋巴管和淋巴管生成
- 批准号:
10413663 - 财政年份:2020
- 资助金额:
$ 44.3万 - 项目类别:
Lymphatics and lymphangiogenesis in kidney function and inflammation
肾功能和炎症中的淋巴管和淋巴管生成
- 批准号:
10529283 - 财政年份:2020
- 资助金额:
$ 44.3万 - 项目类别:
Lymphatics and lymphangiogenesis in kidney function and inflammation
肾功能和炎症中的淋巴管和淋巴管生成
- 批准号:
10507856 - 财政年份:2020
- 资助金额:
$ 44.3万 - 项目类别:
Lymphatics and lymphangiogenesis in kidney function and inflammation
肾功能和炎症中的淋巴管和淋巴管生成
- 批准号:
9886866 - 财政年份:2020
- 资助金额:
$ 44.3万 - 项目类别:
Adiponectin transport: endothelial modulation of adipokine function
脂联素转运:脂肪因子功能的内皮调节
- 批准号:
8040911 - 财政年份:2010
- 资助金额:
$ 44.3万 - 项目类别:
Adiponectin transport: endothelial modulation of adipokine function
脂联素转运:脂肪因子功能的内皮调节
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7912521 - 财政年份:2010
- 资助金额:
$ 44.3万 - 项目类别:
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