Nucleophosmin Centered Diagnostics and Treatment of Ischemic Acute Kidney Injury
以核磷蛋白为中心的缺血性急性肾损伤的诊断和治疗
基本信息
- 批准号:10171840
- 负责人:
- 金额:$ 24.92万
- 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:2019-08-20 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Renal Failure with Renal Papillary NecrosisAnimalsAntibodiesApoptosisBiochemicalBiologicalBiological AssayBiological MarkersBiopsyBlood flowCell DeathCell SurvivalCellsCessation of lifeChronic DiseaseChronic Kidney FailureClinicalClinical TrialsComplexComputer AnalysisCouplingDataDetectionDiagnosisDiagnosticDisease ProgressionDoseEarly treatmentEnzymesEpithelial CellsEventExcretory functionFriendsGenderGoalsHealthcareHematoxylin and Eosin Staining MethodHourHumanHypoxiaIn VitroInjuryInterventionIschemiaKidneyKidney DiseasesKidney FailureLifeLinkMammalian CellMass Spectrum AnalysisMeasuresMediatingMitochondriaModificationMolecular ChaperonesMorbidity - disease rateMusNecrosisNuclear TranslocationOrganOrgan PreservationOrgan failureOuter Mitochondrial MembranePathway interactionsPatientsPeptidesPharmacologic SubstancePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPreparationProteinsPublic HealthReagentRecoveryRenal functionRoleSeveritiesSiteStainsStressTestingTherapeuticTimeTissuesToxic effectTranslatingTreatment EfficacyTubular formationUrinebasecell injurydesigneffective interventioneffective therapyimprovedin vitro testingin vivokidney biopsykidney cellmitochondrial membranemortalitymutantnovelnovel diagnosticsnovel therapeuticsnucleophosminpeptide drugpreservationrenal epitheliumrenal ischemiaresearch clinical testingsuccesstargeted treatmenttherapeutically effectivetoolurinary
项目摘要
Project Summary/Abstract
Ischemic acute kidney injury (AKI) is a common and often a life-threatening consequence of reduced
blood flow to this critical organ causes major morbidity and mortality, and lacks an effective treatment.
For the first time, we have detected identical biochemical events in both ischemic murine and human
kidneys that mediate renal cell death leading to AKI. In this proposal, we study the role of
nucleophosmin (NPM), a protein present in all mammalian cells that is converted from “friend” to a
“foe” during ischemic stress. During renal ischemia, NPM undergoes biochemical changes that
promote its toxicity in renal epithelial cells, a major contributor to organ failure during AKI. These steps
include: NPM translocation from the nuclear to the cytosolic compartment, NPM de-oligomerization,
interaction with Bax, a major cause of outer mitochondrial membrane injury, and renal cell death by
both apoptosis and necrosis, the two forms of cell death consistently detected in ischemic human
kidneys. Preliminary data using mass spectroscopy have identified 5 phosphorylation changes in
murine and human proximal tubule cells, kidney tissue, and urine that regulate NPM toxicity during
renal ischemia. In three AIMS, we will link post-translational phosphorylation events with NPM toxicity,
identify the role of NPM in human renal disease using banked kidney biopsy tissue, test NPM
phospho-mutant proteins that replicate toxic modifications, and develop novel peptide reagents for
ameliorating NPM toxicity. Once identified in vitro, we will test the most effective peptides and
pharmaceuticals to treat ischemic AKI in vivo. This in vitro testing minimizes the number of animals
required to perform our proposed studies that will examine the biologic effects of gender in AKI
diagnosis and treatment. We have developed a novel urinary NPM assay that will be used to as an
early AKI biomarker and also for measuring the therapeutic efficacy of our treatment. Assessment of
total and site-specific phosphorylated NPM in urine and tissue will trigger early treatment, and may
ultimately permit us to predict the severity of AKI and its recovery. Detection of NPM in human kidney
biopsy tissue will identify potential AKI causes (e.g., ischemia or nephrotoxin-induced AKI) that are
amenable to anti-NPM therapeutics. Since NPM is identically regulated during ischemia in mice and
humans, it is likely that effective interventions in mice will translate to human clinical trials.
项目摘要/摘要
缺血性急性肾损伤(AKI)是一种常见的,通常威胁生命的后果
血液流向这一关键器官会导致严重的发病率和死亡率,并且缺乏有效的治疗方法。
我们第一次在缺血小鼠和人类身上检测到相同的生化事件。
介导肾细胞死亡导致急性肾损伤的肾脏。在这项建议中,我们研究了
核磷蛋白(NPM),一种存在于所有哺乳动物细胞中的蛋白质,它从“Friend”转化为
缺血应激时的“敌人”。在肾缺血期间,NPM经历了
促进其对肾上皮细胞的毒性,肾上皮细胞是AKI期间器官衰竭的主要贡献者。这些步骤
包括:NPM从核到胞质的移位,NPM的去寡聚,
与Bax的相互作用,线粒体膜外膜损伤和肾细胞死亡的主要原因
细胞凋亡和坏死,这两种细胞死亡形式在缺血型人类中持续存在
肾脏。使用质谱学的初步数据已经确定了5个磷酸化变化
调节NPM毒性的小鼠和人近端小管细胞、肾组织和尿
肾缺血。在三个目标中,我们将翻译后磷酸化事件与NPM毒性联系起来,
用肾活检组织库鉴定NPM在人类肾脏疾病中的作用,检测NPM
复制有毒修饰的磷酸突变蛋白,并开发新的多肽试剂
改善NPM的毒性。一旦在体外鉴定,我们将测试最有效的多肽和
治疗体内缺血性AKI的药物。这种体外测试将动物的数量降到了最低
需要执行我们拟议的研究,该研究将检查AKI中性别的生物影响
诊断和治疗。我们已经开发出一种新的尿液NPM检测方法,将用于
早期AKI生物标志物,也用于衡量我们治疗的疗效。评估
尿液和组织中总的和特定部位的磷酸化NPM将触发早期治疗,并可能
最终使我们能够预测AKI的严重程度及其恢复。人肾组织中NPM的检测
活检组织将确定潜在的AKI原因(例如,缺血或肾毒素诱导的AKI)
对抗NPM疗法顺从。由于NPM在小鼠缺血期间受到相同的调控,
对于人类来说,在老鼠身上进行有效的干预很可能会转化为人类临床试验。
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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STEVEN C. BORKAN其他文献
STEVEN C. BORKAN的其他文献
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{{ truncateString('STEVEN C. BORKAN', 18)}}的其他基金
Nucleophosmin Centered Diagnostics and Treatment of Ischemic Acute Kidney Injury
以核磷蛋白为中心的缺血性急性肾损伤的诊断和治疗
- 批准号:
10660551 - 财政年份:2019
- 资助金额:
$ 24.92万 - 项目类别:
CYTOPROTECTIVE ROLE OF HSP 72 IN RENAL CELL INJURY
HSP 72 在肾细胞损伤中的细胞保护作用
- 批准号:
6517438 - 财政年份:1999
- 资助金额:
$ 24.92万 - 项目类别:
CYTOPROTECTIVE ROLE OF HSP72 IN RENAL CELL INJURY
HSP72 在肾细胞损伤中的细胞保护作用
- 批准号:
6922030 - 财政年份:1999
- 资助金额:
$ 24.92万 - 项目类别:
CYTOPROTECTIVE ROLE OF HSP72 IN RENAL CELL INJURY
HSP72 在肾细胞损伤中的细胞保护作用
- 批准号:
7253872 - 财政年份:1999
- 资助金额:
$ 24.92万 - 项目类别:
Cytoprotective Role of HSP72 in Renal Cell Injury
HSP72 在肾细胞损伤中的细胞保护作用
- 批准号:
8078160 - 财政年份:1999
- 资助金额:
$ 24.92万 - 项目类别:
Cytoprotective Role of HSP72 in Renal Cell Injury
HSP72 在肾细胞损伤中的细胞保护作用
- 批准号:
7781435 - 财政年份:1999
- 资助金额:
$ 24.92万 - 项目类别:
Cytoprotective Role of HSP72 in Renal Cell Injury
HSP72 在肾细胞损伤中的细胞保护作用
- 批准号:
8279460 - 财政年份:1999
- 资助金额:
$ 24.92万 - 项目类别:
Cytoprotective Role of HSP72 in Renal Cell Injury
HSP72 在肾细胞损伤中的细胞保护作用
- 批准号:
8675837 - 财政年份:1999
- 资助金额:
$ 24.92万 - 项目类别:
Cytoprotective Role of HSP72 in Renal Cell Injury
HSP72 在肾细胞损伤中的细胞保护作用
- 批准号:
8849429 - 财政年份:1999
- 资助金额:
$ 24.92万 - 项目类别:
CYTOPROTECTIVE ROLE OF HSP72 IN RENAL CELL INJURY
HSP72 在肾细胞损伤中的细胞保护作用
- 批准号:
7086854 - 财政年份:1999
- 资助金额:
$ 24.92万 - 项目类别: