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:10660551
- 负责人:
- 金额:$ 54.61万
- 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 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:ADME StudyAcute Renal Failure with Renal Papillary NecrosisAddressAmino Acid SequenceAmino AcidsAnimalsBilateralBindingBiological AssayBlood flowBrainCardiac Surgery proceduresCause of DeathCell DeathCellsCellular biologyClinicClinicalComplexConsensusCoupledCrystallographyDevelopmentDiagnosticDrug DesignDrug KineticsDrug StabilityDrug TargetingEpithelial CellsEscherichia coliEventExposure toFinancial costGenerationsGoalsHeartHistologicHumanIn VitroInflammationInjectableInjuryInterventionIschemiaIsotopesKidneyKidney FailureKidney TransplantationLengthLifeLigand BindingLiverMass Spectrum AnalysisMeasuresMediatingMedicineMetabolicMitochondriaMolecular ChaperonesMolecular TargetMusNPM1 geneNuclearPatientsPeptidesPharmaceutical ChemistryPharmaceutical PreparationsPhosphorylationPhotoaffinity LabelsPlasmaPredispositionPropertyProteinsPublic HealthRegulationRenal functionReperfusion InjuryRoleSepsisSerumSeveritiesSiteStressStructural ChemistryStructureStructure-Activity RelationshipTechniquesTestingTherapeuticTissuesToxic effectToxinTranslatingUncertaintyUrineValidationX-Ray Crystallographycrosslinkdelayed graft functiondesigndrug testinghigh riskimprovedin vivoinhibitorischemic injurykidney cellkidney preservationmonomermortalitynew therapeutic targetnovelnovel therapeuticsnucleophosminpeptide drugpost gamma-globulinspre-clinicalpreclinical studypredictive modelingpreventprotein protein interactionprototyperenal ischemiastandard of carestructural biologytherapeutically effectivetissue injuryurinary tract obstructionvirtual
项目摘要
Project Summary/Abstract
We discovered that NPM1, a required Bax chaperone, promotes regulated cell death and acute kidney injury
(AKI) in the ischemic human kidney. The structure-function relationships (SAR) of NPM1 and its site of interaction
with Bax are unknown, limiting the development of novel drugs to prevent NPM/Bax toxicity in kidney cells that
are vulnerable to ischemic injury. Our integrative, cross disciplinary strategy combines cell biology with structural
and medicinal chemistry to identify the features that render NPM toxic to kidney cells and localize the NPM
domain responsible for binding Bax. Using protein structural analysis with x-ray crystallography, photo-labeling
and cross-linking, we will optimize a novel Bax peptide for preventing and treating ischemic AKI in high risk
cardiac surgery patients. In three aims, we will: (1) Characterize NPM structural features that cause regulated
renal cell death; (2) Optimize drug design to inhibit NPM:Bax interaction, and (3) Select an effective therapeutic
to prevent NPM:Bax toxicity in vitro and AKI in vivo. Prior validation of NPM’s causal role in ischemic injury in
the human kidney and its conserved regulation during ischemic cell death across divergent species substantially
increase the likelihood of translating our novel therapeutics to the clinic. Our scientific team has the combined
expertise in regulated cell death, clinical and experimental AKI, peptide and assay design, x-ray crystallography,
and mass spectrometry to advance our mechanistic understanding of ischemic cell death during AKI, identify
targets and novel drugs for pre-clinical study, and potentially change the standard-of care for AKI patients.
项目概要/摘要
我们发现 NPM1(Bax 必需的伴侣)可促进调节性细胞死亡和急性肾损伤
(AKI) 在缺血性人肾中的作用 NPM1 的结构-功能关系 (SAR) 及其相互作用位点。
Bax 的作用尚不清楚,限制了新药的开发,以防止 NPM/Bax 对肾细胞的毒性
我们的综合跨学科策略将细胞生物学与结构结合起来。
和药物化学,以确定 NPM 对肾细胞有毒的特征并定位 NPM
负责结合 Bax 的结构域使用 X 射线晶体学、照片标记进行蛋白质结构分析。
和交联,我们将优化一种新型 Bax 肽,用于预防和治疗高风险缺血性 AKI
在三个目标中,我们将:(1)表征引起调节的 NPM 结构特征。
肾细胞死亡;(2) 优化药物设计以抑制 NPM:Bax 相互作用,以及 (3) 选择有效的治疗方法
预防 NPM:Bax 体外毒性和体内 AKI 预先验证 NPM 在缺血性损伤中的因果作用。
人类肾脏及其在不同物种缺血性细胞死亡过程中的保守调节
增加将我们的新疗法转化为临床的可能性。
调节细胞死亡、临床和实验 AKI、肽和晶体学测定设计方面的专业知识,
和质谱法以增进我们对 AKI 期间缺血性细胞死亡机制的理解,确定
用于临床前研究的靶点和新药,并有可能改变 AKI 患者的护理标准。
项目成果
期刊论文数量(1)
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:
10171840 - 财政年份:2019
- 资助金额:
$ 54.61万 - 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:
$ 54.61万 - 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:
$ 54.61万 - 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:
$ 54.61万 - 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:
$ 54.61万 - 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:
$ 54.61万 - 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:
$ 54.61万 - 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:
$ 54.61万 - 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:
$ 54.61万 - 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:
$ 54.61万 - 项目类别:
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