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：
STEVEN C. BORKAN
金额：
$ 54.61万
依托单位：
BOSTON MEDICAL CENTER
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：
https://reporter.nih.gov/project-details/10660551
关键词：
ADME Study Acute Renal Failure with Renal Papillary Necrosis Address Amino Acid Sequence Amino Acids Animals Bilateral Binding Biological Assay Blood flow Brain Cardiac Surgery procedures Cause of Death Cell Death Cells Cellular biology Clinic Clinical Complex Consensus Coupled Crystallography Development Diagnostic Drug Design Drug Kinetics Drug Stability Drug Targeting Epithelial Cells Escherichia coli Event Exposure to Financial cost Generations Goals Heart Histologic Human In Vitro Inflammation Injectable Injury Intervention Ischemia Isotopes Kidney Kidney Failure Kidney Transplantation Length Life Ligand Binding Liver Mass Spectrum Analysis Measures Mediating Medicine Metabolic Mitochondria Molecular Chaperones Molecular Target Mus NPM1 gene Nuclear Patients Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Phosphorylation Photoaffinity Labels Plasma Predisposition Property Proteins Public Health Regulation Renal function Reperfusion Injury Role Sepsis Serum Severities Site Stress Structural Chemistry Structure Structure-Activity Relationship Techniques Testing Therapeutic Tissues Toxic effect Toxin Translating Uncertainty Urine Validation X-Ray Crystallography crosslink delayed graft function design drug testing high risk improved in vivo inhibitor ischemic injury kidney cell kidney preservation monomer mortality new therapeutic target novel novel therapeutics nucleophosmin peptide drug post gamma-globulins pre-clinical preclinical study predictive modeling prevent protein protein interaction prototype renal ischemia standard of care structural biology therapeutically effective tissue injury urinary tract obstruction virtual

ADME Study Acute Renal Failure with Renal Papillary Necrosis Address Amino Acid Sequence Amino Acids Animals Bilateral Binding Biological Assay Blood flow Brain Cardiac Surgery procedures Cause of Death Cell Death Cells Cellular biology Clinic Clinical Complex Consensus Coupled Crystallography Development Diagnostic Drug Design Drug Kinetics Drug Stability Drug Targeting Epithelial Cells Escherichia coli Event Exposure to Financial cost Generations Goals Heart Histologic Human In Vitro Inflammation Injectable Injury Intervention Ischemia Isotopes Kidney Kidney Failure Kidney Transplantation Length Life Ligand Binding Liver Mass Spectrum Analysis Measures Mediating Medicine Metabolic Mitochondria Molecular Chaperones Molecular Target Mus NPM1 gene Nuclear Patients Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Phosphorylation Photoaffinity Labels Plasma Predisposition Property Proteins Public Health Regulation Renal function Reperfusion Injury Role Sepsis Serum Severities Site Stress Structural Chemistry Structure Structure-Activity Relationship Techniques Testing Therapeutic Tissues Toxic effect Toxin Translating Uncertainty Urine Validation X-Ray Crystallography crosslink delayed graft function design drug testing high risk improved in vivo inhibitor ischemic injury kidney cell kidney preservation monomer mortality new therapeutic target novel novel therapeutics nucleophosmin peptide drug post gamma-globulins pre-clinical preclinical study predictive modeling prevent protein protein interaction prototype renal ischemia standard of care structural biology therapeutically effective tissue injury urinary tract obstruction virtual

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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.

项目摘要/摘要我们发现NPM1是必需的Bax伴侣，可促进受调节的细胞死亡和急性肾脏损伤（AKI）在缺血性人类肾脏中。 NPM1的结构功能关系（SAR）及其相互作用位点 Bax是未知的容易受到缺血性伤害。我们综合的跨学科策略将细胞生物学与结构结合在一起和药物化学，以识别使NPM有毒肾细胞并定位NPM的特征负责结合BAX的领域。使用X射线晶体学，光标记使用蛋白质结构分析和交联，我们将优化一种新型的Bax肽，用于预防和治疗高风险的缺血性AKI 心脏手术患者。在三个目标中，我们将：（1）表征npm结构特征，导致受调节的调节肾细胞死亡；（2）优化药物设计以抑制NPM：BAX相互作用，（3）选择有效的疗法为了防止NPM：体内体外和AKI的Bax毒性。事先验证了NPM在缺血性损伤中的因果作用人类肾脏及其在跨不同物种的缺血性细胞死亡期间的调节大大调节增加将我们的新疗法转化为诊所的可能性。我们的科学团队合计调节细胞死亡，临床和实验性AKI，胡椒和测定设计方面的专业知识，X射线晶体学，和质谱法以提高我们对AKI期间缺血性细胞死亡的机械理解，确定用于临床前研究的靶标和新药物，并有可能改变AKI患者的护理标准。