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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

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，NPM1，一种必需的Bax伴侣，促进调节细胞死亡和急性肾损伤 (Aki)在缺血的人肾脏中。NPM1的结构-功能关系及其相互作用部位与Bax的作用未知，限制了新药的开发，以防止NPM/Bax在肾脏细胞中的毒性易受缺血损伤的影响。我们的综合、跨学科策略结合了细胞生物学和结构和药物化学，以确定使NPM对肾脏细胞有毒的特征并定位NPM 负责绑定BAX的域。利用x射线结晶学、光标记技术进行蛋白质结构分析我们将优化一种新的Bax多肽，用于预防和治疗高危缺血性AKI 心脏手术患者。在三个目标中，我们将：(1)描述引起监管的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；(3)选择有效的治疗方法预防NPM：BAX体外毒性和体内AKI。预先确认NPM在脑缺血损伤中的因果作用人类肾脏及其在跨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。我们的科学团队联合了在调节细胞死亡，临床和实验AKI，多肽和分析设计，x射线结晶学，和质谱学来促进我们对急性心肌梗死期间缺血细胞死亡的机制的理解，识别临床前研究的靶点和新药，并可能改变AKI患者的护理标准。