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Cyclin-dependent Kinase Inhibitor in Acute Renal Failure

急性肾衰竭中的细胞周期蛋白依赖性激酶抑制剂

基本信息

批准号：
8183462
负责人：
PETER M. PRICE
金额：
$ 5.4万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8183462
关键词：
Acute Acute Kidney Failure Acute Renal Failure with Renal Papillary Necrosis Address Affect Apoptosis Binding Cell Cycle Cell Cycle Progression Cell Death Cells Cessation of life Cisplatin Critical Illness Cyclin-Dependent Kinase Inhibitor Development Disease Dominant-Negative Mutation Enzyme Inhibition Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Family member Financial cost Goals Human In Vitro Incidence Injury Intervention Ischemia Kidney Kidney Failure Lead Life Long-Term Effects Methods Mitochondria Modeling Modification Molecular Morbidity - disease rate Mouse Strains Mus Natural regeneration Necrosis Organ failure Pathway interactions Patient Care Patients Personal Satisfaction Phosphorylation Phosphotransferases Population Post-Translational Protein Processing Process Proteins Proximal Kidney Tubules Recovery Reperfusion Therapy Reporting Resistance Risk Factors Role Syndrome Time Toxic effect Toxin Transgenes Transgenic Mice Transgenic Organisms Translating Up-Regulation base cell injury cellular transduction cost cytotoxicity disability human CDK2 protein in vivo inhibitor/antagonist injured kidney cell mortality mutant nephrotoxicity novel oncoprotein p21 prevent protein protein interaction response translational approach

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to prevent/treat acute kidney injury. We are using cisplatin toxicity as a model of renal injury, in vitro using cultured mouse kidney proximal tubule cells, and in vivo using wild-type and transgenic mice. We have established that inhibition of a cell cycle-associated enzyme, cyclin-dependent kinase-2 (Cdk2), protect from cytotoxicity in vitro and protects from kidney injury in vivo caused by cisplatin administration. Based on these findings, we developed two transgenic mouse strains resistant to cisplatin-induced acute renal injury because of specific cdk2 inhibition. We found that several pathways of cell death were dependent on Cdk2 activity and contribute to cisplatin cytotoxicity. We hypothesize that cell death activated by cisplatin and dependent on Cdk2 kinase activity can likely be explained by intersecting rather than parallel pathways. Now we find that in response to cisplatin, Cdk2 phosphorylates two proteins, p21 and Bcl xL, that directly and indirectly could have effects on cell death pathways. In our first specific aim we will investigate whether these proteins provide the intersections of cell cycle and cell death. We hypothesize that Cdk2 inhibition would be an effective short- and long-term strategy to prevent AKI. Our recently developed transgenic mice in which induced expression of either p21 or DN-Cdk2 protected from cisplatin nephrotoxicity confirmed the first half of this hypothesis. The second half of our hypothesis will be addressed in this second specific aim, which will determine whether Cdk2inhibition merely delays nephrotoxicity and whether Cdk2 inhibition and cisplatin exposure causes longer-term effects on kidney recovery. PUBLIC HEALTH RELEVANCE: Acute kidney injury (AKI) is a common disorder affecting up to 5% of hospitalized patients. Despite our increased understanding of the incidence and consequences of AKI, morbidity and mortality associated with this syndrome in critically ill patients has remained above 50%. AKI is an independent risk factor in the setting of multi organ failure leading to death and disability. The financial costs of AKI are estimated to be 8 billion dollars per year, or about $130,000 per life-year saved. It is unlikely that this high mortality and associated cost will be reduced until we understand the cellular and molecular mechanisms of cell injury and recovery. We found that cell cycle enzyme inhibitors will totally protect kidney cells in vitro from cisplatin cytotoxicity and significantly diminish morphologic and functional AKI in vivo. We have developed transgenic mice that are resistant to AKI. The mechanism of protection and its use in vivo will be investigated. Our proposal will lead to the development of agents that can be used to prevent AKI, which will directly impact patient care and well-being.

描述（由申请人提供）：我们的长期目标是预防/治疗急性肾损伤。我们使用顺铂毒性作为肾损伤的模型，在体外使用培养的小鼠肾近端小管细胞，并在体内使用野生型和转基因小鼠。我们已经确定，抑制细胞周期相关酶，细胞周期蛋白依赖性激酶-2（Cdk 2），在体外保护细胞毒性，并在体内保护顺铂给药引起的肾损伤。基于这些发现，我们开发了两种转基因小鼠品系，由于特异性cdk 2抑制而对顺铂诱导的急性肾损伤具有抗性。我们发现，细胞死亡的几种途径依赖于Cdk 2活性，并有助于顺铂的细胞毒性。我们假设顺铂激活的细胞死亡依赖于Cdk 2激酶活性，可能是交叉而不是平行的途径。现在我们发现，在顺铂的反应中，Cdk 2磷酸化两种蛋白质，p21和Bcl xL，这两种蛋白质直接和间接地影响细胞死亡途径。在我们的第一个具体目标中，我们将研究这些蛋白质是否提供细胞周期和细胞死亡的交叉点。我们假设Cdk 2抑制将是预防阿基的有效短期和长期策略。我们最近开发的转基因小鼠中诱导表达的p21或DN-Cdk 2保护顺铂肾毒性证实了这一假设的前半部分。我们的假设的后半部分将在第二个具体目标中得到解决，这将确定Cdk 2抑制是否仅仅延迟肾毒性，以及Cdk 2抑制和顺铂暴露是否会对肾脏恢复产生长期影响。公共卫生相关性：急性肾损伤（阿基）是一种常见疾病，影响高达5%的住院患者。尽管我们对阿基的发病率和后果的了解有所增加，但危重患者中与该综合征相关的发病率和死亡率仍高于50%。阿基是导致死亡和残疾的多器官功能衰竭的独立风险因素。阿基的财务成本估计为每年80亿美元，或每挽救一个生命年约13万美元。在我们了解细胞损伤和恢复的细胞和分子机制之前，这种高死亡率和相关成本不太可能降低。我们发现细胞周期酶抑制剂在体外可完全保护肾细胞免受顺铂的细胞毒性，并在体内显著减少形态和功能阿基。我们已经开发出了对阿基具有抵抗力的转基因小鼠。将研究保护机制及其在体内的应用。我们的提案将导致可用于预防阿基的药物的开发，这将直接影响患者的护理和福祉。