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Biologic Effects of Cdk2 Substrate Phosphorylation on Acute Kidney Injury

Cdk2 底物磷酸化对急性肾损伤的生物学效应

基本信息

批准号：
8398965
负责人：
PETER M. PRICE
金额：
--
依托单位：
CENTRAL ARKANSAS VETERANS HLTHCARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8398965
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Address Affect Apoptosis BCL-2 Protein BCL2 gene Binding Cell Cycle Cell Cycle Progression Cell Death Cells Cessation of life Cisplatin Cyclins DNA Damage Data Dependency Development Disease Dominant-Negative Mutation E2F1 gene Enzyme Inhibition Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Family member Financial cost Goals Health In Vitro Injury Intervention Ischemia Kidney Kidney Failure Lead Life Link Mission Mitochondria Mitochondrial Proteins Modeling Modification Molecular Mouse Strains Mus Mutate Natural regeneration Nephrotoxic Organ failure Outer Mitochondrial Membrane Pathway interactions Patient Care Patients Personal Satisfaction Phosphorylation Population Post-Translational Protein Processing Proteins Proximal Kidney Tubules Recovery Renal tubule structure Reperfusion Therapy Reporting Research Resistance Risk Factors Role Stress Testing Time Transgenes Transgenic Mice Transgenic Organisms Up-Regulation Veterans base cell injury cost cytotoxicity disability endoplasmic reticulum stress human CDK2 protein in vivo inhibitor/antagonist injured kidney cell kidney necrosis mortality mutant nephrotoxicity novel oncoprotein p21 prevent protein protein interaction public health relevance renal ischemia response

项目摘要

DESCRIPTION (provided by applicant): Ourlong-termgoalistoprevent/treatacutekidneyinjury. Weareusingcisplatintoxicityasamodelofrenal 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-dependentkinase-2 (Cdk2), protects 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. Wefoundthatinresponsetocisplatin,Cdk2phosphorylatestwoproteins,p21andBcl-xL,thatdirectly and indirectly could have effects on cell death pathways. In our first specific aim we will investigate whether these phosphorylations have biologic effects on the proteins, and the mechanism of these effects. We hypothesized that Cdk2 inhibition is an effective strategy to prevent AKI. Our recently developed transgenic mice in which Cdk2 inhibitors can be induced in kidney tubules confirmed this hypothesis for cisplatin nephrotoxicity. In our second specific aim our transgenic mice will be used to determine whether Cdk2 inhibition will ameliorate other models of AKI, such as ischemia-reperfusion, nephrotoxic injury, or ER stress. We will determine whether the protein phosphorylations described above also occur in vivo, and using our transgenic mice, whether they correlate to the activation of kidney cell death pathways.

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。我们使用顺铂中毒作为肾损伤的模型，在体外使用培养的小鼠肾近曲小管细胞，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。我们发现顺铂、Cdk 2磷酸化的两种蛋白p21和Bcl-xL可以直接或间接影响细胞死亡途径。在我们的第一个具体目标中，我们将研究这些磷酸化是否对蛋白质具有生物学效应，以及这些效应的机制。我们假设Cdk 2抑制是预防阿基的有效策略。我们最近开发的转基因小鼠中，Cdk 2抑制剂可以诱导肾小管证实了顺铂肾毒性的这一假设。在我们的第二个具体目标中，我们的转基因小鼠将用于确定Cdk 2抑制是否会改善阿基的其他模型，例如缺血-再灌注、肾毒性损伤或ER应激。我们将确定上述蛋白质磷酸化是否也发生在体内，并使用我们的转基因小鼠，它们是否与肾细胞死亡途径的激活相关。