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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：
8546326
负责人：
PETER M. PRICE
金额：
$ 25.86万
依托单位：
BIOMEDICAL RESEARCH FDN/CENTRAL ARKANSAS
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 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8546326
关键词：
Acute Acute Kidney Failure 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 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.

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模型，体外使用培养的小鼠肾近端小管细胞，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 (Cdk2)，在体外保护细胞毒性，并保护体内由顺铂引起的肾损伤。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cdk2抑制，可抵抗顺铂诱导的急性肾损伤。我们发现细胞死亡的几种途径依赖于Cdk2活性，并有助于顺铂的细胞毒性。我们假设由顺铂激活并依赖于Cdk2激酶活性的细胞死亡可能可以通过交叉途径而不是平行途径来解释。现在我们发现，在对顺铂的反应中，Cdk2磷酸化了两种蛋白，p21和Bcl xL，这两种蛋白直接或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。我们假设抑制Cdk2将是一种有效的短期和长期预防AKI的策略。我们最近开发的转基因小鼠，诱导p21或DN-Cdk2的表达保护顺铂肾毒性，证实了这一假设的前半部分。我们假设的后半部分将在第二个特定目标中得到解决，这将确定Cdk2抑制是否仅仅延迟肾毒性，以及Cdk2抑制和顺铂暴露是否会对肾脏恢复产生长期影响。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cdk2 phosphorylation of Bcl-xL after stress converts it to a pro-apoptotic protein mimicking Bax/Bak.

DOI：
10.1038/cddiscovery.2015.66
发表时间：
2016
期刊：
Cell death discovery
影响因子：
7
作者：
Megyesi J;Tarcsafalvi A;Seng N;Hodeify R;Price PM
通讯作者：
Price PM

A possible mechanism of renal cell death after ischemia/reperfusion.

DOI：
10.1038/ki.2011.495
发表时间：
2012-04
期刊：
Kidney international
影响因子：
19.6
作者：
通讯作者：

Mimicking Cdk2 phosphorylation of Bcl-xL at Ser73 results in caspase activation and Bcl-xL cleavage.

模拟 Bcl-xL Ser73 位点的 Cdk2 磷酸化会导致 caspase 激活和 Bcl-xL 裂解。

DOI：
10.1038/cddiscovery.2016.1
发表时间：
2016
期刊：
Cell death discovery
影响因子：
7
作者：
Seng,NS;Megyesi,J;Tarcsafalvi,A;Price,PM
通讯作者：
Price,PM

The cell cycle and acute kidney injury.

DOI：
10.1038/ki.2009.224
发表时间：
2009-09
期刊：
KIDNEY INTERNATIONAL
影响因子：
19.6
作者：
Price, Peter M.;Safirstein, Robert L.;Megyesi, Judit
通讯作者：
Megyesi, Judit

Increased expression of p21WAF1/CIP1 in kidney proximal tubules mediates fibrosis.

DOI：
10.1152/ajprenal.00489.2014
发表时间：
2015-01
期刊：
American journal of physiology. Renal physiology
影响因子：
0
作者：
J. Megyesi;A. Tarcsafalvi;Shenyang Li;Rawad Hodeify;N. S. H. L. Seng;D. Portilla;P. Price
通讯作者：
J. Megyesi;A. Tarcsafalvi;Shenyang Li;Rawad Hodeify;N. S. H. L. Seng;D. Portilla;P. Price