METAL CHELATES IN PREVENTION OF CISPLATIN-INDUCED KIDNEY CELL DEATH

金属螯合物预防顺铂引起的肾细胞死亡

• 批准号: 8168101
• 负责人: GRANT W WANGILA
• 金额: $ 12.21万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-19 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168101
• 关键词: Antioxidants; Apoptosis; Apoptotic; Appearance; Cell Death; Chemicals; Cisplatin; Complex; Computer Retrieval of Information on Scientific Projects Database; Cytosol; DNA Fragmentation; Data; Elements; Enzymes; Epithelial Cells; Extravasation; Funding; Grant; Hydrogen Peroxide; In Vitro; Injury; Inner mitochondrial membrane; Institution; Kidney; Lipids; Metals; Mitochondria; Modeling; Nuclear Import; Oxidative Stress; Pathology; Peroxidases; Peroxonitrite; Prevention; Reactive Oxygen Species; Recovery; Research; Research Personnel; Resources; Salicylic Acids; Source; Superoxide Dismutase; Testing; Tubular formation; United States National Institutes of Health; aminothiol; base; biological systems; caspase-3; catalase; cytochrome c; endonuclease G; human disease; in vivo; interest; kidney cell; metal complex; mimetics; nephrotoxicity; perhydroxyl radical; prevent

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We propose to synthesize, characterize, and test several new metal (Cu and Zn) complexes of salicylic acid and aminothiol derivatives as catalytic antioxidants that scavenge a wide range of reactive oxygen species (ROS), such as superoxide dismutase (SOD), hydrogen peroxide, peroxynitrite, and lipid peroxyl radicals. Several compounds in this class have been shown to be efficacious in a variety of ways in in vitro and in vivo oxidative stress models of human diseases. Our preliminary data strongly indicate that these metal complexes satisfy many of the criteria for prevention and treatment of cisplatin-induced nephrotoxicity, as they are active, stable, and nontoxic antioxidants. Thus, we hypothesize that Cu- and Zn-metallo-element chelates will protect kidney tubular epithelial cells from cisplatin injury because these chelates have antioxidant activity, and can suppress apoptosis and facilitate recovery. We propose two specific aims: Aim 1: Synthesize and characterize the Cu- and Zn-metalloelement chelates. This aim will focus on chemical studies of new and previously known but not fully characterized compounds. And Aim 2: Test the nephroprotective activity of the metallocompounds in biological systems. The study will involve (1) an assessment of antiapoptotic activity of the SOD-mimetic metal chelates with regard to cellular mechanisms by which metal chelates may prevent cisplatin-induced proximal tubule cell death; (2) an examination of the mechanism by which metal chelates suppress apoptosis by preventing cisplatin-induced translocation of proapoptotic Bax from the cytosol to the mitochondria; (3) a study of how metal chelates prevent cisplatin-induced cytochrome c release from the inner mitochondrial membrane and its appearance in the cytosol, and significantly reduces cisplatin-induced caspase-3 activation, based on the SOD-mimetic, catalase-mimetic, and/or peroxidase-mimetic reactivities of metal chelate enzymes required to overcome cisplatin-induced pathology; and (4) a determination of the effects of metal chelates on endonuclease G leakage from mitochondria, its nuclear import, and apoptotic DNA fragmentation. A logical extension of the studies in this proposal carried out in vitro will be extended in vivo. More specifically, we plan to study the mechanisms by which the SOD-mimetic and metal chelates offer protection to cisplatin-induced biological system. For these studies, we will collaborate with investigators at UAMS who have a long-standing interest and enthusiasm in studying metal chelates and mimetic activities of essential metal chelates.

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