Protein Kinase C in the Repair of Cellular Functions

蛋白激酶 C 在细胞功能修复中的作用

• 批准号: 6322699
• 负责人: Grazyna Nowak
• 金额: $ 23.76万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6322699
• 关键词: acute renal failure; biological signal transduction; enzyme activity; isozymes; kidney; laboratory rabbit; protein kinase C; protein localization; regeneration; renal toxin; renal tubule; tissue /cell culture

DESCRIPTION (Adopted from the Applicant's Abstract): The long-term goal of this research is to elucidate the mechanisms that regulate the recovery of physiological functions in renal proximal tubular cells (RPTC) following toxicant-induced injury. Kidney exposure to a variety of drugs and toxicants results in acute renal failure (ARF). RPTC are the major target for many nephrotoxicants and the recovery of the kidney following injury occurs through the regeneration of the non-injured and repair of sublethally-injured RPTC. Therapeutic strategies used to treat ARF are often unsuccessful due to the poor understanding of the mechanisms regulating RPTC regeneration and repair. The goal of this proposal is to elucidate the role of 3 major isozymes of protein kinase C (PKCx, PKCo, and PKCc) in the repair of RPTC functions following toxicant-induced injury. In our in vitro model of cell regeneration and repair (primary cultures of rabbit RPTC grown in improved culture conditions) RPTC recover their mitochondrial and transport functions following exposure to an oxidant (tertbutylhydroperoxide, TBHP) but not a halocarbon (dichlorovinyl-L-cysteine, DCVC). Inhibition of these functions in sublethally-injured RPTC following TBHP exposure is accompanied with the decrease in protein kinase C (PKC) activity. Activation of PKC prior to TBHP exposure accelerates recovery while inhibition of PKC prevents the return of RPTC functions. Lack of RPTC repair after DCVC exposure is accompanied by sustained inhibition of PKC activity and PKC activation prior to DCVC exposure promotes recovery of RPTC functions. Therefore, the central hypothesis of this proposal is that PKCa, PKC6, and PKCc play a pivotal role in the repair of mitochondrial and transport functions of RPTC following toxicant injury and that the recovery of these functions depends on re-establishment of PKC-mediated signaling. Specific Aim I will examine the alterations in the activity, protein levels and subcellular localization of major PKC isozymes after toxicant injury and during recovery. Specific Aim II will demonstrate that the recovery of mitochondrial and transport functions following toxicant injury is mediated through PKCa, PKCS and/or PKCe. Specific Aim III will identify pathways that are involved in regulation of recovery of RPTC functions by PKC. Completion of these aims will result in a better understanding of the role of PKC isozymes in the repair of RPTC functions and may help to identify agents that protect against ARF or accelerate recovery from ARF.

描述（摘自申请人摘要）：该项目的长期目标