The effects of protein kinase C epsilon peptide inhibitor (YT-001) in warm murine kidney ischemia-reperfusion

项目总结 该项目的目标是测试一种蛋白激酶C epsilon多肽抑制剂(YT-001)对肾脏的疗效 体内(小鼠)缺血再灌注(I/R)，在再灌流开始时给予。损伤和组织 与肾脏I/R相关的损伤是一个公认的现象，尤其是在肾移植后。 美国每年有2万例肾移植，25%的移植接受者 在一周内经历移植功能延迟(DGF)，这是I/R的直接后果。目前， DGF的治疗是通过透析控制液体和电解质水平的姑息支持；然而，这些 这些措施只能提供姑息治疗。杨博士已经展示了几种体内和体外的心脏I/R模型。 在再灌流开始时给予YT-001可恢复器官功能，减少细胞死亡。这个 FDA已经认识到在DGF中也有完全相同的机制在起作用。一期工程计划研究 YT-001对小鼠双侧肾I/R模型不同时间缺血再灌流的影响 实施时间最长为四天。在此期间，将监测血浆肌酐作为监测 肾功能。这一建议的方法最好地模拟了DGF患者的I/R损伤情况。 监测YT-001在治疗肾后DGF的药物开发过程中的作用至关重要 移植病人。在第一阶段之后，我们可以开始测试YT-001在第二阶段(小鼠肾脏)的效果 移植模型)，这将支持IND和随后的临床试验。

PROJECT SUMMARY The goal of the project is to test the efficacy of a protein kinase C epsilon peptide inhibitor (YT-001) in kidney ischemia reperfusion (I/R) in vivo (in mice) when given at the beginning of reperfusion. Injury and tissue damage associated with I/R in the kidney is a well-recognized phenomenon notably post kidney transplant. There are 20,000 kidney transplants per year in the US and twenty five percent of transplant recipients experience delayed graft function (DGF) within one week, a direct consequence of I/R. Currently, the only treatment for DGF is palliative support by managing fluid and electrolyte levels via dialysis; however, these measures provide only palliative care. Dr. Young has shown several cardiac I/R models both in-vivo and ex- vivo that giving YT-001 at the beginning of reperfusion restores organ function and reduces cell death. The FDA has recognized that the exact same mechanisms are at play in DGF. Phase 1 project is planned to study the effect of YT-001 in a murine bilateral kidney I/R model to different lengths of ischemia, and reperfusion will be carried out up to four days. During this time, serum plasma creatinine will be monitored as an index for kidney function. This proposed methodology best mimics the settings of I/R injury seen in DGF patients. Monitoring the role of YT-001 is crucial in the drug development process for treatment of DGF in post renal transplant patients. After phase 1, we can begin testing the effects of YT-001 in Phase 2 (murine kidney transplant model), which will support an IND and subsequent clinical trials.