Mammalian target of rapamycin (mTOR) signaling in polycystic kidney disease (PKD)

描述(由申请人提供)：我们已经在一个大鼠模型中证明了这一点。本研究提出的总体假说提供了一个完整的病理生理学方案，在该方案中，胰岛素样生长因子-L/Akt/mTor/p70S6信号通路可导致PKD的细胞凋亡和增殖、囊变形成和肾功能衰竭。新的初步数据表明，Akt的激活和雷帕霉素诱导的PKD肾脏中p70S6K活性的抑制。补充研究将在汉族人：SPRD大鼠、PKD2WS25/-和CPK小鼠模型的PKD和具有功能的PKD1等位基因的小鼠中进行。具体目标1侧重于使用mTOR抑制剂的体内研究。MTOR抑制对细胞凋亡和增殖、囊性形成和肾功能的影响将检验其临床应用的潜力。在特定的目标2中，我们将研究胰岛素样生长因子-L/Akt/mTor/p70S6信号通路在PKD中的作用。我们的初步数据表明，雷帕霉素降低了PKD中caspase-3的激活和细胞凋亡。初步数据还表明，HIF-1a在PKD肾脏中增加。MTOR是HIF-1依赖反应的正调节因子，雷帕霉素可以抑制HIF-1a。我们认为HIF-1在多囊肾中是促凋亡的，雷帕霉素抑制了HIF-1诱导的caspase-3的激活和凋亡。在特定的目标#3中，我们将确定HIF-1a激活的时间进程以及雷帕霉素对HIF-1a、caspase-3和细胞凋亡的影响。这些研究与ADPKD的临床相关性很大，其结果应该为改变ADPKD的病程提供线索。这尤其是因为目前mTOR拮抗剂，如雷帕霉素及其类似物的可获得性，以及它们在体内被证明作为免疫抑制药物和癌症治疗的有益作用。

DESCRIPTION (provided by applicant): We have demonstrated that the in a rat model. The overall hypothesis presented in this grant provides an integrated pathophysiological schema whereby the IGF-l/Akt/mTOR/p70S6 kinase signaling pathway can lead to apoptosis and proliferation, cyst formation and renal failure in PKD. Novel preliminary data demonstrates activation of Akt and rapamycin-induced inhibition of p70S6K activity in PKD kidneys. Complementary studies will be performed in Han:SPRD rats, PKD2WS25/- and cpk mouse models of PKD and mice with a functional floxed allele of Pkd1. Specific Aim 1 focuses on in vivo studies using mTOR inhibitors. The effect of mTOR inhibition on apoptosis and proliferation, cyst formation and renal function will test the potential for clinical application. In Specific Aim 2, we shall investigate the IGF-l/Akt/mTOR/p70S6 kinase signaling pathway in PKD. Our preliminary data demonstrate that rapamycin decreases caspase-3 activation and apoptosis in PKD. Preliminary data also demonstrate that HIF-1a is increased in PKD kidneys. mTOR functions as a positive regulator of HIF-1- dependent responses and rapamycin is known to inhibit HIF-1a. We propose that HIF-1 is proapoptotic in polycystic kidneys and that rapamycin inhibits HIF-1 induced caspase-3 activation and apoptosis. In Specific Aim#3, we shall determine the time course of HIF-1a activation and the effect of rapamycin on HIF-1a, caspase-3 and apoptosis. The relevance of these studies to clinical ADPKD is substantial and the results should provide leads to altering the course of ADPKD. This is particularly true because of the current availability of mTOR antagonists e.g. rapamycin and its analogs and their proven in vivo beneficial effect as immunosuppressive drugs and cancer treatments.