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

描述（由申请人提供）：我们已经在大鼠模型中证明了。本授权中提出的总体假设提供了一个综合的病理生理学模式，其中IGF-I/Akt/mTOR/p70 S6激酶信号传导途径可以导致PKD中的细胞凋亡和增殖、囊肿形成和肾衰竭。新的初步数据表明PKD肾脏中Akt的激活和雷帕霉素诱导的p70 S6 K活性抑制。将在Han：SPRD大鼠、PKD的PKD 2 WS 25/-和cpk小鼠模型以及具有Pkd 1的功能性floxed等位基因的小鼠中进行补充研究。具体目标1侧重于使用mTOR抑制剂的体内研究。抑制mTOR对细胞凋亡和增殖、囊肿形成和肾功能的影响将测试其临床应用的潜力。在具体目标2中，我们将研究PKD中的IGF-1/Akt/mTOR/p70 S6激酶信号通路。我们的初步数据表明，雷帕霉素降低PKD中caspase-3的活化和凋亡。初步数据还表明，HIF-1a在PKD肾脏中增加。mTOR作为HIF-1依赖性反应的正调节剂发挥作用，已知雷帕霉素抑制HIF-1 a。我们认为HIF-1在多囊肾中是促凋亡的，雷帕霉素抑制HIF-1诱导的caspase-3激活和凋亡。在具体目标#3中，我们将确定HIF-1a活化的时间过程和雷帕霉素对HIF-1a、半胱天冬酶-3和细胞凋亡的影响。这些研究与临床ADPKD的相关性是实质性的，结果应该提供改变ADPKD病程的线索。这是特别真实的，因为mTOR拮抗剂例如雷帕霉素及其类似物的当前可用性以及它们作为免疫抑制药物和癌症治疗的经证实的体内有益效果。

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.