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

多囊肾病 (PKD) 中的哺乳动物雷帕霉素靶标 (mTOR) 信号转导

基本信息

批准号：
7941690
负责人：
CHARLES Louis EDELSTEIN
金额：
$ 19.76万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7941690
关键词：
1-Phosphatidylinositol 3-Kinase Accounting Adverse effects Alleles Animal Model Apoptosis Apoptotic Attenuated Autosomal Dominant Polycystic Kidney Autosomal Recessive Polycystic Kidney Blood Cell Proliferation Cells Chronic Clinical Complex Cyst Cyst Fluid Cytoplasm Data Development Dialysis procedure End stage renal failure Epithelial Cells FDA approved Female Future Genes Grant Growth Growth Factor Hereditary Disease Human Hypoxia Inducible Factor Immunosuppressive Agents Inhibition of Apoptosis Insulin-Like Growth Factor I Kidney Kidney Failure Kidney Transplantation Lead Life Link Longitudinal Studies Measures Mediating Mediator of activation protein Membrane Modeling Mus Mutation PKD2 gene PTEN gene Pathway interactions Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Polycystic Kidney Diseases Production Proteins Protocols documentation Publishing Rattus Renal function Research Personnel Ribosomal Protein S6 Role Severity of illness Signal Pathway Signal Transduction Sirolimus Site Stimulus TSC1/2 gene Testing Therapeutic Time Tuberous Sclerosis Tubular formation Tumor Suppressor Genes Tumor Suppressor Proteins Vascular Endothelial Growth Factors analog base cancer therapy caspase-3 clinical application cpk mouse effective therapy in vivo inhibitor/antagonist mTOR protein male mouse model novel programs response tumor

项目摘要

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.

描述（由申请人提供）：我们已经证明了大鼠模型中的。该赠款中提出的总体假设提供了一个综合的病理生理模式，在该图案中，IGF-L/AKT/MTOR/P70S6激酶信号传导途径可以导致PKD中的凋亡和增殖，囊肿形成和肾衰竭。新的初步数据表明，PKD肾脏中Akt和雷帕霉素诱导的P70S6K活性的抑制作用。互补研究将在HAN：SPRD大鼠，PKD2WS25/ - 和PKD和小鼠的CPK小鼠模型中进行PKD1的功能性等位基因。特定目标1专注于使用MTOR抑制剂的体内研究。 MTOR抑制对凋亡和增殖，囊肿形成和肾功能的影响将测试临床应用的潜力。在特定的目标2中，我们将研究PKD中的IGF-L/AKT/MTOR/P70S6激酶信号通路。我们的初步数据表明，雷帕霉素降低了caspase-3激活和PKD中的凋亡。初步数据还表明，PKD肾脏中HIF-1A的增加。 MTOR充当HIF-1-依赖性反应的阳性调节剂，雷帕霉素可抑制HIF-1A。我们建议HIF-1在多囊肾脏中是凋亡的，雷帕霉素抑制HIF-1诱导的caspase-3激活和凋亡。在特定的目标＃3中，我们将确定HIF-1A激活的时间过程以及雷帕霉素对HIF-1A，caspase-3和凋亡的影响。这些研究与临床ADPKD的相关性很大，结果应提供改变ADPKD进程的结果。由于MTOR拮抗剂的当前可用性，例如雷帕霉素及其类似物及其被证明是免疫抑制药物和癌症治疗的体内有益作用。