Regulation of the mTOR pathway in polycystic kidney disease

多囊肾病中 mTOR 通路的调节

基本信息

批准号：
8324852
负责人：
Thomas Weimbs
金额：
$ 6.99万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8324852
关键词：
Affect Apical Apoptosis Autosomal Dominant Polycystic Kidney Biological Preservation C-terminal Cell Differentiation process Cell Proliferation Cells Chimeric Proteins Chronic Cilia Clinical Trials Co-Immunoprecipitations Complex Cyst Cystic kidney Cytoplasmic Tail Data Dialysis procedure Disease Disease Progression Dose Drug usage Effectiveness Epithelial Cells Esthesia Event Foundations Future Genes Growth Hereditary Disease Human Immunoblotting Immunofluorescence Microscopy Immunosuppression Investigation Kidney Kidney Failure Kidney Transplantation Length Life MDCK cell Mediating Modeling Mus Mutation PKD1 gene Pathway interactions Patients Phospho-Specific Antibodies Phosphotransferases Play Polycystic Kidney Diseases Preparation Proteins Recovery Recruitment Activity Regulation Renal function Research Research Personnel Role Sampling Sirolimus Staging Testing Time Transplant Recipients Treatment Protocols Tuberous sclerosis protein complex Weight advanced disease base cell growth design dosage efficacy testing fluid flow genetic regulatory protein human FRAP1 protein human TSC1 protein human TSC2 protein kinetosome mTOR Inhibitor mTOR inhibition mouse model novel polycystic kidney disease 1 protein research study

项目摘要

DESCRIPTION (provided by applicant): Autosomal-dominant (ADPKD) is the most common life-threatening genetic disease. Tuberous Sclerosis Complex (TSC) is 10-times less common than ADPKD. Both diseases are characterized by renal cysts. No treatment is currently available to slow the onset or progression of either disease. We have recently found that polycystin-1 (PC1), the protein affected in ADPKD, interacts with tuberin, the protein affected in TSC, and regulates the activity of the kinase mTOR. mTOR plays an important role in cell growth and proliferation and is known to be inhibited by tuberin. We propose a model in which the C-terminal cytoplasmic tail of PC1 functions to induce the formation of a complex between tuberin and mTOR and other regulatory proteins. The function of this complex is to suppress mTOR activity in normal renal epithelial cells. Our results suggest that mTOR inhibition is regulated by apical fluid flow. We found that mTOR is inappropriately active in the kidneys of ADPKD patients and in mice with polycystic kidneys. Treatment of polycystic kidney mice with the mTOR inhibitor rapamycin results in the dramatic reduction of renal and cyst sizes and in the preservation of kidney function. This strongly suggests that aberrant mTOR activation in ADPKD is critical for renal cyst growth. We now propose to study in detail the mechanism of the suppression of mTOR activity by PC1. In Aim 1, we will investigate the interaction between PC1 and mTOR and identify additional regulatory factors and the subcellular localization of the complex. We will test whether this complex is disrupted in renal cysts. In Aim 2, we will test how fluid flow regulates mTOR activity. In Aim 3, using samples from ADPKD kidneys and a mouse model with a conditionally inactivated PKD1 gene we will characterize which of the known downstream effectors and upstream regulators of mTOR are affected in the disease. In Aim 4, in preparation for possible future clinical trials, we will investigate the effects of rapamycin on the PKD1 mouse model. We will assess dosage and treatment regimens and investigate the effects on proliferation and apoptosis of cystic epithelial cells. These investigations will be important to guide possible future clinical trials. Rapamycin is already a clinically approved drug, used for long-term treatment for immunosuppression in renal transplant patients. Based on our data, we are cautiously optimistic that rapamycin has promise to become the first available treatment to slow the disease progression in ADPKD. Furthermore, results from this research will enhance our understanding of the mechanisms underlying the renal involvement in TSC.

描述（由申请人提供）：常染色体主导（ADPKD）是最常见的威胁生命的遗传疾病。结节性硬化症复合物（TSC）比ADPKD少10倍。两种疾病的特征是肾囊肿。目前尚无治疗方法可以减慢任何一种疾病的发作或进展。我们最近发现，在ADPKD中受影响的蛋白质蛋白质与Tuberin相互作用，Tuberin，TSC中受影响的蛋白质，并调节激酶MTOR的活性。 MTOR在细胞生长和增殖中起着重要作用，已知会受到Tuberin的抑制作用。我们提出了一个模型，其中PC1的C末端细胞质尾能诱导Tuberin和MTOR和其他调节蛋白之间的复合物的形成。该复合物的功能是抑制正常肾上皮细胞中的MTOR活性。我们的结果表明，MTOR抑制受到顶液流量的调节。我们发现MTOR在ADPKD患者的肾脏和多囊肾脏的小鼠中不适当地活跃。用MTOR抑制剂雷帕霉素治疗多囊性肾脏小鼠会导致肾脏和囊肿大小的显着减少以及肾功能的保存。这强烈表明，ADPKD中异常的MTOR激活对于肾囊肿生长至关重要。现在，我们建议详细研究PC1抑制MTOR活性的机制。在AIM 1中，我们将研究PC1与MTOR之间的相互作用，并确定其他调节因素以及复合物的亚细胞定位。我们将测试该复合物是否在肾囊肿中被破坏。在AIM 2中，我们将测试流体流量如何调节MTOR活性。在AIM 3中，使用来自ADPKD肾脏的样品和具有条件灭活的PKD1基因的小鼠模型，我们将表征MTOR的哪些已知下游效应子和上游调节剂中的哪个在疾病中受到影响。在AIM 4中，为了准备未来的临床试验，我们将研究雷帕霉素对PKD1小鼠模型的影响。我们将评估剂量和治疗方案，并研究对囊性上皮细胞增殖和凋亡的影响。这些调查对于指导可能的未来临床试验将很重要。雷帕霉素已经是临床批准的药物，用于长期治疗肾移植患者的免疫抑制。根据我们的数据，我们谨慎乐观地说，雷帕霉素有望成为第一个减缓ADPKD疾病进展的治疗方法。此外，这项研究的结果将增强我们对肾脏参与TSC的机制的理解。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cleavage fragments of the C-terminal tail of polycystin-1 are regulated by oxidative stress and induce mitochondrial dysfunction.

DOI：
10.1016/j.jbc.2023.105158
发表时间：
2023-09
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Pellegrini, Hannah;Sharpe, Elizabeth H.;Liu, Guangyi;Nishiuchi, Eiko;Doerr, Nicholas;Kipp, Kevin R.;Chin, Tiffany;Schimmel, Margaret F.;Weimbs, Thomas
通讯作者：
Weimbs, Thomas

Identification of targets of IL-13 and STAT6 signaling in polycystic kidney disease.