Interaction of protein-targeted therapeutics and ciliary dynamics

蛋白质靶向治疗与纤毛动力学的相互作用

基本信息

批准号：
9337444
负责人：
ERICA A. GOLEMIS
金额：
$ 40.16万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-29 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9337444
关键词：
Ablation Affect Antineoplastic Agents Benchmarking Cardiovascular system Cells Chaperone Protein Inhibition Cilia Client Clinical Clinical Trials Complement Contrast Media Cyclic AMP-Dependent Protein Kinases Cyst Cystic kidney Data Defect Development Dialysis procedure Disease Disease Management Disease Progression Disease model Drug Targeting Drug effect disorder Drug usage Elderly Employee Strikes End stage renal failure Evaluation Generations Genetic Genotype Goals HSP 90 inhibition Heat-Shock Proteins 90 Heterodimerization Hypertension Individual Integral Membrane Protein Kidney Lead Liquid substance Lisinopril Maintenance Malignant Neoplasms Metformin Modeling Molecular Chaperones Mus Mutation Outcome PKD1 gene PKD2 gene Patient risk Patients Pattern Performance Status Pharmaceutical Preparations Pharmacotherapy Phase Phenotype Phosphotransferases Polycystic Kidney Diseases Preclinical Testing Protein Inhibition Proteins Public Health Quality of life Regulation Renal Tissue Reporting Risk STK6 gene Severities Signal Transduction Signaling Protein Stress Structural defect Symptoms Syndrome Tamoxifen Technology Testing Therapeutic Therapy Evaluation Tissues Treatment Efficacy United States Work cancer therapy experience experimental study hazard improved in vivo inhibitor/antagonist insight kidney cell kinase inhibitor middle age mouse model pre-clinical preclinical evaluation small molecule inhibitor targeted cancer therapy targeted treatment

项目摘要

Project Summary Autosomal polycystic kidney disease (ADPKD) patients typically experience hypertension and other cardiovascular symptoms commencing in their 20s, and develop an increasing burden of fluid-filled renal cysts in middle age, culminating typically in end stage renal disease (ESRD) and the need for dialysis or kidney replacement in later life. The goal of this application is to gain mechanistic insights that will improve clinical outcomes in patients with ADPKD. ADPKD arises from mutations reducing or eliminating function of the PKD1 or PKD2 genes, which encode polycystins: large transmembrane proteins that heterodimerize at cell cilia, and influence activity of multiple downstream signaling proteins. Pre-clinical experiments and clinical trials have shown that targeting polycystin-dependent signaling defects can slow disease progression. Our preliminary studies in mouse models have shown that inhibition of the protein chaperone HSP90 is extremely beneficial in reducing ADPKD symptoms, while inhibition of Aurora-A (AURKA) is deleterious, and begun to define related signaling mechanisms. Interestingly, recent reports indicate that severe manifestation of ADPKD depends in part on the maintenance of intact cilia, while we have found that AURKA inhibition stabilizes cilia. This suggests use of inhibitors of AURKA and proteins with similar activity may be harmful in ADPKD patients. Conversely, our studies of HSP90, its protein clients, and polycystin-regulated signaling effectors indicate these may act in part by contributing to ciliary resorption. This proposal will explore the mechanisms of action of these drugs in the context of a ciliary model for ADPKD cystogenesis, testing the hypothesis that part of their activity arises from control of ciliary dynamics, and perform preclinical tests intended to suggest improved therapy for ADPKD. In this proposal, Aim 1 will use mouse models to evaluate the HSP90 inhibitor ganetespib in combination with other promising therapies for efficacy in ADPKD versus in non-ADPKD cystic syndromes, and will use recently developed multiplexed kinase inhibitor beads (MIBs) technology to profile the interaction of ganetespib with ADPKD-specific signaling. Aim 2 will complement this aim, evaluating how ganetespib alone and in therapeutic combinations influences ciliary dynamics and cilia-dependent signaling, in ADPKD versus non-ADPKD renal cells and tissue. Finally, 35-40% of individuals with ADPKD will develop some form of cancer in their lifetime, and many will be treated with systemic cancer therapies. Inhibitors of AURKA and functionally related proteins are becoming common in cancer therapy. Aim 3 will use mouse models to test the idea that AURKA inhibitors and other drugs predicted to stabilize cilia pose risks for patients with ADPKD.

项目概要常染色体多囊肾病 (ADPKD) 患者通常会出现高血压和其他症状 20 多岁开始出现心血管症状，并逐渐加重充满液体的肾囊肿负担中年时，通常最终导致终末期肾病 (ESRD) 并需要透析或肾脏治疗以后的生活中进行更换。该应用程序的目标是获得机制见解，从而改善临床 ADPKD 患者的结果。 ADPKD 是由减少或消除 PKD1 功能的突变引起的或 PKD2 基因，编码多囊蛋白：在细胞纤毛处异二聚化的大跨膜蛋白，以及影响多个下游信号蛋白的活性。临床前实验和临床试验已研究表明，针对多囊蛋白依赖性信号传导缺陷可以减缓疾病进展。我们的初步小鼠模型研究表明，抑制蛋白伴侣 HSP90 对于减少 ADPKD 症状，而抑制 Aurora-A (AURKA) 是有害的，并开始定义相关的信号机制。有趣的是，最近的报告表明 ADPKD 的严重表现取决于部分维持纤毛完整，而我们发现 AURKA 抑制可以稳定纤毛。这建议使用 AURKA 抑制剂和具有相似活性的蛋白质可能对 ADPKD 患者有害。相反，我们对 HSP90、其蛋白质客户和多囊蛋白调节的信号传导效应物的研究表明这些可能部分通过促进纤毛吸收而起作用。该提案将探讨行动机制这些药物在 ADPKD 囊肿发生的睫状体模型中的应用，检验了其部分药物的假设活动源于对纤毛动力学的控制，并进行旨在建议改善的临床前测试 ADPKD 的治疗。在该提案中，Aim 1将使用小鼠模型来评估HSP90抑制剂ganetespib 与其他有前景的疗法相结合，对 ADPKD 与非 ADPKD 囊性综合征的疗效相比，并将使用最近开发的多重激酶抑制剂珠 (MIB) 技术来分析相互作用 ganetespib 具有 ADPKD 特异性信号传导。目标 2 将补充该目标，评估单独使用 ganetespib 的效果并且在治疗组合中影响纤毛动力学和纤毛依赖性信号传导，在 ADPKD 与非 ADPKD 肾细胞和组织。最后，35-40% 的 ADPKD 患者会出现某种形式的在他们的一生中，许多人将接受全身癌症疗法的治疗。 AURKA 抑制剂和功能相关的蛋白质在癌症治疗中变得越来越常见。 Aim 3将使用鼠标模型来测试 AURKA 抑制剂和其他预计稳定纤毛的药物会给 ADPKD 患者带来风险。