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

• 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
• 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

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.

项目摘要 常染色体多囊性肾脏疾病（ADPKD）患者通常患有高血压和其他 心血管症状从20多岁开始，并产生越来越多的充满流体肾脏囊肿的负担 在中年，最终在末期肾病（ESRD）中达到最终形式，并且需要透析或肾脏 替代后来的生活。该应用程序的目的是获得机械见解，以改善临床 ADPKD患者的结果。 ADPKD源于降低或消除PKD1功能的突变 或PKD2基因，它们编码polycystins：在细胞纤毛中异二聚二聚体的大型跨膜蛋白，而 影响多个下游信号蛋白的活性。临床前实验和临床试验具有 表明靶向多囊依赖性信号传导缺陷会减慢疾病的进展。我们的初步 小鼠模型中的研究表明，抑制蛋白质伴侣HSP90对 减少ADPKD症状，而抑制Aurora-A（Aurka）是有害的，并开始定义相关 信号机制。有趣的是，最近的报告表明，ADPKD的严重表现取决于 一部分是维持完整的纤毛，而我们发现Aurka抑制作用稳定了Cilia。这 建议使用具有相似活性的Aurka和蛋白质的抑制剂可能对ADPKD患者有害。 相反，我们对HSP90，其蛋白质客户和多囊调节的信号传导效应子的研究表明 这些可能部分通过促成睫状吸收来起作用。该建议将探讨行动机制 这些药物在用于ADPKD囊肿发生的睫状模型的背景下，检验了其一部分的假设 活动来自对睫状动力学的控制，并进行临床前测试，以提出改进 ADPKD的治疗。在此提案中，AIM 1将使用鼠标模型评估HSP90抑制剂Ganetespib 结合其他有希望的疗法ADPKD的功效与非ADPKD囊性综合征的疗效， 并将使用最近开发的多路复用激酶抑制剂珠（MIBS）技术来介绍相互作用 带有ADPKD特异性信号传导的Ganetespib。 AIM 2将补充这一目标，评估单独使用Ganetespib 在治疗组合中，在ADPKD中影响睫状动力学和依赖纤毛的信号传导 非ADPKD肾细胞和组织。最后，有35-40％的ADPKD患者将发展某种形式的 癌症一生，许多人将接受全身性癌症疗法的治疗。 Aurka的抑制剂和 功能相关的蛋白质在癌症治疗中变得普遍。 AIM 3将使用鼠标模型测试 Aurka抑制剂和其他预测会稳定ADPKD患者的纤毛风险的想法。