Interaction of protein-targeted therapeutics and ciliary dynamics

 描述（由申请方提供）：常染色体多囊肾病（ADPKD）患者通常在20多岁时开始出现高血压和其他心血管症状，并在中年时出现液体填充性肾囊肿的负担增加，通常最终出现终末期肾病（ESRD），并在以后的生活中需要透析或肾脏置换。此应用程序的目标是获得机制见解，这将改善临床 ADPKD患者的结局。ADPKD由PKD 1或PKD 2基因的突变引起，PKD 1或PKD 2基因编码多囊蛋白：在细胞纤毛处异二聚化的大跨膜蛋白，并影响多种下游信号蛋白的活性。临床前实验和临床试验表明，靶向多囊蛋白依赖性信号缺陷可以减缓疾病进展。我们在小鼠模型中的初步研究表明，抑制蛋白伴侣HSP 90对减轻ADPKD症状极为有益，而抑制Aurora-A（AURKA）则是有害的，并开始定义相关的信号传导机制。有趣的是，最近的报道表明，ADPKD的严重表现部分取决于保持完整的纤毛，而我们已经发现，AURKA抑制稳定纤毛。这表明使用AURKA抑制剂和具有类似活性的蛋白质可能对ADPKD患者有害。相反，我们对HSP 90、其蛋白质客户和多囊蛋白调节的信号效应物的研究表明，这些可能部分通过促进纤毛吸收而起作用。该提案旨在探索这些药物在ADPKD囊性增生睫状体模型背景下的作用机制，并进一步改善这种疾病的治疗。在该提案中，目标1将使用小鼠模型来评估HSP 90抑制剂ganetespib与其他有前景的疗法联合治疗ADPKD与非ADPKD囊性综合征的疗效，并将使用最近开发的多重激酶抑制剂珠（MIB）技术来分析ganetespib与ADPKD特异性信号的相互作用。目的2将补充这一目的，评价ganetespib单独和治疗组合如何影响ADPKD与非ADPKD肾细胞和组织中的纤毛动力学和纤毛依赖性信号传导。最后，35-40%的ADPKD患者在其一生中会患上某种形式的癌症，许多人将接受全身性癌症治疗。AURKA和功能相关蛋白质的抑制剂在癌症治疗中越来越常见。目标3将使用小鼠模型来测试AURKA抑制剂和其他预计可稳定纤毛的药物对ADPKD患者构成风险的想法。

 DESCRIPTION (provided by applicant): 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 seeks to explore the mechanisms of action of these drugs in the context of a ciliary model for ADPKD cystogenesis, and to further improve therapy for this disease. 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.