mTOR signaling in Polycystic Kidney Disease

多囊肾病中的 mTOR 信号传导

• 批准号: 8201682
• 负责人: Atif Kidwai
• 金额: $ 3.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2012-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201682
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Active Sites; Acute; Affect; Alleles; Animal Model; Antibodies; Apoptosis; Biochemical; Blood; Blood Cell Count; Blood flow; Body Weight; Breeding; CCI-779; Chemistry; Clinical Trials; Complex; Cyst; Cyst Fluid; DNA Sequence Rearrangement; Data; Development; Disease; Disease Progression; Dose; Down-Regulation; Effectiveness; End stage renal failure; Excision; Funding Opportunities; Grant; Growth; Heterozygote; Human; Hypertension; Immune; Indium; Individual; Infection; Ion Transport; Kidney; Kidney Failure; Knock-out; Lead; Learning; Life Cycle Stages; Literature; Liver; Long-Term Effects; Mediator of activation protein; Metabolism; Methods; Modeling; Monitor; Mus; Mutant Strains Mice; Mutation; Nephrolithiasis; Organ; Partner in relationship; Pathologic; Pathology; Pharmaceutical Preparations; Phase; Phenotype; Phosphorylation; Play; Polycystic Kidney Diseases; Process; Proprotein Convertase 1; Protein Biosynthesis; Rattus; Regulation; Relative (related person); Renal function; Rodent; Rodent Model; Role; SDZ RAD; Signal Pathway; Signal Transduction; Sirolimus; Spleen; Testing; Thymus Gland; Time; Tissues; Toxic effect; Tubular formation; Urine; Work; human FRAP1 protein; improved; inhibitor/antagonist; mTOR Inhibitor; mTOR Signaling Pathway; mTOR protein; mutant; prevent; research study

DESCRIPTION (provided by applicant): Polycystic Kidney Disease (PKD) is a common cause of kidney failure, and affects around 600,000 people in the US (1), and is characterized by progressively enlarging cysts that eventually destroys the surrounding renal parenchyma. PKD also causes disturbances in renal tubular and blood flow, potentially leading to manifestations such as nephrolithiasis, infection and hypertension. Recent evidence in several animal models and in human PKD supports the idea that the mTOR signaling pathway is hyperactivated and may be a common pathogenic element in PKD (2). MTOR functions in two known complexes, mTORC1 and mTORC2; mTORC1 functions primarily in protein synthesis and proliferation, while mTORC2 functions in the regulation of metabolism, ion transport, cytoskeletal rearrangements and apoptosis, which are all altered in PKD (4). Recent literature and our own preliminary data support the idea that both complexes are activated in PKD (5). It has been shown that progression of the disease can be slowed by use of the mTOR inhibitor rapamycin in some animal models of PKD (17-22); however, two recent human trials did not show any significant benefit to reducing kidney size or preserving renal function with either rapamycin or everolimus (a rapamycin analogue) (23,24). We postulate that there are two potential reasons for these observations: one is that the dose needed to adequately down-regulate mTOR in the kidney may be too high for other tissues, including liver and immune organs, as the dose of rapamycin used in the rodent models was much higher than those in the clinical trials (17). The other reason is that rapamycin is primarily an inhibitor of mTORC1 and has variable effects on mTORC2, and it has been suggested that the inconsistent effect on mTORC2 may play a role in its efficacy (5). Recently developed mTOR active site inhibitors, torkinibs (26), block both mTOR complexes and present an attractive alternative to rapamycin for the study and treatment of PKD. We hypothesize that both mTORC1 and mTORC2 play significant but distinct roles in cystogenesis, and that blockade of both mTORC1 and mTORC2 through torkinibs may have a significant impact on preventing cystogenesis. Inhibiting all of the targets of mTOR in combination may allow for more tolerable doses of drug or simply be a more effective method of inhibiting cyst formation and growth. We look to further characterize the distinct contributions of each mTOR complex on cystogenesis in mice with PKD1 mutation "(V/V)" (31) and in the Han:SPRD rat (33). We are also currently working on assessing the torkinibs in their effectiveness in treating PKD. To that end, we will test the above animal models of PKD with torkinibs and assess for changes to renal function, kidney size, cyst volume and parenchymal volume as well as monitor for adverse biochemical effects. Finally, we will generate and characterize compound mutants which are homozygous for the PKD (V/V) allele and also homozygous null for SGK1, Akt or p4EBP1 respectively, to potentially better understand the relative contributions of the various mediators downstream of mTOR in the development of PKD. PUBLIC HEALTH RELEVANCE: The thrust of this grant will be to fund an opportunity to investigate a new class of drugs, the torkinibs, and their usefulness in the treatment of Polycystic Kidney Disease, which is marked by conditions of unrestrained cyst growth and eventually progress to End Stage Renal Disease (ESRD). There has been substantial evidence in specific rodent models showing that cysts can be reduced and kidney function can be improved with the drug rapamycin, most likely due to the fact that the protein mTOR, rapamycin's target, is hyperactive and its' blockade ameliorative. However, a clinical trial showed no significant benefit to using rapamycin in humans, potentially due to the fact that it does not block mTOR uniformly. The torkinibs would allow for this uniform blockade of mTOR and in studying them we hope to investigate a potential treatment option for PKD and learn more about mTOR's signaling pathways and its' relation to cyst formation and growth.

描述（由申请人提供）：多囊肾病 (PKD) 是肾衰竭的常见原因，在美国影响约 600,000 人 (1)，其特点是囊肿逐渐增大，最终破坏周围的肾实质。多囊肾还会引起肾小管和血流紊乱，可能导致肾结石、感染和高血压等症状。几种动物模型和人类 PKD 中的最新证据支持这样的观点：mTOR 信号通路过度激活，并且可能是 PKD 中常见的致病因素 (2)。 MTOR 在两个已知的复合物 mTORC1 和 mTORC2 中发挥作用； mTORC1 主要在蛋白质合成和增殖中发挥作用，而 mTORC2 在代谢、离子转运、细胞骨架重排和细胞凋亡的调节中发挥作用，这些都在 PKD 中发生改变 (4)。最近的文献和我们自己的初步数据支持这两种复合物在 PKD 中均被激活的观点 (5)。研究表明，在一些 PKD 动物模型中使用 mTOR 抑制剂雷帕霉素可以减缓疾病的进展 (17-22)；然而，最近的两项人体试验并未显示雷帕霉素或依维莫司（雷帕霉素类似物）对于减小肾脏大小或保留肾功能有任何显着益处（23,24）。我们假设这些观察结果有两个潜在原因：一是充分下调肾脏中 mTOR 所需的剂量对于其他组织（包括肝脏和免疫器官）可能过高，因为啮齿动物中使用的雷帕霉素剂量模型的结果远高于临床试验中的结果（17）。另一个原因是雷帕霉素主要是 mTORC1 的抑制剂，对 mTORC2 具有不同的影响，有人认为对 mTORC2 的不一致影响可能在其功效中发挥作用 (5)。最近开发的 mTOR 活性位点抑制剂 torkinibs (26) 可阻断两种 mTOR 复合物，为 PKD 的研究和治疗提供了一种有吸引力的雷帕霉素替代品。我们假设 mTORC1 和 mTORC2 在囊肿发生中发挥重要但不同的作用，并且通过托基尼阻断 mTORC1 和 mTORC2 可能对预防囊肿发生产生显着影响。联合抑制 mTOR 的所有靶标可能会产生更耐受的药物剂量，或者只是一种更有效的抑制囊肿形成和生长的方法。我们希望进一步表征每个 mTOR 复合物对 PKD1 突变“(V/V)”小鼠 (31) 和 Han:SPRD 大鼠 (33) 的囊肿发生的独特贡献。我们目前还致力于评估托基尼治疗多囊肾的有效性。为此，我们将用托基尼测试上述 PKD 动物模型，评估肾功能、肾脏大小、囊肿体积和实质体积的变化，并监测不良生化效应。最后，我们将生成并表征 PKD (V/V) 等位基因纯合的复合突变体，以及 SGK1、Akt 或 p4EBP1 分别纯合无效的复合突变体，以更好地了解 mTOR 下游各种介质在开发中的相对贡献公钥簿。 公共健康相关性：这笔赠款的主旨将是资助研究一类新型药物托基尼及其在治疗多囊肾病中的有效性，该病的特点是囊肿生长不受限制，并最终发展为多囊肾病。终末期肾病（ESRD）。在特定的啮齿动物模型中已有大量证据表明，雷帕霉素药物可以减少囊肿并改善肾功能，这很可能是由于雷帕霉素的靶标蛋白 mTOR 过度活跃且其阻断得到改善。然而，一项临床试验表明，在人体中使用雷帕霉素并没有显着的益处，这可能是因为它不能均匀地阻断 mTOR。 Torkinib 可以实现对 mTOR 的均匀阻断，在研究它们的过程中，我们希望研究 PKD 的潜在治疗选择，并更多地了解 mTOR 的信号传导途径及其与囊肿形成和生长的关系。