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）：多囊性肾脏疾病（PKD）是肾衰竭的常见原因，在美国影响约60万人（1），其特征是逐渐扩大囊肿，最终破坏周围周围肾脏实质的囊肿。 PKD还会引起肾小管和血液流动的干扰，可能导致肾上石症，感染和高血压等表现。在几种动物模型和人类PKD中的最新证据支持了MTOR信号通路过度激活的想法，并且可能是PKD中常见的致病元素（2）。 MTOR在两个已知的复合物MTORC1和MTORC2中的功能； MTORC1主要在蛋白质合成和增殖中起作用，而MTORC2在代谢，离子转运，细胞骨架重排和细胞凋亡的调节中起作用，在PKD中都改变了（4）。最近的文献和我们自己的初步数据支持了在PKD中激活两个复合物的想法（5）。已经表明，在某些PKD的动物模型中，使用MTOR抑制剂雷帕霉素可以减慢疾病的进展（17-22）。但是，最近的两项人类试验没有显示出减少肾脏大小或用雷帕霉素或依维莫司（雷帕霉素类似物）保存肾脏功能的显着好处（23,24）。我们假设这些观察结果有两个潜在的原因：一个是，对于其他组织，包括肝脏和免疫器官在内的其他组织中充分下调MTOR所需的剂量可能太高，因为啮齿动物模型中使用的雷帕霉素的剂量比临床试验中的啮齿动物模型要高得多（17）。另一个原因是雷帕霉素主要是MTORC1的抑制剂，对MTORC2具有可变影响，并且有人提出对MTORC2的不一致作用可能在其功效中起作用（5）。最近开发的MTOR活性位点抑制剂Torkinibs（26）阻止了MTOR复合物，并为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在囊肿发生中起着显着但独特的作用，并且通过托基尼通过torkinibs对MTORC1和MTORC2的封锁可能对预防囊肿发生有重大影响。抑制MTOR组合的所有靶标可能会允许使用更多的药物剂量，或者简单地成为抑制囊肿形成和生长的更有效方法。我们要进一步表征每个MTOR复合物对PKD1突变的小鼠的囊肿发生的不同贡献“（v/v）”（31）和HAN：SPRD大鼠（33）。我们目前还在努力评估托基尼在治疗PKD方面的有效性。为此，我们将用托基尼（Torkinibs）测试上述PKD的动物模型，并评估肾功能，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，我们将生成和表征对PKD（v/v）等位基因纯合子的复合突变体，以及分别为SGK1，AKT或P4EBP1的纯合子null，以更好地了解MTOR在PKD发展中下游各种介体的相对贡献。 公共卫生相关性：这笔赠款的推力是为调查新的药物，托基尼尼比人及其在治疗多囊性肾脏疾病的有用性提供机会，该疾病以不受约束的囊肿生长的条件为特征，并最终发展为终结阶段肾脏疾病（ESRD）。在特定的啮齿动物模型中，已经有大量证据表明可以降低囊肿，并且可以通过药物雷帕霉素来改善肾脏功能，这很可能是由于蛋白MTOR，雷帕霉素的靶标具有过度活跃性并且其封锁的改善。然而，一项临床试验对在人类中使用雷帕霉素没有显着好处，这可能是由于它不一致地阻止mTOR。托基尼比（Torkinibs）将允许对MTOR的这种统一的封锁，并在研究它们时，我们希望研究PKD的潜在治疗选择，并了解更多有关MTOR的信号通路及其与囊肿形成和生长的关系。