Small Molecule-Mediated Augmentation of Kidney Regeneration

描述（由申请人提供）：本申请涉及本RFA的三个主题领域：1）应用基因组学和其他高通量技术; 2）将基础科学发现转化为新的和更好的治疗方法; 3）重振生物医学研究社区。我们的具体重点是确定新的化合物，可以加速肾脏恢复的速度时，受伤后给予急性肾损伤（阿基）患者。严重阿基是一种常见疾病，死亡率高。尽管进行了肾脏替代治疗，但在过去20年中，与缺血性、肾毒性或脓毒性肾小管损伤导致的阿基相关的死亡率和发病率并未降低。由于先天性肾小管再生发生在组织损伤后，因此对开发在诱导损伤后施用时增强肾脏再生能力的治疗有相当大的兴趣。这将是该领域的一个重大进展，因为大多数阿基疗法在实验模型中肾损伤发作前给药时显示出有用，但在人类中未能显示出治疗益处。阿基中肾小管再生的第一个分子标志之一是器官发生期间通常需要的胚胎基因的再激活。因此，我们假设，在胚胎发育期间引起这些祖细胞扩增的任何治疗也会加速阿基的恢复速度。为了验证这一假设，我们开发了一种高含量的筛选技术来鉴定促进斑马鱼胚胎中胚胎肾祖细胞扩增的化合物。使用这种方法，我们已经确定了一类新的组蛋白去乙酰化酶抑制剂（HDACi），这导致了肾祖细胞在胚胎肾发育过程中的扩张。重要的是，我们现在已经表明，这种新型HDACi增加了阿基小鼠模型中的肾脏恢复率。本申请的目标是利用我们建立的斑马鱼筛选来开发HDACi类似物，其显示出比第一代化合物更有效的活性和更低的毒性。除了从我们的HDACi类中筛选一系列类似物外，我们还将扩展我们的初始筛选，包括含有FDA批准药物的化合物库，以便加快从实验室到临床的翻译应用。优先的第二代化合物将在斑马鱼和小鼠模型中进行靶向功效、毒性和损伤后再生潜力测定。使用这种方法，我们希望确定一些候选化合物与确定的潜在应用，用于人类疾病。此应用程序是匹兹堡大学和范德比尔特大学之间的合资企业。研究的目的是利用这些机构的调查人员的具体和互补的专门知识。组合化学，高含量筛选和化合物验证将在匹兹堡大学进行，以确定更有效的HDACi类似物，并使用我们最先进的筛选来确定协同化合物。所有小鼠工作，包括靶标验证、毒性测定和阿基研究将在范德比尔特大学进行，并将确定第二代化合物是否可以加速小鼠从阿基中恢复的速度。由于这类药物已经用于治疗其他人类疾病，我们预测这些研究的结果可以很容易地应用于降低严重阿基患者的死亡率。2. 公共卫生相关性：严重急性肾损伤是一种常见的、大部分可逆的疾病，具有高死亡率，并且没有特异性的临床治疗。我们的研究已经确定了一类新的组蛋白去乙酰化酶抑制剂（HDACi），加速急性肾损伤小鼠模型的肾脏恢复速度。这些研究的目的是确定新的HDACi类似物，这些类似物具有很高的进入临床试验的潜力。1.

DESCRIPTION (provided by applicant): This application addresses three of the thematic areas of this RFA: 1) Applying Genomics and Other High Throughput Technologies; 2) Translating Basic Science Discoveries into New and Better Treatments; and 3) Reinvigorating the Biomedical Research Community. Our specific focus is the identification of new compounds that can accelerate the rate of renal recovery when administered post-injury to patients with acute kidney injury (AKI). Severe AKI is a common disorder with a high mortality rate. The mortality and morbidity associated with AKI resulting from ischemic, nephrotoxic or septic renal tubular injury has not decreased over the last twenty years despite renal replacement therapy. Since innate renal tubular regeneration occurs after tissue injury, there has been considerable interest in the development of treatments that enhance the regenerative capacity of the kidney when administered after induction of injury. This would be a significant advance in the field, since most therapies for AKI, which have been shown to be of use when administered prior to the onset of renal injury in experimental models, have failed to show therapeutic benefit in humans. One of the first molecular hallmarks of renal tubular regeneration in AKI is the reactivation of embryonic genes normally required during organogenesis. We therefore hypothesized that any treatment that causes expansion of these progenitor cells during embryonic development would also accelerate the rate of recovery in AKI. To test this hypothesis, we have developed a high-content screening technology to identify compounds that promote expansion of embryonic renal progenitor cells in zebrafish embryos. Using this approach we have identified a novel class of histone deacetylase inhibitors (HDACi), which caused an expansion of renal progenitor cells during embryonic renal development. Importantly, we have now shown that this novel class of HDACi increases the rate of renal recovery in a mouse model of AKI. The goal of this application is to exploit our established zebrafish screen to develop HDACi analogues that show more potent activity and lower toxicity than the first-generation compound. In addition to screening a set number of analogues from our HDACi class, we will also extend our initial screen to include libraries of compounds that contain FDA-approved drugs so that translational applications from the bench to the clinic can be expedited. Priority second-generation compounds will be subjected to target efficacy, toxicity, and post-damage regeneration potential assays in zebrafish and mouse models. Using this approach we expect to identify a number of candidate compounds with defined potential applications for use in human disease. This application is a joint venture between the University of Pittsburgh and Vanderbilt University. Studies are designed to take advantage of specific and complementary expertise of investigators at these institutions. Combinatorial chemistry, high-content screening and compound validation will be performed at the University of Pittsburgh to identify more potent HDACi analogues, and to identify synergistic compounds using our state of the art screen. Al mouse work, including target validation, toxicity assays and AKI studies will be performed at Vanderbilt University and will determine whether the second- generation compounds can accelerate the rate of recovery from AKI in mice. As this general class of agents is already being used for treatment of other human diseases, we predict that the results of these studies could be easily applied to reduce the mortality in patients with severe AKI. 2. PUBLIC HEALTH RELEVANCE: Severe acute kidney injury is common and largely reversible disorder that has a high mortality and for which there is no specific clinical treatment. Our studies have identified a new class of histone deacetylase inhibitors (HDACi) that accelerate the rate of renal recovery in a mouse model of acute kidney injury. The purpose of these studies is to identify new HDACi analogues that have a high potential for moving to clinical trials. 1.