Novel Anti-Proteinuric Strategies Targeting Podocytes

项目摘要 肾小球功能障碍是蛋白尿肾病的主要原因。它占&gt；90% 仅在美国，终末期肾病(ESRD)病例的治疗成本就高达200亿美元。目前， 蛋白尿肾病是用抗高血压药物等具有系统活性的药物来治疗的。 暂时缓解症状。足细胞是形成肾小球滤过器所必需的。 因为足细胞损伤是各种蛋白尿肾脏疾病发病机制中的早期事件，如 作为局灶性节段性肾小球硬化(FSGS)和糖尿病肾病(DN)，这些细胞是一种极好的 靶向疗法发展的目标。然而，为合理发展的努力 足细胞定向治疗因缺乏任何基于定量细胞的治疗方法而受到阻碍 筛选试验。此外，虽然许多特定的遗传异常和环境因素背后 患者足细胞损伤已被识别，将这种机械洞察力转化为药物 发现方面的努力严重不足。最近，我们在解决这些问题方面取得了重大进展 挑战(在提案中作为初步数据提供)，其中包括-a)开发一部小说 基于足细胞的高通量筛选(HTS)分析，并用它来鉴定24个新的命中 在体外和体内保护足细胞免受损伤；b)证明我们的足细胞检测可以 准确、重复性地测量患者血清或携带足细胞的足细胞损伤 患者特有的基因缺陷，并表明基因缺陷可以通过新的小分子 C)建立一种新的人源化小鼠模型。 蛋白尿肾病，可用于验证新的HIT化合物，以更快地转化为 诊所。这些令人振奋的发现构成了我们目前提案的基础。我们假设我们的小说 基于足细胞的筛选试验可以用来发现直接作用于 患者相关设置中的足细胞。我们进一步提出了基于药物化学的优化方法。 已确认命中。此外，我们假设人足细胞与患者血清在这方面的适应 化验系统将使我们能够识别独特的PODO保护化合物。最后，我们还假设 纳入人源化的小鼠肾脏损伤模型将为我们提供一个改进的HIT体内模型 验证，以便我们可以快速提名用于开发人类疗法的候选药物 未来的病人。我们还建议对我们的命中结果进行独立的体内验证。我们的长期目标是 开发以足细胞为靶点并稳定足细胞的新型治疗剂，作为治疗糖尿病的一种策略 蛋白尿性肾病。

Project Summary Glomerular dysfunction is a leading cause of the proteinuric kidney disease. It accounts for >90% of end stage renal disease (ESRD) cases, costing >$20B for treatment in the US alone. Currently, proteinuric kidney disease is treated with drugs, such as anti-hypertensives, that are systemically active to temporarily relieve the symptoms. Podocytes are essential for the formation of the glomerular filter. Because podocyte injury is an early event in the pathogenesis of various proteinuric kidney diseases, such as focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy (DN), these cells are an excellent target for the development of targeted therapeutics. However, efforts for the rational development of podocyte-directed therapeutics have been hampered by the absence of any quantitative cell-based screening assay. Moreover, while many specific genetic abnormalities and environmental factors behind podocyte injury in patients have been identified, translation of such mechanistic insights into drug discovery efforts is sorely lacking. Recently, we have made significant progress in addressing these challenges (presented as preliminary data in the proposal), which includes – a) development of a novel podocyte cell-based high throughput screening (HTS) assay and using it to identify 24 novel hits that protect podocytes from damage in vitro and in vivo; b) demonstration that our podocyte assay can accurately and reproducibly measure podocyte injury from patient-derived sera or in podocytes carrying patient-specific genetic defects, and showing that the genetic defects can be rescued via novel small molecules in knock-in animal models; and c) development of a novel humanized mouse model of proteinuric kidney disease, which can be used to validate novel hit compounds for faster translation into clinic. These exciting findings form the basis of our current proposal. We hypothesize that our novel podocyte-based screening assay could be used to discover novel candidate drugs that directly act on podocytes in patient-relevant settings. We further propose medicinal chemistry based optimization of confirmed hits. Furthermore, we hypothesize that adaptation of human podocytes with patient sera in this assay system will allow us to identify unique podo-protective compounds. Finally, we also hypothesize that inclusion of a humanized mouse model of kidney injury will provide us an improved in vivo model for hit validation so that we can rapidly nominate drug candidates for development into therapeutics for human patients in the future. We also propose an independent, in vivo validation of our hits. Our long-term goal is to develop novel therapeutic agents that target and stabilize podocytes as a strategy for the treatment of proteinuric kidney disease.