The role of neutral ceramidase in acute kidney injury and its progression to chronic kidney disease.

总结： 该提案的长期目标是为严重未满足的医疗需求开发新的治疗方法，即 急性肾损伤（阿基）及其进展为无治疗方法的慢性肾病（CKD） 除了支持性护理。肾损伤及其进展为CKD的机制尚不清楚 而这项建议旨在填补其中一些知识空白。该提案的短期目标是验证 治疗阿基及其进展为CKD的新靶点，用于未来的药物开发。这个目标是中立的 神经酰胺酶（NCD），一种参与鞘脂神经酰胺代谢的酶。所涉提议主要是 支持初步数据的坚实基础，表明缺乏NCD的小鼠在模型中受到保护 体外数据表明，NCD的缺失或抑制增加了自噬， 使细胞免受各种细胞应激。因此，该提议将检验以下假设： NCD通过上调自噬来保护阿基和损伤诱导的CKD。我们将测试这个 假设有三个相互关联但独立的具体目标，将（1）确定的机制 当NCD被删除或抑制时，在体外保护肾细胞免受细胞应激;（2）确定 NCD在阿基中的作用;和（3）确定NCD在肾损伤进展为CKD中的作用。本建议书中获得的数据 将提供许多科学和转化的进步，这对实现我们的长期目标至关重要。 为这种未满足的医疗需求开发治疗方法。

Summary: The long-term goal of this proposal is to develop novel therapeutics for a serious unmet medical need, namely acute kidney injury (AKI) and its progression to chronic kidney disease (CKD) for which there are no treatments other than supportive care. The mechanisms of kidney injury and its progression to CKD are largely unknown and this proposal aims to fill some of these knowledge gaps. The short-term goal of this proposal is to validate a novel target for treating AKI and its progression to CKD for future drug development. This target is neutral ceramidase (NCD), an enzyme involved in metabolism of the sphingolipid ceramide. The proposal is based on a strong foundation of supporting preliminary data that indicates that mice lacking NCD are protected in models of AKI and CKD and in vitro data indicating that deletion or inhibition of NCD increases autophagy and protects cells from a variety of cellular stresses. Thus, this proposal will test the hypothesis that deletion or inhibition of NCD confers protection from AKI and injury-induced CKD via upregulation of autophagy. We will test this hypothesis with three interrelated but independent specific aims that will (1) determine the mechanism of protection of kidney cells in vitro from cellular stress when NCD is deleted or inhibited; (2) determine the role of NCD in AKI; and (3) determine the role of NCD in kidney injury progression to CKD. Data obtained in this proposal will provide many scientific and translational advances that are essential for achieving our long-term goal of developing therapeutics for this unmet medical need.