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

摘要： 这项提议的长期目标是为严重未得到满足的医疗需求开发新的疗法，即 急性肾损伤(AKI)及其进展为慢性肾脏病(CKD)，目前尚无治疗方法 而不是支持性护理。肾脏损伤及其进展为慢性肾脏病的机制目前尚不清楚。 这项提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AKI的新靶点及其进展为未来药物开发的CKD。这个目标是中性的 神经酰胺酶(NCD)，一种参与鞘磷脂神经酰胺代谢的酶。该提案的基础是 支持初步数据的坚实基础，这些数据表明缺乏NCD的小鼠在模型中受到保护 AKI和CKD和体外数据表明NCD的缺失或抑制会增加自噬并保护 细胞受到各种细胞压力的影响。因此，这一提议将检验以下假设：删除或抑制 NCD通过上调自噬，提供对AKI和损伤诱导的CKD的保护。我们将对此进行测试 具有三个相互关联但独立的具体目标的假说，它们将(1)决定 当NCD缺失或被抑制时对体外培养的肾细胞的保护作用；(2)确定 NCD在AKI中的作用；(3)确定NCD在肾损伤进展为CKD中的作用。在本建议书中获得的数据 将提供许多科学和翻译方面的进展，对于实现我们的长期目标是必不可少的 为这一未得到满足的医疗需求开发疗法。

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.