Necroinflammation, kidney regeneration, and long term outcomes of acute tubular necrosis

急性肾小管坏死是急性肾损伤的一个重要临床表现。急性肾小管坏死患者至今仍无治愈性治疗选择的原因有很多。本项目旨在通过五个创新的想法来克服这些限制：1。减少坏死性炎症。细胞坏死和炎症在急性肾小管坏死的早期和晚期损伤阶段占主导地位。我们将首先确定在先发制人的研究设计中已被证明有效的调节性细胞坏死抑制剂、细胞因子和化学物质的治疗窗口。2.促进内在肾脏再生。肾单位损失是基于小管再生不足。我们将首先确定促再生化合物的治疗窗口。3克隆性肾小管细胞增殖？有多少坏死的肾小管细胞真正通过存活的肾小管细胞的增殖而被替换是未知的。我们将首先使用克隆增殖的谱系追踪来回答这个问题。4.肾单位损失决定长期结果。急性肾小管坏死之后是否会出现肾脏再生或萎缩取决于不可逆丢失的肾单位的数量。我们将量化肾单位损失，并将其作为所有治疗干预的主要终点。5.序贯联合治疗。我们希望通过结合早期抑制坏死和炎症，然后刺激小管再生来获得最有效的治疗效果。该项目旨在将急性肾小管坏死转变为可治疗的疾病。

Acute tubular necrosis is a clincially important entity of acute kidney injury. There are many reasons why there are still no curative therapeutic options for patients with acute tubular necrosis. This project intends to overcome these limitations by five innovative ideas: 1. Minimizing necroinflammation. Cell necrosis and Inflammation dominate the early and late injury phase of acute tubular necrosis. We will at first determine the therapeutic window of inhibitors of regulated cell necrosis, cytokines and chemokies that have proven effective in preemptive study designs. 2. Promoting intrinsic kidney regeneration. Nephron loss is based on an insufficient tubule regeneration. We will at first determine the therapeutic window of pro-regenerative compounds. 3 Clonal tubular cell proliferation? How many of the necrotic tubular cells are really replaced via proliferation of surviving tubular cells is unknown. We will use lineage tracing of clonal proliferation to at first answer this question. 4. Nephron loss determines long term outcomes. Whether acute tubular necrosis is followed by kidney regeneration or atrophy depends on the number of irreversibly lost Nephrons. We will quantify nephron loss and use it as a primary end point for all therapeutic interventions. 5. Sequential combination therapy. We expect the most efficient treatment effect by combining early Inhibition of necrosis and Inflammation followed by stimulating tubule regeneration. This project intends to turn acute tubular necrosis into a treatable disease.