Cell type-specific functions of HMGB1 in necroinflammation of the kidney

前期研究结果表明，细胞外组蛋白和中性粒细胞胞外陷阱在急性缺血后肾损伤的肾坏死性炎症中起重要作用。但细胞外组蛋白的特定细胞类型来源无法研究，因为特定细胞类型的组蛋白去除在技术上是不可行的。因此，我们在这里关注核蛋白高迁移率基团框(HMGB)-1，它在细胞外空间引起类似于组蛋白的抑制作用。由于HMGB1在细胞核中是可分配的，HMGB1-FLOX小鼠已经出现。我们将建立选择性去除肾小管上皮细胞、常驻免疫细胞和浸润性免疫细胞中HMGB1的小鼠株系。在诱导急性肾损伤的缺血后肾小管坏死后，可以研究来自每种细胞类型的HMGB1的贡献。有必要区分HMGB1的胞内和胞外功能。在我们前期工作的基础上，这个项目将特别关注急性肾损伤的长期结果，即肾脏再生和肿瘤形成，这两者在急性肾损伤后都是紧密联系的。我们将研究HMGB1的药理抑制以及HMGB1的细胞类型特异性缺陷对这些结果的影响。我们期望对急性肾损伤后肾脏坏死性炎症及其对长期预后的影响有更好的认识。

The rsults of the previous project document that extracellular histones and neutrophil extracellular traps have important roles in renal necroinflammaiton of acute postischemic kidney injury. But the cell type-specific sources of extracellular histones could not be studied, because cell type-specific depletion of histones is technically not feasible. Therefore, we focus here on the nucleoprotein high mobility group box (Hmgb)-1, which elicits similar DAMP effects as histones in the extracellular space. Because Hmgb1 is dispensible in the nucleus Hmgb1-flox mice have become available. We will generate mouse lines with selective depletion of Hmgb1 in tubular epithelial cells, resident immune cells, and infiltrating immune cells. After induction of a postischemic tubular necrosis with acute kidney injury the contribution of Hmgb1 from each cell type can be studied. It will be necessary to distingiush intracellular from extracellular functions of Hmgb1. Based on our preliminary work this project will focus in particular on the long-term outcomes of acute kidney injury, i.e. kidney regeneration and tumorigenesis, which are both tightly connected after acute kidney injury. We will study the effects of pharmacological inhibition of Hmgb1 as well as the cell type-specific deficiency of Hmgb1 on these outcomes. We expect a bette runderstanding of renal necroinflammation and its impact on the long-term outcomes after acute kidney injury.