Molecular physiology and epigenetics of NF-kB/BMP interactions in the post-ischemic kidney

急性肾损伤(AKI)通常由肾组织一过性缺氧引起，它同时影响肾小管上皮细胞和血管。然而，这些隔室的具体和个体贡献以及隔室特定的分子调节因子仍然没有被描述得很清楚。在本研究中，我们将探讨核因子-骨形态发生蛋白B(NF-κB，NF-κB)和骨形态发生蛋白信号转导途径在急性骨损伤发病机制中的作用及其可能的分子相互作用。我们在小鼠缺血性AKI模型中提供了在缺血后早期阶段这两个信号通路之间的激活和串扰的初步证据。我们进一步计划使用在NF-κB或骨形态发生蛋白信号中血管或小管特异缺陷的小鼠突变体来确定这些通路的单独作用，从而剖析血管和管腔的单独作用。已知的建立和维持肾组织损伤的因素，包括肾小管反应(细胞凋亡、增殖)、免疫细胞渗透和血流动力学将被分析。这些研究将促进我们对AKI的基本分子机制的理解，更广泛地说，对隔室串扰的理解。我们的最终目标是确定预防和治疗AKI的潜在新分子靶点。

Acute kidney injury (AKI) is frequently caused by transient renal tissue hypoxia, which affects both tubular epithelial and vascular compartments. However, the specific and individual contribution these compartments as well as the compartment-specific molecular regulators remain poorly delineated. In the present project, we will investigate the role of nuclear factor-κB (NF-κB) and bone morphogenic protein (BMP) signaling and their potential molecular interaction during the pathogenesis of AKI. We provide preliminary evidence for activation and crosstalk between these two signaling pathways during the early post-ischemic phase in a mouse model of ischemic AKI. We further plan to use mouse mutants with vascular- or tubular-specific deficiency in NF-κB or BMP signaling to identify the individual contributions of these pathways, thereby dissecting the individual roles of the vascular and tubular compartments. Factors known to establish and maintain renal tissue damage, including tubular responses (apoptosis, proliferation), immune cell infiltration and hemodynamics will be analyzed. These studies will advance our understanding on the basic molecular mechanisms of AKI and, more generally, on the compartmental crosstalk. Our ultimate aim is to identify potential novel molecular targets for the prevention and treatment of AKI.