Caspase-1 signaling in ischemic acute renal failure

描述(由申请人提供)：本赠款中提出的总体假设提供了一个综合的病理生理学方案，在该方案中，caspase-1和caspase-1相关的细胞因子，如IL-18和IL-1a，导致肾脏中巨噬细胞和NK细胞浸润增加，从而导致缺血性急性肾功能衰竭(ARF)。新公布的数据表明，IL-18处理受损保护caspase-1缺陷小鼠免受缺血性ARF的影响，支持这一假说。在小鼠身上的补充研究将在不同的模型中进行：1)活体缺血性ARF，2)悬液中新鲜分离的肾近端小管，3)培养中的微血管内皮细胞。在特定的目标1中，将确定缺血性ARF中caspase-1和IL-18表达增加的时间进程。此外，还将测试新开发的caspase-1和IL-18抑制剂的治疗潜力。Fractalkine是巨噬细胞和NK细胞的主要趋化因子。在特定的目标2中，我们将确定是否存在细胞因子介导的内皮细胞分裂因子的增加。具体目的3主要集中在巨噬细胞和NK细胞在缺血性ARF中作为caspase-1、IL-18、IL-1a和其他细胞因子的来源。使用巨噬细胞和NK细胞抑制剂的体内研究将检验其临床应用的潜力。已知IL-18激活的巨噬细胞和NK细胞通过穿孔素和/或颗粒酶介导细胞裂解。在特定的目标4中，我们认为巨噬细胞和NK细胞依赖或独立产生穿孔素和gzmA参与了FT损伤(体外)和ATN(体内)。这些研究与临床ARF的相关性很大。这一结果将为缺血性ARF的病理生理机制提供新的见解，并有助于改变缺血性ARF的病程。这一点尤其正确，因为目前有caspase-1和IL-18抑制剂，如普拉卡桑和IL-18结合蛋白(IL-18 BP)，正在进行临床试验。

DESCRIPTION (provided by applicant): The overall hypothesis presented in this grant provides an integrated pathophysiological schema whereby caspase-1 and caspase-1-related cytokines like IL-18 and IL-1a lead to increased macrophage and NK cell infiltration in the kidney and resultant ischemic acute renal failure (ARF). Novel published data demonstrating that impaired IL-18 processing protects caspase-1 deficient mice from ischemic ARF supports the hypothesis. Complementary studies in mice will be performed in different models: 1) ischemic ARF in vivo, 2) freshly isolated renal proximal tubules in suspension and 3) microvascular endothelial cells in culture. In Specific Aim 1, the time course of increased caspase-1 and IL-18 expression in ischemic ARF will be determined. In addition, the therapeutic potential of newly developed caspase-1 and IL-18 inhibitors will be tested. Fractalkine is a major chemoattractant for macrophages and NK cells. In Specific Aim 2, we shall determine whether there is a cytokine-mediated increase of fractalkine in the endothelium. Specific Aim 3 focuses on macrophages and NK cells as sources of caspase-1, IL-18, IL-1a and other cytokines in ischemic ARF. In vivo studies using inhibitors of macrophages and NK cells will test the potential for clinical application. Activated macrophages and NK cells stimulated by IL-18 are known to mediate cell lysis via perforin and/or granzymes. In Specific Aim 4, we propose that IL-18-dependent or independent production of perforin and gzmA by macrophages and NK cells contributes to FT injury (in vitro) and ATN (in vivo). The relevance of these studies to clinical ARF is substantial. The results should provide new insights into the pathophysiology of ischemic ARF as well as leads to altering the course of ischemic ARF. This is particularly true because of the current availability of caspase-1 and IL-18 inhibitors e.g. pralnacasan and IL-18 binding protein (IL-18 BP) that are being tested in clinical trials.