Caspase-1 signaling in ischemic acute renal failure

Caspase-1 信号在缺血性急性肾衰竭中的作用

• 批准号: 7991407
• 负责人: CHARLES Louis EDELSTEIN
• 金额: $ 9.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-18 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991407
• 关键词: Acute; Acute Kidney Failure; Acute Kidney Tubular Necrosis; Adherence; Adhesions; Adoptive Transfer; Affinity; Antibodies; Apoptosis; Attenuated; CD4 Positive T Lymphocytes; CX3CL1 gene; Caspase-1; Cell Adhesion; Cell Adhesion Molecules; Cell Death; Cells; Chemotactic Factors; Chemotaxis; Clinical; Clinical Trials; Creatinine; Cytolysis; Data; Disease; Eels; Encapsulated; Endothelial Cells; Endothelium; Event; Failure; Fractalkine; Functional disorder; Grant; Granzyme; Histology; Immune Sera; Immunohistochemistry; In Vitro; Infiltration; Inflammation; Inflammatory; Injury; Interleukin-11; Interleukin-18; Ischemia; Kidney; Lead; Liposomes; Macrophage Activation; Mediating; Messenger RNA; Modeling; Mus; Necrosis; Patients; Play; Process; Production; Proteins; Protocols documentation; Proximal Kidney Tubules; Publishing; Receptor Inhibition; Recombinants; Renal function; Reperfusion Therapy; Research Personnel; Role; Series; Serum; Severity of illness; Signal Transduction; Source; Suspension substance; Suspensions; Testing; Therapeutic; Time; Transgenic Organisms; Up-Regulation; chemokine; clinical application; cytokine; fractalkine receptor; granzyme A; in vivo; inhibitor/antagonist; insight; interest; interleukin-18 binding protein; interleukin-1beta-converting enzyme inhibitor; interstitial; macrophage; migration; monocyte; neutrophil; novel; perforin; perforin 1; perforin 2; pralnacasan; programs; protein expression; receptor

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.

描述（由申请人提供）：该赠款中提出的总体假设提供了一个综合的病理生理模式，caspase-1和Caspase-1相关的细胞因子（如IL-18和IL-1A）和IL-1A（IL-1A）导致巨噬细胞和NK细胞浸润增加，导致肾脏和由此导致的缺血性急性肾衰竭（ARF）。新型发布的数据表明，IL-18处理受损可保护caspase-1缺陷小鼠免受缺血性ARF的影响支持该假设。小鼠的互补研究将在不同的模型中进行：1）体内缺血性ARF，2）悬浮液中的新鲜分离的肾近端小管和3）培养中微血管内皮细胞。在特定的目标1中，将确定缺血性ARF中caspase-1和IL-18表达增加的时间过程。此外，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细胞的主要趋化剂。在特定的目标2中，我们将确定内皮中的细胞因子介导的分裂量增加。特定的目标3专注于巨噬细胞和NK细胞作为缺血性ARF中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测试临床应用的潜力。已知IL-18刺激的活化巨噬细胞和NK细胞通过穿孔和/或颗粒酶介导细胞裂解。在特定的目标4中，我们提出，巨噬细胞和NK细胞对IL-18依赖性或独立产生perforin和gzma产生了FT损伤（体外）和ATN（体内）。这些研究与临床ARF的相关性是很大的。结果应为缺血性ARF的病理生理学提供新的见解，并导致改变缺血性ARF的过程。由于目前的caspase-1和IL-18抑制剂，例如pralnacasan和IL-18结合蛋白（IL-18 bp）正在临床试验中进行测试。

项目成果

Mediators of inflammation in acute kidney injury.

• DOI: 10.1155/2009/137072
• 发表时间: 2009
• 期刊: Mediators of inflammation
• 影响因子: 4.6
• 作者: Akcay A;Nguyen Q;Edelstein CL
• 通讯作者: Edelstein CL

Therapeutic and predictive targets of AKI.

• DOI: 10.5414/cnp70453
• 发表时间: 2008-12
• 期刊: Clinical nephrology
• 影响因子: 1.1
• 作者: Yalavarthy R;Edelstein CL
• 通讯作者: Edelstein CL

Pathways of caspase-mediated apoptosis in autosomal-dominant polycystic kidney disease (ADPKD).

• DOI: 10.1111/j.1523-1755.2005.00155.x
• 发表时间: 2005-03
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Y. Tao;Jun Kim;M. Stanley;Zhibin He;S. Faubel;R. Schrier;C. Edelstein

Different ways to die: cell death modes of the unicellular chlorophyte Dunaliella viridis exposed to various environmental stresses are mediated by the caspase-like activity DEVDase.

• DOI: 10.1093/jxb/ern330
• 发表时间: 2009
• 期刊: Journal of experimental botany
• 影响因子: 6.9
• 作者: Jiménez C;Capasso JM;Edelstein CL;Rivard CJ;Lucia S;Breusegem S;Berl T;Segovia M
• 通讯作者: Segovia M

Neutrophil-independent mechanisms of caspase-1- and IL-18-mediated ischemic acute tubular necrosis in mice.

• DOI: 10.1172/jci15623
• 发表时间: 2002-10
• 期刊: The Journal of clinical investigation
• 作者: V. Y. Melnikov;S. Faubel;B. Siegmund;M. Lucia;D. Ljubanović;C. Edelstein