Ferritin mediates epithelial cell-macrophage cross talk in acute kidney injury

铁蛋白介导急性肾损伤中上皮细胞-巨噬细胞的相互作用

• 批准号: 9322623
• 负责人: Subhashini Bolisetty
• 金额: $ 15.04万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322623
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Anatomy; Antioxidants; Apoptosis; Apoptotic; Atherosclerosis; Biology; Cardiac Surgery procedures; Cells; Clinical; Complex; Consequentialism; Critical Illness; Data; Dialysis procedure; Disease; Dyes; Epithelial Cells; Epithelium; Event; Exhibits; Ferritin; Fibrosis; Gene Deletion; Genes; Goals; Graft Rejection; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Innovative Therapy; Interleukin-6; Intervention; Iron; Ischemia; Kidney; Laboratories; Lead; Macrophage Activation; Macrophage Colony-Stimulating Factor; Mediating; Mentors; Modality; Modeling; Molecular; Monocyte Chemoattractant Protein-1; Morbidity - disease rate; Multiple Organ Failure; Nephrology; Nephrons; Oxidative Stress; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Play; Procedures; Process; Proximal Kidney Tubules; Radio; Recovery; Recruitment Activity; Renal function; Reperfusion Therapy; Research Training; Resolution; Role; Seminal; Signal Pathway; Signal Transduction; Site; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training Programs; Transgenic Mice; Tubular formation; Up-Regulation; Ureteral obstruction; Work; Wound Healing; base; career; cytotoxicity; effective intervention; experience; injured; insight; macrophage; monocyte chemoattractant protein 1 receptor; mortality; novel; novel therapeutics; public health relevance; regenerative; repaired; response

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is often seen in the setting of multiple organ failure in critically ill patients. Lack of established therapeutic approaches to overcome AKI has led to unacceptably high incidence of morbidity and mortality in these patients. The molecular mechanisms that lead to AKI often have oxidative stress and inflammation as common pathogenic events. The kidney responds by prompt induction of its own antioxidant machinery including the highly inducible and anti-apoptotic heavy chain of the ferritin gene (FtH). FtH catalyzes the conversion of the reactive ferrous iron to ferric form thereby enabling safe sequestration of iron in the ferritin shell. Preliminary studies from our laboratory have shown that selective deletion of FtH in renal proximal tubules leads to increased structural and functional damage and macrophage accumulation following AKI. In addition, FtH expression in macrophages determines macrophage activation and polarization. The hypothesis of this proposal is that the cross talk between proximal tubules vs. macrophage FtH expression regulates the inflammatory response and the subsequent cascade of resolution of injury in response to IL-6, CSF-1 and MCP- 1. In aim 1, the deleterious effects of proximal tubule specific FtH deletion on kidney injury and macrophage accumulation and polarization in AKI will be determined. Aim 2 will test the hypothesis that FtH expression in macrophages will determine their potential to polarize towards distinct phenotypes and thereby regulate injury mediated cytotoxicity and fibrosis. Aim 3 will test the hypothesis that FtH mediates the cross-talk between kidney and macrophages through modulation of signaling cascades that facilitate macrophage recruitment and polarization. Elucidating the inherent signaling pathways modulated by protective genes such as FtH in the kidney and macrophages and its contribution to injury or repair is integral in defining new treatment modalities in the reparative processes following AKI. This project will also provide an intensive research training program in macrophage biology and cell signaling in AKI under guidance of an experienced mentoring team allowing the applicant to develop and launch an independent career in academic nephrology.

描述（由申请人提供）：急性肾损伤（阿基）常见于重症患者的多器官功能衰竭。缺乏既定的治疗方法， 阿基的治疗已经导致这些患者中不可接受的高发病率和死亡率。导致阿基的分子机制通常具有氧化应激和炎症作为常见的致病事件。肾脏通过迅速诱导其自身的抗氧化机制（包括铁蛋白基因（FtH）的高度诱导性和抗凋亡重链）作出反应。FtH催化反应性亚铁转化为三价铁形式，从而能够将铁安全地封存在铁蛋白壳中。我们实验室的初步研究表明，肾近端小管中FtH的选择性缺失导致阿基后结构和功能损伤以及巨噬细胞积聚增加。此外，巨噬细胞中的FtH表达决定巨噬细胞活化和极化。该建议的假设是近端小管与巨噬细胞FtH表达之间的串扰调节炎症反应和随后响应于IL-6、CSF-1和MCP- 1的损伤消退级联。在目的1中，将确定近端小管特异性FtH缺失对阿基中肾损伤和巨噬细胞积累和极化的有害影响。目的2将检验巨噬细胞中的FtH表达将决定其向不同表型转化的潜力，从而调节损伤介导的细胞毒性和纤维化的假设。目的3将检验FtH通过调节促进巨噬细胞募集和极化的信号级联介导肾脏和巨噬细胞之间的串扰的假设。阐明由肾脏和巨噬细胞中的保护性基因（如FtH）调节的固有信号传导途径及其对损伤或修复的贡献，对于确定阿基后修复过程中的新治疗方式至关重要。该项目还将在经验丰富的指导团队的指导下，提供阿基中巨噬细胞生物学和细胞信号传导的强化研究培训计划，使申请人能够在学术肾脏病学领域发展和开展独立的职业生涯。