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: 8805166
• 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/8805166
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Anatomy; Antioxidants; Apoptosis; Apoptotic; Atherosclerosis; Biology; CCL2 gene; Cardiac Surgery procedures; Cells; Clinical; Complex; 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; 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; Pathway interactions; Patients; Phenotype; Play; Procedures; Process; Proximal Kidney Tubules; Radio; Recovery; Recruitment Activity; Relative (related person); 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; experience; injured; innovation; 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(申请人提供)：急性肾损伤(AKI)常见于危重病患者的多器官衰竭。缺乏既定的治疗方法 克服AKI导致这些患者的发病率和死亡率高得令人无法接受。导致AKI的分子机制通常有氧化应激和炎症作为常见的致病事件。肾脏的反应是迅速诱导其自身的抗氧化机制，包括高度诱导和抗凋亡的铁蛋白基因重链(FTH)。FTH催化活性亚铁转化为铁形式，从而能够安全地将铁隔离在铁蛋白外壳中。我们实验室的初步研究表明，选择性缺失肾近端小管中的FTH会增加AKI后结构和功能的损伤以及巨噬细胞的聚集。此外，巨噬细胞中FTH的表达决定了巨噬细胞的激活和极化。这一设想的假设是近端小管和巨噬细胞FTH表达之间的串扰调节炎症反应以及随后IL-6、CSF-1和MCP-1响应的损伤消退的级联反应。在目标1中，将确定近端小管特异性FTH缺失对肾损伤和AKI中巨噬细胞聚集和极化的有害影响。目的2将验证一种假设，即巨噬细胞中FTH的表达将决定其向不同表型极化的可能性，从而调节损伤介导的细胞毒性和纤维化。目的3将验证FTH通过调节促进巨噬细胞募集和极化的信号级联来调节肾脏和巨噬细胞之间的串扰的假设。阐明肾脏和巨噬细胞中受FTH等保护性基因调控的固有信号通路及其对损伤或修复的贡献对于确定AKI后修复过程中的新治疗方式是不可或缺的。该项目还将在一个经验丰富的指导团队的指导下，在AKI的巨噬细胞生物学和细胞信号方面提供密集的研究培训计划，使申请者能够在学术肾脏学领域发展和开始独立的职业生涯。