Regulation of Macrophage Phenotype by Ferritin Heavy Chain in CKD

CKD 中铁蛋白重链对巨噬细胞表型的调节

• 批准号: 10562610
• 负责人: Abolfazl Zarjou
• 金额: $ 42.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562610
• 关键词: Address; Affect; American; Anemia; Area; Biopsy; Cells; Chronic Kidney Failure; Clinical; Creatinine; Data; Deposition; Development; Disease; Disease model; Equilibrium; Ferritin; Fibrosis; Foundations; Goals; Health; Health Expenditures; Homeostasis; Individual; Inflammation; Inflammatory; Injury; Injury to Kidney; Iron; Iron Overload; Iron binding capacity measurement; Kidney; Knowledge; Laboratories; Leukocytes; Light; Macrophage; Maintenance; Modeling; Molecular; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Nerve Degeneration; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Persons; Phenotype; Process; Proteins; Public Health; Recycling; Regulation; Renal Replacement Therapy; Renal function; Reporter; Resolution; Role; Serum; Source; Techniques; Testing; Transcriptional Regulation; Transgenic Mice; Tubular formation; United States Dept. of Health and Human Services; Up-Regulation; Work; alpha synuclein; experimental study; feasibility testing; health plan; iron deficiency; iron metabolism; monocyte; mortality; nephrogenesis; new therapeutic target; novel strategies; novel therapeutic intervention; overexpression; repaired; response; response to injury; single-cell RNA sequencing; trafficking; transcription factor; transcriptome sequencing; transcriptomics; urinary

Abstract Chronic kidney disease (CKD) is a worldwide public health problem affecting ~850 million people including 37 million Americans. Advanced CKD results in a number of adverse clinical outcomes leading to high rates of mortality, morbidity, and healthcare expenditure. Recognizing these staggering challenges, the Department of Health and Human Services initiated the “Advancing American Kidney Health (AAKH)” through Executive Order in July 2019. Derangements in iron metabolism are a hallmark of advanced CKD, however, the mechanistic underpinnings of such perturbations and their clinical impact on the course of CKD are not fully understood. The overall goal of this project is to fill the current gaps in knowledge and address this unmet need for the development of novel therapeutic interventions by targeting iron metabolism to slow progression of CKD and delay the need for kidney replacement therapy, two of the major goals of the AAKH initiative. By conducting preliminary studies, we have discovered that macrophage ferritin heavy chain (FtH) diminishes development and progression of CKD. Guided by our findings we propose the unifying hypothesis that myeloid FtH orchestrates iron distribution and regulates macrophage plasticity under injurious/inflammatory conditions. This premise is substantiated by (i) significant upregulation of Spic, a lineage-defining transcription factor that selectively controls development of iron recycling macrophages and (ii) marked elevation and aggregation of synuclein-alpha (Snca), a common pro-inflammatory factor in neurodegenerative conditions in in two models of CKD with substantially higher levels observed in kidneys of mice with targeted deletion of FtH in myeloid compartment. To confirm our hypothesis, we will execute the following specific aims: Aim 1: To test the hypothesis that myeloid FtH regulates monocyte/MΦ differentiation towards iron recycling phenotype through controlling transcription factor Spic. Aim 2: To test the hypothesis that myeloid FtH establishes disease tolerance to CKD via suppression of Snca. Successful completion of the proposed aims will have a significant impact on our understanding of the individual and collective effects of myeloid FtH, Spic and Snca expression in iron handling by the kidney and their detailed connotative roles in the pathogenesis of CKD, thereby paving the way for a new therapeutic approach in this disease by targeting iron metabolism in CKD.

摘要 慢性肾脏疾病（CKD）是一个全球性的公共卫生问题，影响约8.5亿人，其中包括37 数百万美国人晚期CKD导致许多不良临床结局，导致高发生率的 死亡率、发病率和医疗费用。认识到这些惊人的挑战， 卫生与公众服务部通过行政部门发起了“推进美国肾脏健康（AAKH）”， 2019年7月订购。铁代谢紊乱是晚期CKD的标志，然而， 这种扰动的机制基础及其对CKD病程的临床影响还不完全 明白该项目的总体目标是填补目前的知识空白，解决这一未满足的需求 通过靶向铁代谢以减缓CKD进展，开发新型治疗干预措施 并推迟肾脏替代治疗的需要，这是AAKH倡议的两个主要目标。通过 进行初步研究，我们发现巨噬细胞铁蛋白重链（FtH）减少， CKD的发展和进展。根据我们的研究结果，我们提出了一个统一的假设，即骨髓 FtH在损伤/炎症条件下协调铁分布并调节巨噬细胞可塑性。 这一前提得到了证实：（i）Spic的显著上调，Spic是一种谱系定义转录因子， 选择性地控制铁循环巨噬细胞的发育，和（ii）铁循环巨噬细胞的显著升高和聚集， 突触核蛋白-α（Snca），一种神经退行性疾病中常见的促炎因子，在两种模型中， 在骨髓中靶向缺失FtH的小鼠的肾脏中观察到显著更高水平的CKD 车厢为了证实我们的假设，我们将执行以下具体目标：目标1：为了测试 髓系FtH调节单核细胞/MΦ向铁再循环表型分化的假设 控制转录因子Spic。目的2：检验髓样FtH建立疾病的假设 通过抑制Snca耐受CKD。成功完成拟议目标将对 对我们理解髓系FtH、Spic和Snca表达的个体和集体效应的影响 肾脏对铁的处理及其在CKD发病机制中的详细内涵作用， 通过靶向CKD中的铁代谢，为这种疾病的新治疗方法开辟了道路。