Macrophages and attenuation of inflammation resolution in APOL1 nephropathy

APOL1 肾病中巨噬细胞和炎症消退的减弱

• 批准号: 10345803
• 负责人: Jennie J LIn
• 金额: $ 57.51万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-20 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345803
• 关键词: Address; Affect; African Trypanosomiasis; African ancestry; Alleles; American; Anti-Inflammatory Agents; Apolipoproteins; Apoptotic; Attenuated; Automobile Driving; Biological Factors; Biological Models; Biology; Black race; Cells; Cholesterol Homeostasis; Chronic; Chronic Kidney Failure; Code; Complex; Conflict (Psychology); Cytokine Signaling; DNA; Development; Disease; Disease Progression; End stage renal failure; Endoplasmic Reticulum; Functional disorder; Genes; Genetic Transcription; Genetic study; Genotype; Goals; Health Care Costs; Homeostasis; Human; Human Genetics; Immune; Immune response; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Injury; Injury to Kidney; Innate Immune Response; Interferon Type II; Interleukin-10; Interleukin-4; Investigation; Kidney; Kidney Diseases; Link; Measures; Mediating; Mitochondria; Modeling; Molecular Chaperones; Natural Immunity; Pathogenesis; Pathway interactions; Patients; Phagocytes; Phenotype; Play; Primates; Process; Proteins; Quality of life; Reactive Oxygen Species; Resolution; Respiration; Risk; Risk Factors; Role; Signal Transduction; Signaling Protein; Sterility; Stimulus; Stress; Testing; Therapeutic; Tissues; Transgenic Mice; United States; Validation; Variant; Work; attenuation; biological adaptation to stress; cell type; comorbidity; disease phenotype; endoplasmic reticulum stress; experience; genome editing; genomic locus; health difference; high risk; immune function; in vivo; induced pluripotent stem cell; inhibitor; injury and repair; insight; kidney cell; kidney fibrosis; lipid metabolism; macrophage; metabolic abnormality assessment; mitochondrial dysfunction; mitochondrial metabolism; mortality; novel; pathogen; podocyte; protein activation; protein function; response; response to injury; risk variant; socioeconomics; tissue repair; transcriptomics

PROJECT SUMMARY Individuals who self-identify as Black in the United States experience disproportionately higher rates of developing chronic kidney disease (CKD) and experiencing CKD progression to end-stage kidney disease (ESKD). A portion of this health difference is not explained by socioeconomic and traditional risk factors, necessitating the study of other biological factors contributing to disease pathogenesis. Human genetics studies have identified and validated two common coding variants in the primate-specific Apolipoprotein L1 (APOL1) gene that contribute to high rates of proteinuric CKD in patients with African ancestry. These alleles, termed G1 and G2, evolved and became common due to the survival advantage they confer against African trypanosomiasis. Despite their role in primate innate immunity, not much is known about the role immune cells such as macrophages, which contribute to kidney injury and repair, play in APOL1 nephropathy. To address this gap, we propose to use genome-edited induced pluripotent stem cell (iPSC) derived macrophages and transgenic mice to investigate how G1 and G2 APOL1 alter macrophage function to promote kidney disease. We focus on the macrophage due to its dual role in innate immune responses to pathogens and contribution to kidney injury and fibrosis. In preliminary studies, we have generated genome-edited G1 iPSCs sharing an isogenic background with G0 controls and found that G1 iPSC derived macrophages maintain higher expression of proinflammatory genes under multiple conditions. Because chronic sterile macrophage inflammation can drive kidney disease, we are investigating mechanisms by which G1 and G2 APOL1 promote a sustained proinflammatory macrophage phenotype and maladaptive tissue repair. In various complex diseases including CKD, resolution of tissue inflammation requires anti-inflammatory reprogramming of immune cells and clearance of apoptotic cells by macrophages via efferocytosis. Additionally, macrophage inflammation can be induced by stress or dysfunction of the endoplasmic reticulum (ER), which has been implicated in APOL1 biology in other cell types. Therefore, we hypothesize that G1 and G2 macrophages undergo impaired anti-inflammatory reprogramming and inefficient efferocytosis through enhanced ER stress, thereby contributing to non-resolving kidney inflammation and APOL1 nephropathy. To test this central hypothesis, we will delineate which ER stress pathways G1 and G2 APOL1 perturb (Aim 1), investigate anti-inflammatory signaling and mitochondrial dysfunction in the attenuation of reparative reprogramming of G1 and G2 macrophages (Aim 2), and determine the mechanisms by which G1 and G2 APOL1 impair efferocytosis (Aim 3). The proposed investigations will test a novel hypothesis that APOL1 risk alleles amplify kidney injury through macrophage dysfunction. Elucidating the macrophage’s role in APOL1 nephropathy will offer critical insight for developing complementary strategies to treat APOL1 disease through enhancing macrophage-mediated tissue repair.

项目摘要 在美国自我认同为黑人的个人的人数不成比例 发展慢性肾脏疾病（CKD），并经历了CKD发展为终末期肾脏疾病 （ESKD）。这种健康差异的一部分没有由社会经济和传统危险因素解释 需要研究其他有助于疾病发病机理的生物学因素。人类遗传学研究 已经确定并验证了私有特异性载脂蛋白L1（APOL1）中的两个常见编码变体 在非洲血统患者中导致蛋白尿CKD高率的基因。这些等位基因，称为G1 G2，由于他们对非洲的生存优势而发展并变得很普遍 锥虫病。尽管它们在灵长类动物的先天免疫中作用，但对免疫细胞的作用并不了解 例如巨噬细胞在APOL1肾病中发挥作用，会导致肾脏损伤和修复。 为了解决这一差距，我们建议使用基因组编辑的诱导多能干细胞（IPSC）得出的 巨噬细胞和转基因小鼠研究G1和G2 Apol1如何改变巨噬细胞的功能 肾脏疾病。由于巨噬细胞在对病原体的先天免疫反应中的双重作用，我们专注于巨噬细胞 对肾脏损伤和纤维化的贡献。在初步研究中，我们生成了基因组编辑的G1 IPSC 与G0控件共享同源背景，发现G1 IPSC衍生的巨噬细胞保持较高 在多种条件下的促炎基因的表达。由于慢性无菌巨噬细胞 炎症会引起肾脏疾病，我们正在研究G1和G2 APOL1促进的机制 持续的促炎性巨噬细胞表型和不良适应组织修复。在各种复杂疾病中 包括CKD在内，组织注射的分辨率需要免疫细胞和 巨噬细胞通过传染性细胞增多症清除凋亡细胞。另外，巨噬细胞炎症可能是 由内质网（ER）的压力或功能障碍诱导，在Apol1生物学中已暗示 在其他细胞类型中。因此，我们假设G1和G2巨噬细胞受到抗炎的受损 通过增强的ER应力来重新编程和效率低下的效率，从而有助于非分解 肾脏炎症和APOL1肾病。为了检验这一中心假设，我们将描绘出压力 途径G1和G2 apol1扰动（AIM 1），研究抗炎信号和线粒体 G1和G2巨噬细胞的修复重编程的衰减功能障碍（AIM 2），并确定 G1和G2 APOL1损害肿瘤的机制（AIM 3）。拟议的调查将测试 一个新的假设，即Apol1风险等位基因通过巨噬细胞功能障碍扩大肾脏损伤。阐明 巨噬细胞在APOL1肾病中的作用将为制定完整策略提供关键的见解 通过增强巨噬细胞介导的组织修复来治疗Apol1疾病。