Contrasting roles for neutrophils and macrophages during acute pyelonephritis

中性粒细胞和巨噬细胞在急性肾盂肾炎期间的作用对比

• 批准号: 10407517
• 负责人: Juan de Dios Ruiz Rosado
• 金额: $ 14.36万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10407517
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Adoptive Cell Transfers; Advanced Practice Nurse; Advisory Committees; Affect; Antibiotic Therapy; Area; Award; Biological Assay; Biological Process; Bladder; Cells; Cicatrix; Complex; Cystitis; Data; Development; End stage renal failure; Escherichia coli Infections; Fibrosis; Foundations; Funding; Healthcare; Histopathology; Human; Immune; Immune response; Immunology; Impaired Renal Function; Infection; Infection prevention; Inflammation; Inflammatory; Injury to Kidney; Innate Immune Response; Innate Immune System; Interstitial Nephritis; K-Series Research Career Programs; Kidney; Knockout Mice; Lead; Mediating; Mentors; Mentorship; Methodology; Microbiology; Modeling; Molecular Biology; Mus; NADPH Oxidase; Nephrology; Office Visits; Outcome; Oxidative Stress; Pathogenesis; Patients; Persons; Phagocytes; Phenotype; Predisposition; Public Health; Pyelonephritis; Reactive Oxygen Species; Renal function; Research; Role; Scientist; Structure; Testing; Training; United States; Urinary tract infection; Uropathogenic E. coli; acute pyelonephritis; antimicrobial; ascending urinary tract infection; career; career development; clinically significant; conditional knockout; defined contribution; functional disability; innovation; interstitial; kidney dysfunction; kidney fibrosis; long-term sequelae; macrophage; microbicide; monocyte; mouse model; nephrogenesis; neutrophil; novel; novel therapeutic intervention; oxidative damage; pre-clinical; prevent; renal damage; renal scarring; response; therapeutic target; transcriptome

Project Summary/Abstract Urinary tract infections (UTIs) are among the most frequent and severe infections worldwide. Uropathogenic Escherichia coli (UPEC) is the primary causative agent of UTI. UPEC ascension from the bladder (cystitis) to the kidneys results in pyelonephritis (PN). Despite prompt antibiotic treatment, patients with PN can develop acute kidney injury (AKI) and renal scarring, which can ultimately lead to end-stage renal disease. Currently, no therapy is available to prevent the long-term sequelae following PN. The innate immune system serves instrumental roles in controlling UTI and represents a potential therapeutic target for UTI prevention and treatment. However, mounting evidence argues that dysregulated innate immune responses can lead to persistent inflammation and renal scarring during PN. A greater understanding of the cellular immune mechanisms underlying the development of renal inflammation and kidney fibrosis during PN will lead to novel therapeutic strategies to treat UTI and prevent the development of detrimental sequelae. I have recently demonstrated that neutrophils and macrophages have distinct roles during PN pathogenesis. While neutrophils prevent widespread UPEC dissemination, macrophages promote pro-inflammatory and pro- fibrotic immune responses during PN. The overall objective of this proposal is to investigate the functional roles of neutrophils and macrophages in the development of kidney fibrosis and dysfunction after a PN episode. My central hypothesis is that neutrophils eradicate UPEC and prevent permanent kidney damage, while macro- phage-mediated inflammation drives kidney injury and renal scarring during PN. The specific aims during this K award will test the following hypotheses: 1) Neutrophils have a protective antimi- crobial function, while macrophages induce interstitial fibrosis and renal dysfunction during PN (Aim 1). 2) Mac- rophages exert pro-inflammatory and pro-fibrotic functions during PN, which contribute to renal inflammation, scarring, and reduced kidney function (Aim 2). 3) Neutrophil NOX2 limits bacterial dissemination during PN, whereas macrophage NOX2 promotes oxidative stress and kidney injury (Aim 3). The proposed research will use an innovative preclinical mouse model of APN that replicates the development of kidney fibrosis following UTI and bridges methodologies in the areas of immunology, microbiology, molecular biology, and nephrology. The expected outcomes from this proposal will reveal novel biological functions for macrophages and neutrophils during PN, and will identify new targets that may alleviate PN-mediated sequelae. This approach in combination with structured career development activities under the guidance of my mentors and research advisory team, will prepare me to successfully compete for R01 funding and launch my career as an independent scientist focused on resolving some of the most challenging obstacles in the treatment of UTI.

项目概要/摘要 尿路感染 (UTI) 是全球最常见、最严重的感染之一。泌尿道致病性 大肠杆菌 (UPEC) 是尿路感染的主要病原体。 UPEC 从膀胱（膀胱炎）提升到 肾脏导致肾盂肾炎（PN）。尽管及时进行抗生素治疗，PN 患者仍可能发展为急性 肾损伤（AKI）和肾疤痕，最终可能导致终末期肾病。目前尚无治疗 可预防 PN 后的长期后遗症。 先天免疫系统在控制尿路感染方面发挥着重要作用，是一种潜在的治疗方法 UTI 预防和治疗的目标。然而，越来越多的证据表明，先天免疫失调 PN 期间的反应可能导致持续炎症和肾脏疤痕。更深入地了解 PN 期间肾脏炎症和肾纤维化发展的细胞免疫机制 将带来治疗尿路感染并预防有害后遗症发展的新治疗策略。 我最近证明中性粒细胞和巨噬细胞在 PN 发病机制中具有不同的作用。 虽然中性粒细胞阻止广泛的 UPEC 传播，但巨噬细胞促进促炎和促炎症反应。 PN 期间的纤维化免疫反应。该提案的总体目标是调查职能角色 中性粒细胞和巨噬细胞在 PN 发作后肾纤维化和功能障碍发展中的作用。 我的中心假设是中性粒细胞消除 UPEC 并防止永久性肾脏损伤，而宏观- 噬菌体介导的炎症会导致 PN 期间的肾损伤和肾疤痕形成。 本次 K 奖的具体目标将检验以下假设：1) 中性粒细胞具有保护性抗微生物作用。 PN 期间巨噬细胞会诱导间质纤维化和肾功能障碍（目标 1）。 2) 麦克- 噬菌体在 PN 期间发挥促炎和促纤维化功能，从而导致肾脏炎症， 疤痕和肾功能下降（目标 2）。 3) 中性粒细胞 NOX2 限制 PN 期间的细菌传播， 而巨噬细胞 NOX2 会促进氧化应激和肾损伤（目标 3）。拟议的研究将 使用创新的 APN 临床前小鼠模型，该模型复制了肾纤维化的发展过程 UTI 和免疫学、微生物学、分子生物学和肾脏学领域的方法学之间的桥梁。 该提案的预期结果将揭示巨噬细胞和中性粒细胞的新生物学功能 PN 期间，并将确定可能减轻 PN 介导的后遗症的新靶点。 在我的导师的指导下，这种方法与结构化的职业发展活动相结合 和研究咨询团队，将为我成功竞争 R01 资金并开启我的职业生涯做好准备 一位独立科学家致力于解决尿路感染治疗中一些最具挑战性的障碍。