Contrasting roles for neutrophils and macrophages during acute pyelonephritis

项目总结/摘要 尿路感染（UTI）是世界上最常见和最严重的感染之一。尿路病原 大肠杆菌（UPEC）是UTI的主要病原体。UPEC从膀胱（膀胱炎）Ascension到 肾脏导致肾盂肾炎（PN）。尽管及时抗生素治疗，PN患者可发生急性 肾损伤（阿基）和肾瘢痕形成，最终可能导致终末期肾病。目前，没有治疗 可用于预防PN后的长期后遗症。 先天性免疫系统在控制UTI中起重要作用，并代表了一种潜在的治疗方法 目标是预防和治疗UTI。然而，越来越多的证据表明，先天免疫失调 反应可导致PN期间持续性炎症和肾瘢痕形成。更好地了解 PN期间肾脏炎症和肾纤维化发生的细胞免疫机制 将导致新的治疗策略来治疗UTI和预防有害后遗症的发展。 我最近证明了中性粒细胞和巨噬细胞在PN发病过程中有不同的作用。 虽然中性粒细胞防止广泛的UPEC传播，但巨噬细胞促进促炎和促炎性细胞增殖。 PN期间的纤维化免疫应答。本提案的总体目标是调查 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，防止永久性肾损伤，而宏观- 在PN期间，噬菌体介导的炎症驱动肾损伤和肾瘢痕形成。 在这个K奖的具体目标将测试以下假设：1）中性粒细胞具有保护性抗- 肠外营养期间，巨噬细胞可诱导间质纤维化和肾功能障碍（目的1）。2)麦克 在PN期间，罗格列酮发挥促炎和促纤维化功能，这有助于肾脏炎症， 瘢痕形成和肾功能下降（目标2）。3)神经营养素NOX 2限制PN期间的细菌传播， 而巨噬细胞NOX 2促进氧化应激和肾损伤（目的3）。拟议的研究将 使用创新的APN临床前小鼠模型，该模型复制了以下肾纤维化的发展： UTI和桥梁的免疫学，微生物学，分子生物学和肾脏学领域的方法。 这项提议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 在PN期间，并将确定可能减轻PN介导的后遗症的新靶点。 在导师的指导下，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，将准备我成功地竞争R 01资金，并启动我的职业生涯， 一位独立的科学家专注于解决UTI治疗中一些最具挑战性的障碍。

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.