Urinary Lipidomic profile in FSGS: A novel biomarker

FSGS 中的尿脂质组学特征：一种新型生物标志物

• 批准号: 10218880
• 负责人: Elif Erkan
• 金额: $ 7.95万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218880
• 关键词: Adolescent; American; Animal Model; Apoptosis; Area Under Curve; Biochemical; Biological Assay; Biological Markers; Biopsy; Cardiovascular system; Child; Childhood; Chronic Kidney Failure; Clinical; Clinical Trials; Cognitive; Creatinine; Cytosolic Phospholipase A2; Data; Deposition; Development; Diagnosis; Dialysis procedure; Disease; Disease Progression; End stage renal failure; Enrollment; Enzymes; Epithelial Cells; Excretory function; Failure; Focal Segmental Glomerulosclerosis; Future; Generations; Genes; Genetic Transcription; Glomerular Filtration Rate; Goals; Growth; Histopathology; Human; Inflammation; Injury; Kidney; Kidney Diseases; Kidney Transplantation; Knock-out; Knowledge; Laboratories; Link; Lipids; Lysophosphatidylcholines; Lysophospholipids; Maintenance; Measures; Mediating; Membrane; Methods; Mitochondria; Modeling; Monitor; Mus; Nature; Nephrology; Nephrotic Syndrome; Nonesterified Fatty Acids; Outcome; Oxidative Stress; Pathology; Pathway interactions; Patient Care; Patients; Phospholipase A2; Phospholipids; Plasma; Predictive Value; Production; Prognosis; Proteins; Proteinuria; Quality of life; ROC Curve; Rattus; Recurrence; Refractory; Registries; Renal function; Reporting; Research Proposals; Risk; Role; Sampling; Sensitivity and Specificity; Serum; Steroid therapy; Testing; Tissues; Toxic effect; Translating; Tubular formation; Urinary tract; Urine; base; biomarker panel; care outcomes; cell injury; cohort; comorbidity; congenital anomaly; cooperative study; early detection biomarkers; experimental study; follow-up; human disease; improved; kidney biopsy; lipid metabolism; lipidomics; molecular targeted therapies; mortality; mouse model; novel; novel diagnostics; novel marker; novel therapeutics; outcome prediction; oxidative damage; patient population; pediatric patients; podocyte; predictive marker; prognostic; tool; treatment response; treatment strategy; urinary

Focal segmental glomerulosclerosis (FSGS) is the most common glomerular pathology that leads to progression and end-stage kidney disease during childhood. There is a lack of non-invasive, reliable biomarkers that predict the diagnosis, prognosis and outcome of FSGS. Furthermore, FSGS diagnosis can be delayed as most of the patients with nephrotic syndrome do not undergo kidney biopsies until they have failed steroid therapy. Increased concentrations of circulating lipids and intracellular lipid deposits is a common finding in FSGS. However how lipid anomalies are linked to progression remains unsolved. We discovered a distinct urinary lipid metabolite panel in FSGS that predicted the diagnosis and prognosis of FSGS by untargeted lipidomics analysis. Patients with FSGS displayed increased urinary concentrations of lysophosphotidycholine (LPC) and free fatty acids (FFA). We propose that implementation of this phospholipid profile as a biomarker panel is a powerful tool in prediction of diagnosis and prognosis of FSGS and to monitor response to treatment. SA-1 of this proposal will further validate the use of phospholipid and FFA panel by measuring these lipid metabolites in baseline serum and urine samples of patients collected in a national cohort of patients with FSGS and minimal change disease (MCD) (NEPTUNE) by targeted lipid analysis. The enrolled patients have completed at least 5 years of follow-up. We will assess the correlation between clinical outcomes (change in urine protein excretion and kidney function) and concentrations of the lipid metabolites in patient biosamples obtained at the entry to NEPTUNE. We will investigate sensitivity, specificity, positive predictive value, and negative predictive value of lipid biomarkers in diagnosis and prognosis of FSGS. SA- 2 of this proposal, will examine the mechanism of increased urinary LPC and FFA in an animal model of FSGS. We demonstrated increased activation of cytosolic phospholipase A2 (cPLA2) enzyme that breaks down membrane phosphotidylcholines to LPC and FFA in podocytes and tubular epithelial cells in a mouse model of FSGS. In SA-2 our goal is to investigate the role of cPLA2 in cellular injury and progression of FSGS in Fyn–/–Cd2ap+/– bigenic FSGS mouse model with cPLA2 gene knock-out. In parallel with mouse experiments, we will use BuffaloMna rats to investigate cPLA2 expression in this spontaneous FSGS model. We hypothesize that inhibition of cPLA2 will alleviate cellular injury and progression in FSGS. In this research proposal our goal is to develop a novel lipid metabolite biomarker panel that will aid in prediction of diagnosis and prognosis of FSGS. Furthermore, this novel biomarker panel will improve the way treatment response is monitored. Delineation of the mechanism of lipid mediated injury will lead to development of novel treatments in FSGS. Our overarching goal is to improve the care and outcome of FSGS patients by developing novel diagnostic and prognostic lipid biomarker panel that is directed to dysregulated lipid pathways.

局灶节段性肾小球硬化症 (FSGS) 是最常见的肾小球病理，可导致 儿童期肾病的进展和终末期肾病。缺乏非侵入性、 预测 FSGS 诊断、预后和结果的可靠生物标志物。此外， 由于大多数肾病综合征患者没有接受 FSGS 诊断，因此可能会延迟诊断 肾活检直至类固醇治疗失败。循环脂质浓度增加 细胞内脂质沉积是 FSGS 的常见发现。然而，脂质异常是如何发生的？ 与进展有关的问题仍未解决。我们发现了一种独特的尿脂质代谢组 FSGS 通过非靶向脂质组学分析预测 FSGS 的诊断和预后。 FSGS 患者尿中溶血磷脂酰胆碱 (LPC) 浓度升高 和游离脂肪酸（FFA）。我们建议将此磷脂谱的实施作为 生物标志物组合是预测 FSGS 诊断和预后以及监测的强大工具 对治疗的反应。该提案的SA-1将进一步验证磷脂和FFA的使用 通过测量患者基线血清和尿液样本中的这些脂质代谢物来进行小组 收集于全国 FSGS 和微小病变病 (MCD) 患者队列 (NEPTUNE) 通过靶向脂质分析。入组患者已完成至少 5 年的治疗 后续行动。我们将评估临床结果（尿蛋白变化）之间的相关性 排泄和肾功能）以及患者生物样本中脂质代谢物的浓度 在进入海王星时获得。我们将研究敏感性、特异性、阳性预测 脂质生物标志物在 FSGS 诊断和预后中的价值和阴性预测价值。萨- 该提案的第 2 条将研究动物尿液中 LPC 和 FFA 增加的机制 FSGS 模型。我们证明了胞质磷脂酶 A2 (cPLA2) 的激活增加 在足细胞中将膜磷脂酰胆碱分解为 LPC 和 FFA 的酶 FSGS 小鼠模型中的肾小管上皮细胞。在 SA-2 中，我们的目标是调查 cPLA2 在 Fyn–/–Cd2ap+/– 双基因 FSGS 小鼠模型中细胞损伤和 FSGS 进展中的作用 cPLA2 基因敲除。与小鼠实验并行，我们将使用 BuffaloMna 大鼠 研究自发 FSGS 模型中的 cPLA2 表达。我们假设抑制 cPLA2 将减轻 FSGS 的细胞损伤和进展。 在这项研究提案中，我们的目标是开发一种新型脂质代谢生物标志物组，它将 帮助预测 FSGS 的诊断和预后。此外，这种新型生物标志物组 将改善监测治疗反应的方式。脂质机制的描述 介导的损伤将导致 FSGS 新型治疗方法的开发。我们的总体目标是 通过开发新的诊断和预后来改善 FSGS 患者的护理和结果 针对脂质通路失调的脂质生物标志物组。