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: 10451731
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451731
• 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 anomalies of the kidney; 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（FSGS）是最常见的肾小球病理， 儿童期肾脏疾病的进展和终末期。缺乏非侵入性的， 预测FSGS的诊断、预后和结果的可靠生物标志物。此外，委员会认为， FSGS诊断可能会延迟，因为大多数肾病综合征患者不接受 肾活检直到类固醇治疗失败。循环脂质浓度升高 和细胞内脂质沉积是FSGS中的常见发现。然而，血脂异常是如何 与进展有关的问题仍未解决。我们发现了一个独特的尿脂质代谢物小组， 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）。我们建议将这种磷脂谱作为一种 生物标志物组合是预测FSGS诊断和预后的有力工具， 对治疗反应。本提案的SA-1将进一步验证磷脂和FFA的使用 通过测量患者的基线血清和尿液样品中的这些脂质代谢物， 在FSGS和微小病变疾病（MCD）患者的国家队列中收集 （NEPTUNE）通过靶向脂质分析。入组患者已完成至少5年的 随访我们将评估临床结局（尿蛋白变化）与 排泄和肾功能）和患者生物样品中脂质代谢物的浓度 在海王星入口处获得。我们将研究敏感性，特异性，阳性预测 脂质标志物在FSGS诊断和预后中的价值及阴性预测价值。SA- 本提案的第2部分将研究动物尿LPC和FFA增加的机制 FSGS模型。我们证明了胞浆磷脂酶A2（cPLA 2）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，我们的目标是研究 cPLA 2在Fyn-/-Cd 2ap +/-双基因FSGS小鼠模型细胞损伤和FSGS进展中的作用 cPLA 2基因敲除。在小鼠实验的同时，我们将使用BuffaloMna大鼠， 研究在该自发FSGS模型中cPLA 2表达。我们假设抑制 cPLA 2的表达将减轻FSGS的细胞损伤和进展。 在这项研究计划中，我们的目标是开发一种新的脂质代谢物生物标志物面板， 有助于预测FSGS的诊断和预后。此外，这种新的生物标志物小组 将改善监测治疗反应的方式。血脂作用机制的阐述 介导的损伤将导致FSGS的新治疗方法的开发。我们的首要目标是 通过开发新的诊断和预后方法，改善FSGS患者的护理和预后 脂质生物标志物组，其针对失调的脂质途径。