Integrative Molecular Epidemiology Approach to Identify Nephrotic Syndrome Subgroups

摘要 尽管肾病综合征(NS)患者具有共同的临床症状和体征(蛋白尿， 低蛋白血症、高脂血症和水肿)，预后和反应有很大的不同 治疗，让患者、家属和他们的临床医生感到沮丧。即使在下列组织病理学类别中也是如此 目前的诊断方法(例如微小病变病、局灶节段性肾小球硬化)有 疾病进展和治疗反应的显著差异，突出了潜在的生物学 群体内部的异质性。具有广泛的临床患者纳入标准的小规模研究表明 一部分患者对抗肿瘤坏死因子治疗反应良好，但这些患者的治疗前反应准确 根据常规的临床参数，个体是不可能的。 该项目将利用肾病综合征研究网络(海王星)队列研究，这是一个多中心的研究 600例临床资料丰富的FSGS、MCD和MN患者的前瞻性研究 基因表达谱。这项研究将利用肾组织基因表达数据来识别 肿瘤坏死因子-α途径激活的患者亚组，评估相关的临床结果并确定非 亚群的分子预测因子。目标是： 目的1：确定肾病综合征患者中具有同质性激活的亚群。 肿瘤坏死因子-α转录途径。 目的2：比较分子亚型与传统临床病理分型的异同。 临床结果预测。 目标3：确定非侵入性标记物(如人口学、血液和尿液标记物)、标准 与肿瘤坏死因子-α相关的病理特征和新的病理活检指标 子群。 为了完成这个项目，申请者将接受系统生物学、遗传流行病学的正式培训。 和生物信息学。她将接受一个拥有系统生物学专业知识的多学科团队的指导， 流行病学和生物信息学。长期目标是改善慢性阻塞性肺病患者的临床护理。 通过提高对潜在生物学的理解，识别新的生物标记物和 未来动物模型和机械性介入临床验证的潜在治疗靶点 审判。

ABSTRACT Although patients with Nephrotic Syndrome (NS) present with shared clinical signs and symptoms (proteinuria, hypoalbuminemia, hyperlipidemia and edema), there is dramatic variability in prognosis and response to therapy, frustrating patients, families and their clinicians. Even within the histopathologic categories used in the current diagnostic approach (e.g. minimal change disease, focal segmental glomerulosclerosis), there is dramatic variability in disease progression and response to therapy, highlighting the underlying biological heterogeneity within the groups. Small studies with broad, clinical patient inclusion criteria have demonstrated that a subset of patients respond well to anti-TNF therapy, but accurate pre-treatment response of those individuals is not possible based on routine clinical parameters. This project will leverage the Nephrotic Syndrome Study Network (NEPTUNE) cohort study, a multi-center prospective study of 600 patients with FSGS, MCD and MN with rich clinical data, kidney biopsy tissue and gene expression profiles. This study will leverage the kidney tissue gene expression data to identify a subgroup of patients with TNF-alpha pathway activation, assess associated clinical outcomes and identify non- molecular predictors of the subgroup. The aims are: Aim 1: To identify a subgroup of Nephrotic Syndrome patients with homogeneous activation of the TNF-alpha transcriptional pathway. Aim 2: To compare molecular subgroups with conventional clinical-pathologic classification in clinical outcome prediction. Aim 3: To identify non-invasive markers (e.g. demographics, blood and urine markers), standard pathology features and novel pathologic biopsy descriptors associated with the TNF-alpha subgroup. To accomplish this project, the applicant will pursue formal training in systems biology, genetic epidemiology and bioinformatics. She will be mentored by a multi-disciplinary team with expertise in systems biology, epidemiology and bioinformatics. The long term objective is to improve the clinical care of patients with Nephrotic Syndrome by improved understanding of the underlying biology, identifying novel biomarkers and potential therapeutic targets for future validation in animal models and mechanistic-based interventional clinical trials.