Integrative Molecular Epidemiology Approach to Identify Nephrotic Syndrome Subgroups

识别肾病综合征亚组的综合分子流行病学方法

• 批准号: 9926246
• 负责人: Laura H Mariani
• 金额: $ 16.96万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926246
• 关键词: Affect; Animal Model; Anti-Tumor Necrosis Factor Therapy; Award; Bioinformatics; Biological; Biology; Biopsy; Blood; Categories; Characteristics; Classification; Clinical; Clinical Course of Disease; Clinical Data; Clinical Trials; Cohort Studies; Complement; Complex; Data; Descriptor; Diagnostic; Disease; Disease Progression; Edema; Epidemiology; Etiology; Expression Profiling; Family; Focal Segmental Glomerulosclerosis; Functional disorder; Future; Gene Expression; Genetic; Genetic Transcription; Genotype; Grant; Heterogeneity; Histologic; Histopathology; Hyperlipidemia; Hypoalbuminemia; Individual; Intervention; Kidney; Kidney Diseases; Kidney Failure; Kidney Glomerulus; Leadership; Machine Learning; Membranous Glomerulonephritis; Mentors; Molecular; Molecular Disease; Molecular Epidemiology; Molecular Profiling; Nephrotic Syndrome; Observational Study; Outcome; Participant; Pathologic; Pathology; Pathway interactions; Patient Care; Patient Selection; Patients; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Prediction of Response to Therapy; Probability; Prospective Studies; Prospective cohort study; Proteins; Proteinuria; Publications; Renal glomerular disease; Research Project Grants; Resources; Signs and Symptoms; Structure; Subgroup; Swelling; Syndrome; Systems Biology; TNF gene; Techniques; Therapeutic immunosuppression; Tissues; Toxic effect; Training; Urine; Validation; Work; base; biological heterogeneity; biological systems; clinical care; clinical epidemiology; clinical practice; cohort; demographics; genetic epidemiology; improved; inclusion criteria; kidney biopsy; member; multidisciplinary; novel; novel marker; outcome forecast; outcome prediction; patient response; patient subsets; predict clinical outcome; response; skills; targeted treatment; therapeutic target; treatment response

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.

摘要 尽管肾病综合征（NS）患者呈现出共同的临床体征和症状（蛋白尿， 低白蛋白血症、高脂血症和水肿），预后和对 治疗，令人沮丧的病人，家庭和他们的临床医生。即使在组织病理学分类中， 目前的诊断方法（例如微小病变疾病、局灶节段性肾小球硬化）， 疾病进展和对治疗的反应的显著变化，突出了潜在的生物学效应。 组内的异质性。具有广泛临床患者入选标准的小型研究已经证明 一部分患者对抗TNF治疗反应良好，但这些患者的准确治疗前反应 根据常规临床参数，个体是不可能的。 该项目将利用肾病综合征研究网络（NEPTUNE）队列研究，一项多中心研究， 对600例FSGS、MCD和MN患者进行的前瞻性研究，具有丰富的临床数据、肾活检组织和 基因表达谱这项研究将利用肾组织基因表达数据，以确定一个 TNF-α通路激活患者亚组，评估相关临床结局，并确定非TNF-α通路激活患者亚组。 亚组的分子预测因子。其目标是： 目的1：确定一个肾病综合征患者的亚组， TNF-α转录途径。 目的2：比较分子亚组与传统的临床病理分类， 临床结果预测。 目的3：确定非侵入性标志物（例如人口统计学、血液和尿液标志物），标准 与TNF-α相关的病理学特征和新的病理活检描述符 亚群 为了完成这个项目，申请人将在系统生物学，遗传流行病学， 和生物信息学。她将接受一个具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。长期目标是改善患者的临床护理， 肾病综合征通过提高对潜在生物学的理解，鉴定新的生物标志物和 未来在动物模型和基于机制的介入临床中验证的潜在治疗靶点 审判