Study A: Biopsy Cohort

摘要 NEPTUNE研究招募了750名原发性肾小球疾病患者，并对其进行了前瞻性特征分析。 使用基于全面肾活检组织的分析管道，这些信息的整合 在NEPTUNE知识网络（NKN）中， 以期对肾病综合征（NS）的诊断、预后和治疗提供更准确的依据。目标 这项更新建议的目的是确定深表型NEPTUNE参与者的亚群， 共享分子机制，并将其与目前临床前或临床中的分子靶向治疗联系起来 发展为NS。为此，我们建议招募375例偶发或流行NS患者， 肾活检（活检队列），组织学诊断为微小病变（MCD），局灶性 节段性肾小球硬化（FSGS）和膜性肾病（MN）。尽管临床症状相同， 同一疾病类别中的个体患者在疾病进展速率方面表现出显著的变异性， 对治疗的反应。我们将从过去9年的重点扩大到我们队列的临床试验准备 通过利用跨基因型-表型连续体的多个数据集，参与者和整个领域。 合并的NEPTUNE队列将使我们能够实现以下目标：（a）定义NS患者 使用分子信息结合可量化的组织学方法， 参数、环境暴露和离散的临床特征;（B）将这些功能定义的 具有前瞻性确定的临床结局的亚组，并从 多层数据集;以及（c）在每个个体参与者中识别分子途径的激活状态 在早期临床试验中有针对性地在真实的时间内实施精准医学方法：正确的治疗 在正确的时间为正确的患者进行试验。NEPTUNE活检队列研究将作为全面的 知识网络，以进一步发展疾病进展和治疗的综合生物学方法 响应预测NS分子板临床研究（MNB，参见本申请的研究3）将 与NS的主要干预性试验密切合作，测试这些概念。

ABSTRACT The NEPTUNE study has recruited and prospectively characterized 750 participants with primary glomerular diseases using a comprehensive renal biopsy tissue based analysis pipeline. The integration of this information in the NEPTUNE Knowledge Network (NKN) allowed significant progress by the glomerular disease community towards more precise diagnosis, prognosis and management of patients with nephrotic syndrome (NS). The goal of this renewal proposal is to identify subpopulations of the deeply phenotyped NEPTUNE participants with shared molecular mechanisms and link them to molecular targeted therapies currently in preclinical or clinical development for NS. For this goal, we propose to recruit 375 incident or prevalent NS patients undergoing a renal biopsy (Biopsy Cohort) with the histological diagnoses of Minimal Change Disease (MCD), Focal Segmental Glomerulosclerosis (FSGS) and Membranous Nephropathy (MN). Despite shared clinical symptoms, individual patients in the same disease category manifest marked variability in rates of disease progression and response to therapy. We will expand the focus from the past 9 years towards clinical trial readiness of our cohort participants and the field at large by leveraging the multiple datasets across the genotype-phenotype continuum. The combined NEPTUNE cohorts will enable us to accomplish the following goals: (a) to define NS patient subpopulations in functional terms using molecular information in combination with quantifiable histological parameters, environmental exposures and discrete clinical features; (b) to link these functionally defined subgroups with the prospectively ascertained clinical outcomes and define novel predictors of outcome from the multi-layered datasets; and (c) to identify in each individual participant the activation state of molecular pathways targeted in early stage clinical trials to implement, in real time, a precision medicine approach: the right treatment trial for the right patient at the right time. The NEPTUNE Biopsy Cohort study will serve as the comprehensive knowledge network to further develop the integrated biology approach on disease progression and treatment response prediction. The NS molecular board clinical research study (MNB, see study 3 of this application) will test these concepts in close collaboration with leading interventional trials in NS.