Study A: Biopsy Cohort

摘要 海王星研究招募了750名患有原发性肾小球的参与者，并对其进行了前瞻性研究 疾病使用全面的肾活检组织分析流水线。这些信息的整合 在海王星知识网络(NKN)中，肾小球疾病社区取得了重大进展 为肾病综合征(NS)患者更准确的诊断、预后和治疗提供参考。目标是 这项更新建议的目的是确定深表型海王星参与者的亚群 共享的分子机制，并将它们与目前处于临床前或临床阶段的分子靶向治疗联系起来 为NS开发。为了实现这一目标，我们建议招募375名正在接受 肾活检(活检队列)与微小病变(MCD)的组织学诊断，病灶 节段性肾小球硬化(FSGS)和膜性肾病(MN)。尽管有共同的临床症状， 同一疾病类别中的个别患者在疾病进展速度和 对治疗的反应。我们将把重点从过去的9年扩大到我们队列的临床试验准备 通过利用基因-表型连续体上的多个数据集，参与者和整个领域。 合并的海王星队列将使我们能够实现以下目标：(A)定义NS患者 结合分子信息和可量化组织学的功能亚群 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果并定义新的预后预测因子的亚组 多层数据集；以及(C)在每个个体参与者中识别分子通路的激活状态 在早期临床试验中有针对性地实时实施精准医学方法：正确的治疗 在正确的时间为正确的病人进行试验。海王星活检队列研究将作为全面的 进一步发展疾病进展和治疗的综合生物学方法的知识网络 响应预测。NS分子板临床研究研究(MNB，见本申请的研究3)将 与领先的NS介入试验密切合作，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.