Prediction of Lupus Outcome by Gene Expression Patterns

描述（由申请人提供）：寻求支持进行机制研究，以确定狼疮肾小球肾炎活检切片中分离的肾小球的基因表达谱，其总体目标是确定肾小球基因表达表型是否可以预测正在进行的亲本试验的结果和疗效。本母试验比较了CellCept与IV环磷酰胺对活检证实的狼疮性肾炎的初始控制。我们已经证明了通过激光显微解剖从冷冻活检切片中分离的肾小球通过微阵列分析研究基因表达谱的可行性，以表征导致狼疮性肾炎的分子病理机制。这项工作揭示了在被归类为增殖性肾小球肾炎的样本中基因表达模式的相当大的异质性，提示通过基因表达标准进行狼疮肾活检亚分类的可行性。表达的基因形成了8个主要的簇，在一个给定的样本中包含这些簇的基因的存在或缺失将活组织检查分为3种不同的类型。提出的研究的假设是，不同转录表型揭示的分子病理机制的差异将预测狼疮的异质性自然历史和治疗结果。提出的机制研究的第一个目的是在当前试验中进行的诊断性肾活检中聚集肾小球基因表达模式，并利用它们来扩展对狼疮肾小球炎分子发病机制中涉及的途径的理解。将对通过微阵列评估发现的选定基因进行平行定量PCR，以验证发现的模式，并确定它们的差异表达是否可以用作替代。第二个目的是将集群和途径与常规病理特征联系起来，以确定病理发现的分子基础。第三个目的是确定试验的特定结果是否可以通过初始肾活检的基因表达表型来预测。特别是，我们将首先讨论以细胞凋亡、TNF信号和纤维化为特征的一种基因表达类型是否与预后不良高度相关，从而预测对环磷酰胺或CellCept无反应的亚群。其次，CellCept是否会在不同的基因表达亚群中被证明是有效的，这表明它可以作为环磷酰胺的毒性更小的替代品用于这些病例。

DESCRIPTION (provided by applicant): Support is sought for performing mechanistic studies to define the gene expression profiles of glomeruli isolated from biopsy sections of lupus glomerulonephritis with the overall goals of determining whether the glomerular gene expression phenotype will predict outcome and efficacy in an ongoing parent trial. The parent trial compares administration of CellCept versus IV Cytoxan for initiating control of biopsy-proven lupus nephritis. We have demonstrated the feasibility of studying gene expression profiles by microarray analysis in glomeruli isolated from frozen biopsy sections by laser microdissection t6 characterize the molecular pathologic mechanisms leading to lupus nephritis. This work revealed considerable heterogeneity in gene expression patterns in samples classified as proliferative glomerulonephritis, suggesting the feasibility of lupus renal biopsy subclassification by gene expression criteria. The expressed genes formed 8 main clusters and the presence or absence of genes comprising these clusters in a given sample divided the biopsies into 3 distinct types. The hypothesis underlying the proposed studies is that differences in molecular pathologic mechanisms revealed by the various transcriptional phenotypes will predict the heterogeneous natural history and therapeutic outcome of lupus. The first aim of the proposed mechanistic studies is to cluster glomerular gene expression patterns in diagnostic renal biopsies performed in the current trial and use them to extend understanding of pathways involved in the molecular pathogenesis of lupus glomerulitis. Parallel quantitative PCR for selected genes found through the microarray assessment will be performed to validate the patterns found and determine if their differential expression can be used as a surrogate. The second aim will correlate the clusters and pathways with conventional pathologic features to identify the molecular basis of the pathologic findings. The third aim will determine whether particular outcomes of the trial could be predicted by the gene expression phenotype of the initial renal biopsy. In particular we will address, first, whether one gene expression type, characterized by apoptosis, TNF signaling and fibrosis, is highly correlated with poor outcome and thus predict the subset of non-responders to Cytoxan or CellCept. Second, whether CellCept will prove to be efficacious in a different gene expression subset, suggesting it could be used in these cases as a less toxic alternative to Cytoxan.