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，以确定从狼疮性肾小球肾炎活检切片分离的肾小球的基因表达谱，总体目标是确定肾小球基因表达表型是否将预测正在进行的父母试验的结果和疗效。家长试验比较了CellCept和静脉注射环磷酰胺开始控制活检证实的狼疮性肾炎的效果。我们已经证明了用微阵列分析技术研究基因表达谱的可行性，这些基因表达谱是通过激光显微切割分离的肾小球冰冻切片来描述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，提示根据基因表达标准对狼疮肾活检进行亚型分类的可行性。表达的基因形成了8个主要的簇，在给定的样本中，组成这些簇的基因的存在或不存在将活组织分为3种不同的类型。支持这项研究的假设是，不同转录表型揭示的分子病理机制的差异将预测狼疮的不同自然病史和治疗结果。拟议的机制研究的第一个目标是对当前试验中进行的诊断肾活检中的肾小球基因表达模式进行分类，并利用它们来扩大对狼疮性肾炎分子发病机制的理解。对通过微阵列评估发现的选定基因进行平行定量聚合酶链式反应，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。第二个目的是将这些簇和途径与传统的病理特征相关联，以确定病理发现的分子基础。第三个目的将决定是否可以通过初始肾活检的基因表达表型来预测试验的特定结果。特别是，我们将首先解决，以细胞凋亡、肿瘤坏死因子信号和纤维化为特征的一种基因表达类型是否与不良结局高度相关，从而预测对环磷酰胺或CellCept无应答的亚群。其次，CellCept是否会被证明在不同的基因表达亚群中有效，这表明它可以作为毒性较低的环磷酰胺的替代品在这些情况下使用。

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.