Prediction of Lupus Outcome by Gene Expression Patterns

描述（由申请人提供）：寻求对进行机制研究的支持，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，其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母试验的结果和疗效。母试验比较了头孢噻肟与环磷酰胺静脉给药对经活检证实的狼疮性肾炎的控制作用。我们已经证明了通过激光显微切割从冰冻活检切片中分离的肾小球中的微阵列分析研究基因表达谱的可行性，其特征在于导致狼疮性肾炎的分子病理机制。这项工作揭示了相当大的异质性基因表达模式的样本分类为增生性肾小球肾炎，表明狼疮肾活检子分类的基因表达标准的可行性。表达的基因形成8个主要簇，并且在给定样品中包含这些簇的基因的存在或不存在将活检分成3种不同类型。提出的研究的假设是，不同的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史和治疗结果。提出的机制研究的第一个目的是在目前的试验中进行的诊断性肾活检中聚集肾小球基因表达模式，并使用它们来扩展对狼疮性肾小球炎分子发病机制中所涉及的途径的理解。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，并确定其差异表达是否可用作替代物。第二个目标将相关的集群和途径与传统的病理特征，以确定病理结果的分子基础。第三个目标将确定是否可以通过最初肾活检的基因表达表型预测试验的特定结果。特别是，我们将解决，第一，是否一个基因表达类型，其特征在于细胞凋亡，TNF信号和纤维化，是高度相关的不良结果，从而预测的亚组的非响应者环磷酰胺或头孢菌素。第二，CellCept是否将被证明在不同的基因表达亚群中有效，这表明它可以在这些情况下用作环磷酰胺的毒性较低的替代品。

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.