Leukocyte Gene Expression in Osteoarthritis

描述（由申请人提供）：本授权申请的目的是使用基因组技术来鉴定外周血白细胞（PBL）表达的一组新的生物标志物，这些生物标志物将在临床上用于鉴定胫股膝关节骨关节炎（OA）患者，并鉴定有疾病进展风险的患者。在过去一年中，由OA生物标志物网络资助的初步数据表明，来自OA患者亚组的PBL表现出“细胞因子激活特征”，表明白细胞在疾病关节组织灌注过程中暴露于刺激物。为了追求这些发现，该基金将有三个中心目标：在具体目标1中，我们将确定PBL基因表达模式是否区分早期OA（OA-E，K-L 2级），晚期OA（OA-A，K-L 3级）和健康对照，如半屈曲，透视定位膝关节X线片所定义的。对于这3个队列，将分析PBL基因表达谱的总体和成对比较，以确定区分以下情况的独特谱：1）OA与正常，2）早期与晚期OA。我们将与Virginia Kraus博士合作，在一个独立的人群（杜克膝关节OA队列）中验证膝关节OA的PBL基因表达谱。在具体目标2中，我们将研究PBL基因表达谱与MRI和骨显像结果的相关性。我们将使用临床3.0 T MRI系统对NYU-HJD的180名患者进行MRI研究，这些患者将进入一项为期两年的纵向队列研究。我们将对关节软骨完整性、软骨下骨髓病变、滑膜炎/积液、边缘骨赘进行半定量分析，评估整体和个体间室评分。与Kraus博士合作，我们还研究了PBL基因表达谱与信号膝关节“滑膜炎”和“全身OA负荷”的相关性，分别通过早期和晚期半定量骨密度图进行定义。我们将开发一个OA放射学分期的多变量模型，以确定PBL基因表达谱与其他风险因素（包括BMI、COMP、骨密度和内翻/外翻畸形）的独立相关性。特定目标3将是一项为期2年的纵向研究，以确定特定PBL基因表达模式是否可预测OA疾病进展。我们将评估通过MRI和半定量膝关节X线片确定的进展和未进展的OA患者。将在0和24个月时进行影像学评价。除MRI和X线检查外，每例受试者还将接受：i）临床评价，包括BMI测定，ii）疼痛和功能评估（完整WOMAC），iii）血清COMP。此外，将采集血清、血浆和尿液用于未来的生物标志物测定。 我们预期这些研究将增强我们对OA发病机制的理解，并提供一种可预测OA疾病进展的组合生物标志物。

DESCRIPTION (provided by applicant): The objective of this grant application is to use genomic technology to identify a novel cluster of biomarkers expressed by peripheral blood leukocytes (PBL) that will be clinically useful in the identification of patients with tibio-femoral knee osteoarthritis (OA), and to identify those patients at risk for disease progression. Preliminary data, funded for the past year under the OA Biomarkers Network, indicates that PBL derived from a subset OA patients exhibit a "cytokine activation profile", suggesting leukocyte exposure to stimuli during the course of perfusion of diseases joint tissues. To pursue these findings, the grant will have three central aims: In Specific Aim 1 we will determine whether PBL gene expression patterns distinguish early OA (OA-E, K-L grade 2), advanced OA (OA-A, K-L grade 3) and healthy controls as defined by semi-flexed, fluoroscopically-positioned knee radiographs. For these 3 cohorts, overall and pairwise comparisons of PBL gene expression profiles will be analyzed in order to identify a distinctive profile which discriminates the following: 1) OA versus normal, and 2) early versus advanced stage OA. We will validate PBL gene expression profiles of knee OA in an independent population, the Duke knee OA cohort, in collaboration with Dr. Virginia Kraus. In Specific Aim 2 we will examine the association of PBL gene expression profiles with findings on MRI and bone scintigraphy. We will perform MRI studies using a clinical 3.0 T MRI system on 180 patients at NYU-HJD, who will be entered into a two year longitudinal cohort study. We will perform semiquantitative analyses of articular cartilage integrity, subchondral marrow lesions, synovitis/effusion, marginal osteophytes, assessing both global and individual compartment scores. In collaboration with Dr. Kraus we also examine the association of PBL gene expression profiles with signal knee "synovitis" and with "total body OA burden", as defined by early and late phase semi-quantitative bone scintigraphy, respectively. We will develop a multivariate model of OA radiographic stage to determine the independent associations of PBL gene expression profiles with other risk factors including BMI, COMP, bone scintigraphy and varus/valgus deformities. Specific Aim 3 will be a 2 year longitudinal to determine whether specific PBL gene expression patterns predict OA disease progression. We will assess OA patients with progression and without progression as determined by both MRI and semi-quantitative knee radiography. Imaging evaluations will occur at 0 and 24 months. In addition to MRI and x-ray, each subject will undergo: i) clinical evaluation including BMI determination, ii) pain and function assessment (complete WOMAC), iii) serum COMP. In addition, serum, plasma and urine will be collected for future biomarker determinations. We anticipate that these studies will enhance our understanding of the pathogenesis of OA and provide a combinatorial biomarker that may predict OA disease progression.