Gene Expression Profiles in Osteoarthritis Clinical Variants

描述(由申请人提供)：广泛的目标是学习更多的生物信息学和建立关于骨关节炎(OA)遗传学的合作，并学习和应用实用的方法来评估遗传序列变异是否可能作为疾病基因。这一休假符合NIAMS的任务，因为它将培训一名临床科学家调查关节炎的原因。休假符合基因及其功能研究定义的基因组学领域。我将通过统计遗传学和流行病学的短期课程来更新我的遗传流行病学知识，通过牛津短期课程来熟悉生物信息学，并从牛津人类遗传学和分子医学的研讨会和讨论中学习。该休假项目将通过检验这样一种假设提供实践经验，即骨性关节炎临床变种的基因表达不同于不同的遗传倾向。接受临床指征的关节置换手术的骨性关节炎受试者将被归类为临床变异。将获得手术标本和外周血液，并用于纯化RNA。正常的软骨样本将从种族和人口统计学上相似的来源获得，主要是身体标本。等位基因表达的不平衡将被测量为特定的骨关节炎相关基因，并分析与不同的致病机制相一致的独特差异。比较的方式--骨关节炎变异和正常之间的mRNA不同--将提取与骨关节炎临床变异相关的子集。该项目的成果将包括对要教授的应用程序、有价值的试剂、要发表的结果以及合作项目的新想法的实际掌握；休假经验将为基因研究产生新的概念和技术方法，我可以使用这些方法并将其教授给初级研究人员。骨性关节炎是最常见、最昂贵、最致残性的关节炎。目前还没有药物阻止或改变骨关节炎的进展--部分原因是没有有意义的工具来解决其异质性。有了将骨关节炎分成更同质的亚组的方法，例如通过基因活动模式，我们可以设计更强大和更有成果的未来研究，以发现疾病基因，预测骨关节炎的风险、结果或治疗反应，并研究潜在的疾病修改干预措施，如细胞因子阻滞剂、软骨修复激动剂或其他措施。

DESCRIPTION (provided by applicant): The broad objectives are to learn more about bioinformatics and establish collaborations about osteoarthritis (OA) genetics, and to learn and apply practical approaches to assess whether genetic sequence variants may act as disease genes. The sabbatical fits the NIAMS mission because it will train a clinical scientist to investigate causes of arthritis. The sabbatical fits within the area of genomics as defined by study of genes and their functions. I will refresh my knowledge in genetic epidemiology through short courses in statistical genetics and epidemiology, gain bioinformatics familiarity through Oxford short courses, and learn from Oxford human genetics and molecular medicine seminars and discussions. The sabbatical project will provide practical experience through testing the hypothesis that OA clinical variants differ in gene expression stemming from distinctive genetic predispositions. OA subjects undergoing clinically indicated arthroplasty procedures will be classified as to clinical variant. Surgical specimens and peripheral blood will be obtained and used to purify RNA. Normal cartilage samples will be procured from ethnically and demographically similar sources, largely cadaveric. Imbalance in allele expression will be measured for specific OA-associated genes and analyzed for distinctive differences consistent with separate pathogenetic mechanisms. The manner of comparison-mRNAs differing between OA variants and from normals-will pull out the subsets relevant to osteoarthritis clinical variation. The project's outcomes will include a practical grasp of applications to teach, valuable reagents, results to publish, and new ideas for collaborative projects; the sabbatical experience will generate new conceptual and technical approaches for genetic studies that I can use and teach to junior investigators. Osteoarthritis is the most common, costly, and disabling form of arthritis. No current medicine blocks or modifies osteoarthritis progression-this is partly because no meaningful tools exist to resolve its heterogeneity. With methods to separate osteoarthritis into more homogeneous subgroups, such as with gene activity patterns, we can design more powerful and fruitful future studies to find disease genes, to predict osteoarthritis risk, outcomes, or response to therapy, and to investigate potentially disease-modifying interventions like cytokine blockers, cartilage repair agonists, or other measures.