Large Scale Images of Gene Transcription in MS and EAE

MS 和 EAE 中基因转录的大规模图像

• 批准号: 6696306
• 负责人: LAWRENCE STEINMAN
• 金额: $ 35.81万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-15 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696306
• 关键词: T lymphocyte; biological signal transduction; clinical research; disease /disorder model; experimental allergic encephalomyelitis; functional /structural genomics; genetic transcription; high throughput technology; human tissue; laboratory mouse; leukocyte activation /transformation; microarray technology; molecular pathology; multiple sclerosis; myelin basic proteins; osteopontin; protein tyrosine kinase

DESCRIPTION (provided by applicant): EAE has served as a useful model for MS, yet many therapies which succeed in preventing or reversing paralysis in the animal model, do not succeed when applied to MS. However, approved drugs for MS like beta interferon and Copaxone have been successful in both EAE and MS. There are several convenient models of EAE in rodents with both acute and relapsing features along with demyelination. We shall examine transcription profiles in MS lesions using gene microarray technologies, comparing the transcriptional profiles of these lesions from six MS brains. Genes of interest found in microarray analysis will be corroborated with real time PCR RNAse protection, and Western blotting in selective cases. Lesions, where mRNA was isolated, will also be characterized histopathologically and immunohistochemically. We shall continue comparison of active and chronic lesions, where we have already identified key differences in transcription of immunoglobulin genes p38kinase and alpha-1-antichymotrypsin. Profiles from MS brain will be compared to those obtained from the CNS of rodents with relapse, remission, or acute attacks of EAE. We shall also study transcriptional profiles of pathogenic T cell clones that cause EAE, either stimulated with native myelin peptide or altered peptide ligands. APL's have been successful in treating EAE, and have now been taken into phase II trials in MS. Finally we will study the role of osteopontin a gene identified in large scale transcriptional profiling of EAE and MS. We demonstrate that osteopontin is expressed in MS and EAE lesions, and that in animals with the osteopontin gene deleted there is a profound change in the regulation of disease relapses. The discovery of the role of osteopontin, first identified in large scale profiles, exemplifies how this approach may help us to understand MS and to develop new therapies.

描述(由申请人提供)：EAE已成为MS的有用模型， 然而，许多成功预防或逆转脑瘫的治疗方法 动物模型，当应用于MS时不成功，然而，批准了治疗MS的药物 像β干扰素和Copaxone一样，在EAE和MS中都取得了成功。 有几种方便的啮齿动物EAE模型，既有急性的，也有 伴有脱髓鞘的复发特征。我们将检查一下抄本 使用基因芯片技术在多发性硬化症皮损中的分布，比较 来自六个多发性硬化症大脑的这些病变的转录图谱。关注的基因 在微阵列分析中发现的结果将被实时聚合酶链式反应核糖核酸酶证实 保护，以及在特定情况下的Western blotting。损伤，其中的mRNA是 孤立的，也将被描述为组织病理学和 免疫组织化学。我们将继续比较活动性和慢性性 损伤，我们已经确定了转录的关键差异 免疫球蛋白基因p38激酶和α-1-抗凝乳杆菌胰蛋白酶。来自MS的配置文件 大脑将与从复发啮齿动物的中枢神经系统获得的大脑进行比较， 缓解，或EAE的急性发作。我们还将研究转录 引起EAE的致病T细胞克隆的特征 天然髓磷脂多肽或修饰的多肽配体。APL已经成功地在 治疗EAE，现在已经进入第二阶段试验，最后我们 将研究骨桥蛋白的作用，这是一种大规模发现的基因 EAE和MS的转录图谱我们证明骨桥蛋白是 在MS和EAE皮损中表达，在携带骨桥蛋白基因的动物中表达 删除后，对疾病复发的监管发生了深刻变化。这个 首次在大规模剖面中发现骨桥蛋白的作用， 举例说明此方法如何帮助我们理解MS并开发新的 治疗。