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: 6621627
• 负责人: LAWRENCE STEINMAN
• 金额: $ 34.86万
• 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 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6621627
• 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已用作MS的有用模型， 然而，许多成功预防或逆转瘫痪的疗法 动物模型，不成功时，适用于MS。然而，批准的药物MS 像β干扰素和克帕松在EAE和MS中都取得了成功。 啮齿动物中有几种方便的EAE模型，包括急性和急性 沿着脱髓鞘的复发特征。我们将检查转录 使用基因微阵列技术在MS病变中的分布，比较 这些病变的转录谱来自六个MS脑。感兴趣的基因 将用真实的时间PCR RNA酶证实微阵列分析中发现的 保护，并在选择性的情况下进行Western印迹。病变，mRNA 分离的，也将进行组织病理学表征， 化学上。我们将继续比较活动和慢性 病变，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-抗胰凝乳蛋白酶。MS图谱 将脑与从复发啮齿动物的CNS获得的那些进行比较， 缓解或EAE急性发作。我们还将研究转录 导致EAE的致病性T细胞克隆的概况，或者用 天然髓磷脂肽或改变的肽配体。APL已经成功地在 治疗EAE，现在已经进入MS的II期试验。最后， 将研究骨桥蛋白的作用， EAE和MS的转录谱。我们证明，骨桥蛋白是 在MS和EAE病变中表达，以及在具有骨桥蛋白基因的动物中表达 在疾病复发的调节中有一个深刻的变化。的 骨桥蛋白的作用的发现，首先在大规模分布中被鉴定， 阐明了这种方法如何帮助我们了解MS并开发新的 治疗