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已成为MS的有用模型 然而，许多疗法成功地预防或逆转了瘫痪 动物模型，应用于MS时不会成功。但是，获得了MS的批准药物 像Beta Interferon和Copaxone一样，在EAE和MS中都成功了。 啮齿动物中有几种方便的EAE型号，急性和 复发功能以及脱髓鞘。我们将检查转录 使用基因微阵列技术中MS病变中的曲线，比较 来自六个MS大脑的这些病变的转录谱。感兴趣的基因 在微阵列分析中发现的实时PCR RNase将得到证实 在选择性情况下进行保护和蛋白质印迹。病变，mRNA在那里 孤立的，也将在组织病理学和 免疫组织化学。我们将继续比较活跃和慢性 病变，我们已经确定了转录的关键差异 免疫球蛋白基因p38kinase和alpha-1-抗胰蛋白酶蛋白酶。来自MS的配置文件 将大脑与从啮齿动物中枢神经系统中获得的大脑相比，复发， 缓解或EAE的急性攻击。我们还将研究转录 引起EAE的致病性T细胞克隆的轮廓，要么被刺激 天然髓磷脂肽或肽配体改变。 APL已经成功 治疗EAE，现在已进入MS中的II期试验。最后我们 将研究大规模鉴定的骨桥蛋白A基因的作用 EAE和MS的转录分析。我们证明骨桥是 在MS和EAE病变中表达，并在具有骨桥基因的动物中表达 删除的疾病复发的调节有很大的变化。这 发现骨桥蛋白的作用，首先在大规模剖面中鉴定出来， 体现了这种方法如何帮助我们理解MS并开发新的方法 疗法。