Molecular Stratification of Multiple Sclerosis and Associated Neuro-autoimmune Di

项目摘要/摘要： 研究计划：尽管干扰素-β是治疗多发性硬化症最受欢迎的治疗方法之一 对于硬化症，其作为一种药物的作用模式仍不完全清楚。此外，干扰素-β治疗是 只有部分有效，大约30%的多发性硬化症患者对治疗没有反应。我们 最近发表的研究表明，干扰素-β治疗的反应是由TH1和TH17通路决定的。 在多发性硬化症小鼠模型上，我们发现干扰素-β可以减轻TH1诱导的疾病，但 加重TH17疾病。在一小部分多发性硬化症患者中，我们观察到血清中高水平的 IL-17F，一种TH17细胞因子，在治疗开始前无应答者中。这样做的目的是 研究的目的是： 1.确定干扰素-β治疗的促炎和抗炎机制 效果。这将通过使用多发性硬化症和人类CD4T细胞的小鼠模型来完成 培养实验，分别在目标1和3中描述。 2.确定多发性硬化症血液和脊髓液中的生物标志物，以预测和跟踪对 干扰素治疗。这将通过分析患者血液中的细胞因子谱和 在纵向研究中的脊髓液，在目标2中描述。 培训：本申请中提出的研究涵盖了广泛的实验 需要自身免疫动物模型、人类免疫细胞生物学专业知识的技术， 细胞信号、转录调控和疾病组织实验。因此， 还需要在实验技术、统计分析和 组织临床研究。斯坦曼博士，我的导师，还有邓恩博士 (协作者/顾问)和瑞克博士(顾问)是这些领域的专家，并将确保 这些培训需求得到了满足。 环境：斯坦福大学是一家著名的学术研究机构，在 生产尖端科学。斯坦福大学拥有高度合作的氛围， 许多学科的尖端设施和世界级的调查人员，其中许多人正在进行 对本申请中提出的工作进行补充的研究。 拟议的研究计划、培训发展和斯坦福大学的环境将高度 有利于我向独立学院的过渡。

Project Summary/Abstract: Research Plan: Although Interferon-beta is one of the most popular treatments for multiple sclerosis, its mode of action as a drug is still not fully understood. Moreover, IFN-beta therapy is only partially effective and approximately 30% of MS patients do not respond to treatment. We recently published that response to IFN-beta therapy is dictated by TH1 and TH17 pathways. Using mouse models for MS, we found that IFN-beta attenuates TH1 induced disease but exacerbates TH17 disease. In a small cohort of MS patients, we observed high serum levels of IL-17F, a TH17 cytokine, in non-responders prior to the initiation of treatment. The goals of this research are to: 1. Determine the mechanisms by which IFN-beta treatment exerts its pro- and anti- inflammatory effects. This will be accomplished by using mouse models of MS and human CD4 T-cell culturing experiments, described in Aim 1 and 3 respectively. 2. Identify biomarkers in MS blood and spinal fluid that predict and track the responsiveness to IFN-¿ treatment. This will be accomplished by analyzing cytokine profiles in patient's blood and spinal fluid in a longitudinal study, described in Aim 2. Training: The research proposed in this application covers a wide range of experimental techniques requiring expertise in animal models of autoimmunity, human immune cell biology, cell signaling, transcriptional regulation and experimentation with disease tissue. Therefore, additional training will be required in experimental techniques, statistical analysis, and organization of clinical research. Dr. Steinman, my mentor, along with Dr. Dunn (collaborator/consultant), and Dr. Racke (consultant) are experts in these areas and will ensure that these training needs are met. Environment: Stanford is a renowned academic research institute with a long record of producing cutting edge science. Stanford has a highly collaborative atmosphere with state-of- the-art facilities and world class investigators in many disciplines, many of whom are conducting research that is complementary to the work proposed in this application. The proposed research plan, training development and environment at Stanford will be highly conducive for my transition to an independent faculty.