Molecular Stratification of Multiple Sclerosis and Associated Neuro-autoimmune Di

描述（由申请人提供）： 虽然干扰素-2是多发性硬化症最受欢迎的治疗方法之一，但其作为药物的作用模式仍不完全清楚。此外，IFN-2治疗仅部分有效，约30%的MS患者对治疗无反应。我们最近发表了对IFN-2治疗的反应由TH1和TH17途径决定。使用MS的小鼠模型，我们发现IFN-2减弱TH1诱导的疾病，但加剧TH17疾病。在MS患者的一个小队列中，我们观察到在开始治疗之前无应答者中IL-17F（一种TH17细胞因子）的高血清水平。本研究的目的是：1.确定IFN-2治疗发挥其促炎和抗炎作用的机制。这将通过使用MS和人CD4 T细胞培养实验的小鼠模型来实现，分别在目的1和3中描述。2.确定MS血液和脊髓液中预测和跟踪IFN-2治疗反应性的生物标志物。这将通过在纵向研究中分析患者血液和脊髓液中的细胞因子谱来实现，如目的2所述。培训内容：本申请中提出的研究涵盖了广泛的实验技术，需要在自身免疫，人类免疫细胞生物学，细胞信号传导，转录调控和疾病组织实验的动物模型的专业知识。因此，需要在实验技术、统计分析和临床研究组织方面进行额外的培训。斯坦曼博士，我的导师，沿着邓恩博士（合作者/顾问），和拉克博士（顾问）是这些领域的专家，并将确保这些培训需求得到满足。环境：斯坦福大学是一个著名的学术研究机构，长期以来一直致力于尖端科学的研究。斯坦福大学拥有高度协作的氛围，拥有最先进的设施和许多学科的世界级研究人员，其中许多人正在进行与本申请中提出的工作互补的研究。斯坦福大学提出的研究计划、培训发展和环境将非常有利于我向独立教师的过渡。 公共卫生相关性： β干扰素是多发性硬化症最常用的治疗方法。然而，IFN-β的一个主要限制是大约30%的MS患者对治疗没有反应。该提案的主要目标是确定IFN-β治疗的作用模式，并确定可以预测对该治疗反应性的生物标志物。

DESCRIPTION (provided by applicant): Although Interferon-2 is one of the most popular treatments for multiple sclerosis, its mode of action as a drug is still not fully understood. Moreover, IFN-2 therapy is only partially effective and approximately 30% of MS patients do not respond to treatment. We recently published that response to IFN-2 therapy is dictated by TH1 and TH17 pathways. Using mouse models for MS, we found that IFN-2 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-2 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-2 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. PUBLIC HEALTH RELEVANCE: Interferon-beta is the most popular treatment for multiple sclerosis. However, a major limitation with IFN-beta is that approximately 30% of MS patients do not respond to treatment. The major goal of this proposal is to determine the mode of action of IFN-beta therapy and identify biomarkers that can predict responsiveness to this treatment.