Molecular Stratification of Multiple Sclerosis and Associated Neuro-autoimmune Di

描述(申请人提供)：尽管干扰素-2是多发性硬化症最常用的治疗方法之一，但其作为药物的作用模式仍不完全清楚。此外，干扰素-2治疗只有部分有效，大约30%的多发性硬化症患者对治疗没有反应。我们最近发表了对干扰素-2治疗的反应是由TH1和TH17通路决定的。在MS小鼠模型上，我们发现干扰素-2减轻了TH1诱导的疾病，但加剧了TH17疾病。在一小部分MS患者中，我们观察到在开始治疗之前，无反应者的血清IL-17F水平较高，这是一种TH17细胞因子。本研究的目的是：1.确定干扰素-2发挥促炎和抗炎作用的机制。这将通过分别在目标1和3中描述的多发性硬化症和人类CD4T细胞培养实验的小鼠模型来实现。2.确定多发性硬化症血液和脊髓液中预测和跟踪干扰素-2治疗应答的生物标志物。这将通过在目标2中描述的纵向研究中分析患者血液和脊髓液中的细胞因子图谱来实现。培训：本申请中提出的研究涵盖广泛的实验技术，需要具备自身免疫动物模型、人类免疫细胞生物学、细胞信号、转录调节和疾病组织实验方面的专业知识。因此，需要在实验技术、统计分析和临床研究的组织方面进行额外的培训。我的导师斯坦曼博士、邓恩博士(合作者/顾问)和瑞克博士(顾问)都是这些领域的专家，他们将确保这些培训需求得到满足。环境：斯坦福大学是一家著名的学术研究机构，在生产尖端科学方面有着长期的记录。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调查人员，他们中的许多人正在进行研究，以补充本申请中提出的工作。斯坦福大学拟议的研究计划、培训发展和环境将非常有利于我过渡到独立的教职员工。 公共卫生相关性：干扰素-β是多发性硬化症最受欢迎的治疗方法。然而，干扰素-β的主要限制是大约30%的多发性硬化症患者对治疗没有反应。这项建议的主要目标是确定干扰素-β治疗的作用模式，并确定可以预测该治疗应答的生物标志物。

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.