Molecular Stratification of Multiple Sclerosis and Associated Neuro-autoimmune Di

多发性硬化症和相关神经自身免疫性疾病的分子分层

• 批准号: 8165160
• 负责人: Robert C Axtell
• 金额: $ 8.96万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-05 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8165160
• 关键词: Adoptive Transfer; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attenuated; Autoimmune Process; Autoimmunity; Biological; Biological Markers; Blocking Antibodies; Blood; Blood Tests; CD4 Positive T Lymphocytes; Cell Culture Techniques; Cells; Cellular biology; Cerebrospinal Fluid; Clinical Research; Cytokine Network Pathway; Data; Development; Discipline; Disease; Employee Strikes; Ensure; Environment; Event; Experimental Autoimmune Encephalomyelitis; Faculty; Goals; Human; Immune; In Vitro; Inflammation; Inflammatory; Interferon-beta; Interferons; Interleukin-10; Knockout Mice; Link; Longitudinal Studies; Mentors; Molecular; Multiple Sclerosis; Mus; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Publishing; Regulation; Relapsing-Remitting Multiple Sclerosis; Research; Research Institute; Research Personnel; Role; STAT1 gene; STAT4 gene; Science; Serum; Signal Pathway; Signal Transduction; Stratification; Techniques; Therapeutic; Tissues; Training; Transcriptional Regulation; Work; active method; cell type; cohort; cytokine; effective therapy; meetings; mouse model; planetary Atmosphere; research study; response

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.

描述（由申请人提供）：尽管Interferon-2是多发性硬化症的最受欢迎的治疗方法之一，但其作为药物的作用方式仍未完全了解。此外，IFN-2治疗仅是部分有效的，大约30％的MS患者对治疗没有反应。我们最近发表了对IFN-2疗法的反应，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，在非反应者中，IL-17F（Th17细胞因子）的高血清水平高。这项研究的目标是：1。确定IFN-2治疗产生促炎和抗炎作用的机制。这将通过分别在AIM 1和3中描述的MS和人CD4 T细胞培养实验的小鼠模型和人类CD4 T细胞培养实验来实现。 2。鉴定MS血液和脊髓液中的生物标志物，以预测并跟踪对IFN-2治疗的反应性。这将通过在AIM 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谱来实现这一目标。培训：此应用中提出的研究涵盖了广泛的实验技术，需要在自身免疫性，人体免疫细胞生物学，细胞信号调节，转录，转录，转录，实验和疾病组织中的动物模型中的专业知识。因此，将需要在实验技术，统计分析和临床研究组织中进行其他培训。我的导师Steinman博士以及Dunn博士（合作者/顾问）和Racke博士（顾问）是这些领域的专家，将确保满足这些培训需求。环境：斯坦福大学是一家著名的学术研究所，拥有较长的尖端科学记录。斯坦福大学与许多学科的最先进的设施和世界一流的调查员有着高度协作的氛围，其中许多人正在进行与本申请中提出的工作相辅相成的研究。拟议的研究计划，斯坦福大学的培训发展和环境将在很大程度上有利于我过渡到独立教师。 公共卫生相关性：干扰素β是多发性硬化症的最受欢迎的治疗方法。但是，IFN-beta的主要限制是，大约30％的MS患者对治疗没有反应。该提案的主要目的是确定IFN-β疗法的作用方式，并确定可以预测对该治疗反应能力的生物标志物。