Gravitational Regulation of Osteoblast Genomics and Metabolism

项目概要/摘要： 研究计划：虽然干扰素-β是最受欢迎的治疗多发性骨髓瘤的方法之一， 硬化症，其作为药物的作用模式仍然没有完全了解。此外，IFN-γ治疗是 只有部分有效，大约30%的MS患者对治疗没有反应。我们 最近发表的研究表明，对IFN-γ治疗的反应由TH 1和TH 17途径决定。 使用MS小鼠模型，我们发现IFN-γ减弱了TH 1诱导的疾病， 使TH 17疾病恶化。在一小群MS患者中，我们观察到高水平的 IL-17 F，一种TH 17细胞因子，在治疗开始前的无应答者中。这个的目标 研究的目的是： 1.确定IFN-γ治疗发挥其促炎和抗炎作用的机制 方面的影响.这将通过使用MS和人CD 4 T细胞的小鼠模型来实现。 培养实验，分别在目标1和3中描述。 2.确定MS血液和脊髓液中的生物标志物，以预测和跟踪对 IFN-γ治疗。这将通过分析患者血液中的细胞因子谱来实现， 脊髓液中的纵向研究，如目标2所述。 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， 细胞信号传导、转录调节和疾病组织实验。因此，我们认为， 需要在实验技术、统计分析和 组织临床研究。斯坦曼医生，我的导师，沿着邓恩医生 （合作者/顾问）和Racke博士（顾问）是这些领域的专家，将确保 这些培训需求得到满足。 环境：斯坦福大学是一所著名的学术研究机构， 产生尖端科学。斯坦福大学有一个高度合作的氛围， 先进的设施和世界一流的调查人员在许多学科，其中许多人正在进行 这是补充本申请中提出的工作的研究。 拟议的研究计划，培训发展和环境在斯坦福大学将高度 有助于我向独立学院的过渡

Project Summary/Abstract: Research Plan: Although Interferon-� is one of the most popular treatments for multiple sclerosis, its mode of action as a drug is still not fully understood. Moreover, IFN-� therapy is only partially effective and approximately 30% of MS patients do not respond to treatment. We recently published that response to IFN-� therapy is dictated by TH1 and TH17 pathways. Using mouse models for MS, we found that IFN-� 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-� 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.