Gravitational Regulation of Osteoblast Genomics and Metabolism

成骨细胞基因组和代谢的重力调节

• 批准号: 8733049
• 负责人: BRUCE E HAMMER
• 金额: $ 42.04万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8733049
• 关键词: Adoptive Transfer; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attenuated; 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; Genomics; Goals; Human; Immune; In Vitro; Inflammation; Inflammatory; Interferon-beta; Interferons; Interleukin-10; Knockout Mice; Link; Longitudinal Studies; Mentors; Metabolism; Molecular; Multiple Sclerosis; Mus; Osteoblasts; 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; Techniques; Therapeutic; Tissues; Training; Transcriptional Regulation; Work; abstracting; active method; cell type; cohort; cytokine; effective therapy; meetings; mouse model; planetary Atmosphere; research study; response

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.

项目摘要/摘要： 研究计划：尽管Interferon-是多重多种的最受欢迎的治疗方法之一 硬化症，其作为药物的作用方式仍未完全理解。而且，IFN-€的治疗是 只有部分有效，大约30％的MS患者对治疗没有反应。我们 最近发表了对IFN-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-削弱了Th1诱导的疾病，但 加剧Th17疾病。在一小部分MS患者中，我们观察到高血清水平的高度 IL-17F，Th17细胞因子，在治疗倡议之前，在无反应者中。目标的目标 研究是： 1。确定IFN- - 治疗施加促炎的机制 效果。这将通过使用MS和人CD4 T细胞的鼠标模型来实现 培养实验，分别在AIM 1和3中描述。 2。确定MS血液和脊髓液中的生物标志物，以预测并跟踪对 IFN-处理。这将通过分析患者血液中的细胞因子谱和 在AIM 2中描述的纵向研究中的脊柱液。 培训：此应用中提出的研究涵盖了广泛的实验 需要在自身免疫的动物模型，人类免疫核管生物学中需要专业知识的技术， 细胞信号传导，转录调控和疾病组织实验。所以， 实验技术，统计分析和 临床研究组织。斯坦曼博士，我的心理，邓恩博士 （合作者/顾问）和Racke博士（顾问）是这些领域的专家，将确保 满足了这些培训需求。 环境：斯坦福大学是一家著名的学术研究所 产生尖端科学。斯坦福大学与最先进的氛围高度合作 许多学科的艺术设施和世界一流的调查员，其中许多正在进行 对本应用程序提出的工作的完整研究。 拟议的研究计划，斯坦福大学的培训开发和环境将是高度的 导电我向独立教师过渡。