Gravitational Regulation of Osteoblast Genomics and Metabolism

成骨细胞基因组和代谢的重力调节

基本信息

批准号：
8906852
负责人：
BRUCE E HAMMER
金额：
$ 42.35万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8906852
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 professional atmosphere research study response

项目摘要

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：尽管干扰素-�是多种疾病最流行的治疗方法之一硬化症，其作为药物的作用方式尚未完全了解。此外，IFN-α疗法尚不完全清楚。仅部分有效，并且大约 30% 的多发性硬化症患者对治疗没有反应。最近发表的文章称，对 IFN-α 治疗的反应是由 TH1 和 TH17 通路指导的。使用多发性硬化症小鼠模型，我们发现 IFN-α 可以减轻 TH1 诱导的疾病，但在一小群多发性硬化症患者中，我们观察到高血清水平。 IL-17F，一种 TH17 细胞因子，在治疗开始前出现在无反应者中。研究目的是： 1. 确定 IFN-α 治疗发挥促炎和抗炎作用的机制这将通过使用 MS 小鼠模型和人类 CD4 T 细胞来实现。培养实验，分别在目标 1 和 3 中描述。 2. 识别多发性硬化症血液和脊髓液中的生物标志物，以预测和跟踪对疾病的反应这将通过分析患者血液中的细胞因子谱来完成。纵向研究中的脊髓液，如目标 2 中所述。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专业知识的技术，细胞信号传导、转录调控和疾病组织实验。需要在实验技术、统计分析和我的导师 Steinman 博士和 Dunn 博士一起组织临床研究。（合作者/顾问）和 Racke 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：斯坦福大学是著名的学术研究机构，拥有悠久的历史斯坦福大学拥有高度协作的氛围和最先进的科学成果。拥有最先进的设施和许多学科的世界一流的研究人员，其中许多人正在开展与本申请中提出的工作相补充的研究。斯坦福大学拟议的研究计划、培训发展和环境将受到高度重视。有利于我向独立教师的过渡。