Chemokine Regulation on Central Nervous System Inflammation in Multiple Sclerosis

趋化因子对多发性硬化症中枢神经系统炎症的调节

• 批准号: 7575083
• 负责人: Richard M. Ransohoff
• 金额: $ 16.97万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-08 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7575083
• 关键词: Address; Anatomy; Antibodies; Attention; Biological Markers; Biological Models; Blood - brain barrier anatomy; Brain; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Data; Development; Disease; Evolution; Familiarity; Generations; Goals; Image; Inflammation; Inflammatory; Lesion; Leukocyte Trafficking; Leukocytes; Magnetic Resonance Imaging; Mentors; Mentorship; Microglia; Multiple Sclerosis; Multiple Sclerosis Lesions; Neuraxis; Neurologic; Patients; Pattern; Phase; Regulation; Research; Research Methodology; Research Personnel; Research Technics; Scientist; Series; Staging; T-Lymphocyte; Testing; Tissues; United States; base; chemokine; chemokine receptor; clinical practice; disability; human disease; in vitro Model; in vivo; insight; monocyte; natalizumab; novel; programs; receptor; receptor expression; receptor function; selective expression; small molecule; trafficking

DESCRIPTION (provided by applicant): This revised proposal gives equal attention to the priorities of mentoring and the research plan. The research plan is directed to understanding the anatomic and functional aspects of chemokine receptor expression in the lesions of multiple sclerosis (MS) a disease, which is the most prevalent primary neurological cause of disability in the United States. Our data show that chemokine receptors are selectively expressed by infiltrating cells (monocytes and T cells) in MS lesions, with different patterns, that vary according to lesion character. These findings prompted us to address the following questions: First, how does chemokine receptor expression correlate with MRI-characteristics of MS lesions, as determined in a unique series of tissues subjected to MRI/pathological correlations? Second, is there heterogeneous expression of chemokines and their receptors, in different lesions of MS within a single brain? We will examine these questions by immunohistochemical studies of tissue sections from MS patients and appropriate controls. We will test hypotheses derived from these studies using functional analysis, using a novel in vitro model of the blood brain barrier (BBB). The plan entails new directions for the PI, who will become familiar with imaging research techniques. Further, in the effort to identify biomarkers that indicate which pathological patterns are represented by MRI lesion characteristics in vivo, will require familiarity with a diverse range of clinical research methods. Together, these new directions necessitate a period of intense research focus under the K24 Award. This program will also allow for expanded mentoring activities, for beginning clinician investigators. The mentoring component of this proposal includes progression from descriptive immunohistochemical analysis of MS tissue sections, through hypothesis generation based on the descriptive data, culminating in hypothesis testing, using the BBB model system. The mentorship will be enriched by participation of an advisory team including other clinical and basic researchers as well as biostatistical support. Formal classwork and informal guidance are integrated in the mentoring plan, which will result in development of clinician-scientists who are enabled to use cutting edge research techniques to elucidate human disease.

描述（由申请人提供）：本修订后的提案对指导和研究计划的优先事项给予了同等重视。该研究计划旨在了解多发性硬化症（MS）病变中趋化因子受体表达的解剖学和功能方面，这种疾病是美国最常见的导致残疾的主要神经系统原因。我们的数据表明，趋化因子受体由多发性硬化症病变中的浸润细胞（单核细胞和 T 细胞）选择性表达，具有不同的模式，根据病变特征而变化。这些发现促使我们解决以下问题：首先，趋化因子受体表达如何与多发性硬化症病变的 MRI 特征相关（在一系列独特的组织中进行 MRI/病理相关性测定）？其次，在单个大脑内的不同 MS 病变中，趋化因子及其受体的表达是否存在异质性？我们将通过对多发性硬化症患者和适当对照的组织切片进行免疫组织化学研究来研究这些问题。我们将使用功能分析和新型血脑屏障（BBB）体外模型来测试这些研究中得出的假设。该计划为 PI 提供了新的方向，他们将熟悉成像研究技术。此外，在努力识别指示体内 MRI 病变特征所代表的病理模式的生物标志物时，需要熟悉各种临床研究方法。总之，这些新方向需要 K24 奖进行一段时间的集中研究。该计划还将允许扩大对初级临床医生研究人员的指导活动。该提案的指导部分包括从 MS 组织切片的描述性免疫组织化学分析，到基于描述性数据的假设生成，最终使用 BBB 模型系统进行假设检验。包括其他临床和基础研究人员在内的咨询团队的参与以及生物统计支持将丰富指导。正式的课堂作业和非正式的指导被纳入指导计划中，这将导致临床医生科学家的发展，他们能够使用尖端的研究技术来阐明人类疾病。