Chemokine Regulation on Central Nervous System Inflammation in Multiple Sclerosis

描述(由申请者提供)：这份修订后的提案对指导和研究计划的优先顺序给予了同等的重视。该研究计划旨在了解多发性硬化症(MS)皮损中趋化因子受体表达的解剖和功能方面，多发性硬化症(MS)是美国最常见的导致残疾的主要神经原因。我们的数据显示，趋化因子受体在MS病变中由浸润性细胞(单核细胞和T细胞)选择性表达，其模式随病变性质的不同而不同。这些发现促使我们解决以下问题：第一，趋化因子受体的表达如何与MS病变的MRI特征相关，正如在一系列独特的MRI/病理相关的组织中所确定的那样？第二，在同一个脑内不同的MS病变中，是否存在趋化因子及其受体的异质性表达？我们将通过对多发性硬化症患者和适当对照的组织切片的免疫组织化学研究来检验这些问题。我们将使用一种新的血脑屏障(BBB)体外模型，使用功能分析来检验这些研究得出的假说。该计划为PI带来了新的方向，他们将熟悉成像研究技术。此外，为了努力识别指示哪些病理模式由体内MRI病变特征代表的生物标记物，将需要熟悉各种临床研究方法。总而言之，这些新的方向需要在K24奖下进行一段时间的密集研究。该计划还将允许扩大指导活动，为初学临床医生的研究员提供指导。该建议的指导部分包括从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，最后使用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小组的参与以及生物统计学的支持将丰富指导工作。正式的课堂作业和非正式的指导被整合到指导计划中，这将导致临床医生-科学家的发展，他们能够使用尖端研究技术来阐明人类疾病。

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.