Chemokine Regulation on Central Nervous System Inflammation in Multiple Sclerosis

描述（由申请人提供）：这份修改后的提案对指导和研究计划的优先级给予了同等的关注。该研究计划旨在了解趋化因子受体在多发性硬化症（MS）病变中的解剖和功能方面的表达，多发性硬化症是美国最常见的主要神经系统致残原因。我们的数据表明，趋化因子受体通过浸润细胞（单核细胞和T细胞）在MS病变中选择性表达，并根据病变特征具有不同的模式。这些发现促使我们解决以下问题：首先，在一系列独特的组织中，通过MRI/病理相关性确定趋化因子受体表达与MS病变的MRI特征是如何相关的？第二，趋化因子及其受体在单一大脑内不同MS病变中是否存在异质表达？我们将通过MS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体外血脑屏障（BBB）模型，通过功能分析来检验从这些研究中得出的假设。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，在努力识别生物标志物，表明哪些病理模式是由体内MRI病变特征所代表的，将需要熟悉各种临床研究方法。总之，这些新方向需要在K24奖下进行一段时间的深入研究。该计划还将允许扩大指导活动，为初级临床研究人员。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以及生物统计学支持在内的咨询小组的参与将丰富指导工作。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。

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.