Chemokine Regulation on Central Nervous System Inflammation in Multiple Sclerosis

描述（由申请人提供）：此修订后的建议给予同等重视的指导和研究计划的优先事项。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和功能方面，MS是美国最常见的主要神经系统残疾原因。我们的数据表明，趋化因子受体选择性表达的浸润细胞（单核细胞和T细胞）在MS病变，不同的模式，根据病变的特点。这些发现促使我们解决以下问题：首先，如何与MS病变的MRI特征，如在一个独特的一系列组织进行MRI/病理相关性确定趋化因子受体表达？第二，在同一脑内不同的多发性硬化病灶中，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相应对照组的组织切片进行免疫组织化学研究来探讨这些问题。我们将测试假设来自这些研究使用功能分析，使用一种新的体外模型的血脑屏障（BBB）。该计划为PI带来了新的方向，PI将熟悉成像研究技术。此外，在努力识别生物标志物，指示哪些病理模式是由MRI病变特征在体内，将需要熟悉各种临床研究方法。总之，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，为开始临床研究者。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。指导将通过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来丰富。正式的课堂作业和非正式的指导被整合在指导计划中，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。

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.