Chemokines in a novel murine model of DTH in the brain

描述（由申请人提供）本研究将主要在波兰进行，作为NIH资助# 1 R 01 NS 32151“CNS炎症中的趋化因子”的扩展。白细胞浸润到中枢神经系统（CNS）是许多神经免疫疾病的关键事件。淋巴细胞和巨噬细胞向脑中的募集可能是CNS中趋化因子（化学引诱细胞因子）表达的结果。在家长补助金，我们分析了特定的趋化因子及其受体对管理招聘的炎症细胞的中枢神经系统在动物模型的多发性硬化症（MS）-实验性自身免疫性脑脊髓炎（EAE）。在这个建议中，我们想扩展这些研究和分析的作用，趋化因子和趋化因子受体在一个新描述的局灶性模型MS样中枢神经系统病变引起的脑内注射卡介苗（BCG）。该模型是脑迟发型超敏反应（DTH）的一个例子，其特征在于脑纹状体中存在单个单核炎症灶。与EAE脑不同，DTH模型由非CNS抗原（BCG）诱导，并且允许观察由炎症反应触发的对脑的旁观者损伤。MS的发病机制假定为相似类型的CNS损伤。本研究主要有以下三个方面的内容：1）建立和鉴定小鼠脑DTH反应模型。首先，将描述脑DTH反应的鼠模型。最初，这种模型是在几年前在大鼠中描述的。小鼠DTH模型将使我们能够使用几种小鼠试剂，而这些试剂不适用于大鼠，并在未来使用转基因动物。2)脑DTH模型中趋化因子及其受体表达的分析。一旦描述了新模型的组织病理学，我们将讨论趋化因子在其发展中的潜在作用。将分析DTH损伤发展过程中脑中趋化因子和趋化因子受体的表达。本课题将以目的3）用趋化因子抑制剂预防和治疗脑DTH模型作为结论。在BCG诱导的神经炎症模型中，一些趋化因子及其受体最有可能在脑中上调。这一观察结果可能导致用抗趋化因子策略调节这种病理学。上调的趋化因子也将在目标3中被靶向。这里提议的研究将补充母基金正在进行的研究，而不会重叠。这些研究的结果可能为神经炎性疾病提出新的治疗策略。

DESCRIPTION (provided by applicant) This research will be done primarily in Poland as an extension of NIH grant # 1 R01 NS 32151 "Chemokines in CNS inflammation." Leukocyte infiltration into the central nervous system (CNS) is a key event in many neuroimmunologic diseases. The recruitment of lymphocytes and macrophages into the brain is likely the result of chemokine (chemoattractant cytokine) expression in the CNS. In the parent grant we analyze how specific pairs of chemokines and their receptors govern recruitment of inflammatory cells to the CNS during animal model of multiple sclerosis (MS) - experimental autoimmune encephalomyelitis (EAE). In this proposal, we would like to extend those studies and analyze the role of chemokines and chemokine receptors in a newly described focal model of MS-like CNS lesions induced by intracerebral injection of bacillus Calmette-Guerin (BCG). This model is an example of brain delayed type hypersensitivity (DTH) reaction and is characterized by the presence of a single mononuclear inflammatory focus in brain striatum. Unlike EAE brain, the DTH model is induced by non-CNS antigen (BCG) and allows observation of bystander damage to the brain triggered by inflammatory reaction. Similar types of CNS damage is postulated for MS pathogenesis. This research will concentrate on the following three Specific Aims: 1) Development and characterization of the murine model of brain DTH reaction. Initially, murine model of brain DTH reaction will be described. Originally this model was described in rats a few years ago. Mouse DTH model will enable us to use several murine reagents not available for rats and use genetically modified animals in the future. 2) Analysis of chemokines and chemokine receptor expression in brain DTH model. Once the histopathology of a new model is described, we will address the potential role of chemokines in its development. Expression of chemokines and chemokine receptors in the brain during development of DTH lesion will be analyzed. This project will be concluded with Aim 3) Prevention and treatment of brain DTH model with chemokine inhibitors. Some chemokines and their receptors are most likely upregulated in the brain during BCG-induced model of neuroinflammation. This observation may lead to modulation of this pathology with anti-chemokine strategy. Upregulated chemokines will also be targeted in Aim 3. Research proposed here will complement ongoing studies by the parent grant without overlap. Results of those studies may suggest new therapeutic strategies for neuroinflammatory disorders.