Chemokines in a novel murine model of DTH in the brain

描述(由申请人提供)这项研究将主要在波兰进行，作为国家卫生研究院#1 R01 NS 32151“中枢神经系统炎症中的趋化因子”的延伸。白细胞渗入中枢神经系统(CNS)是许多神经免疫性疾病的关键事件。淋巴细胞和巨噬细胞在大脑中的募集很可能是趋化因子(趋化细胞因子)在中枢神经系统表达的结果。在父母的资助中，我们分析了在多发性硬化症(MS)-实验性自身免疫性脑脊髓炎(EAE)的动物模型中，特定的趋化因子及其受体对如何控制炎症细胞向中枢神经系统募集。在这项提议中，我们希望扩展这些研究，并分析趋化因子和趋化因子受体在新描述的脑内注射卡介苗(BCG)诱导的MS样中枢神经系统损伤的局灶性模型中的作用。该模型是脑迟发型超敏反应(DTH)的一个例子，其特点是在脑纹状体中存在单一的单核炎症灶。与EAE脑不同，DTH模型是由非中枢神经系统抗原(BCG)诱导的，允许观察炎症反应引发的旁观者对脑的损伤。类似类型的中枢神经系统损害被认为是MS的发病机制。本研究主要集中在以下三个方面：1)小鼠脑迟发型超敏反应模型的建立和鉴定。首先，将描述小鼠脑DTH反应的模型。最初，这种模型是几年前在老鼠身上描述的。小鼠迟发型超敏反应模型将使我们能够使用几种大鼠没有的小鼠试剂，并在未来使用转基因动物。2)迟发性脑出血模型中趋化因子及其受体的表达分析。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。将分析在DTH病变发展过程中脑部趋化因子和趋化因子受体的表达。本项目将以3)趋化因子抑制剂防治脑DTH模型为目的。在卡介苗诱导的神经炎症模型中，一些趋化因子及其受体很可能在大脑中上调。这一观察结果可能导致使用抗趋化因子策略来调节这一病理。上调的趋化因子也将成为目标3的目标。这里提出的研究将补充父母拨款正在进行的研究，而不会重叠。这些研究的结果可能会为神经炎性疾病提供新的治疗策略。

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.