CNS Pathobiology of IFN-inducible non-ELR CXC Chemokines

IFN 诱导的非 ELR CXC 趋化因子的 CNS 病理学

• 批准号: 6704589
• 负责人: IAIN Leslie CAMPBELL
• 金额: $ 24.98万
• 依托单位: UNIVERSITY OF SYDNEY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-23 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704589
• 关键词: angiogenesis; astrocytes; biological signal transduction; cell migration; central nervous system disorders; chemokine; chemokine receptor; endotoxins; experimental allergic encephalomyelitis; gene expression; genetic models; genetically modified animals; immunization; immunocytochemistry; in situ hybridization; infectious encephalomyelitis; inflammation; interferon gamma; laboratory mouse; lipopolysaccharides; lymphocytic choriomeningitis; model design /development; neuropathology; transfection; western blottings

DESCRIPTION (provided by applicant): Three chemokines, CXCL9, CXCL10 and CXCL11, comprise the IFN-inducible non-ELR CXC chemokine subgroup. These chemokines bind to a common receptor CXCR3 and possibly additional receptors and are involved in leukocyte trafficking but have other overlapping as well as distinct functions. Here we hypothesize that as dictated by receptor availability and usage as well as through their own differential gene expression, members of this chemokine subgroup play multiple and diverse roles in the pathogenesis of inflammatory neurological diseases such as multiple sclerosis and viral meningoencephalitis.CXCL10 which is widely studied by us, as well as others, is induced locally (e.g. in astrocytes) and implicated in leukocyte trafficking in a variety of CNS diseases ranging from infectious meningoencephalitides to immunoinflammatory demyelinating pathologies. Despite this, we know very little about: (1) the coordinate spatial and temporal regulation of CXCL9, CXCL10 andCXCL11 or CXCR3 in these and other CNS inflammatory disease pathologies, (2) the spectrum of possible CNS functions performed by all three chemokines in this subgroup, and (3) the relative role of CXCR3 versus other putative receptors inmediating the biological actions of these chemokines in the CNS. Accordingly, in the first specific aim of this proposal we will define the coordinate regulation and temporal and spatial expression of CXCL9, 10 &l 1 and CXCR3 in distinct neuroinflammatory pathologies including: (i) LPS-induced endotoxemia, (ii) virus infection (i.e. lymphocytic choriomeningitis and MHV encephalomyelitis), and (iii) myelin oligodendrocyte peptide (MOG) immunization-induced experimentalautoimmune encephalomyelitis (EAE). Further, these disease paradigms will be studied in mice lacking the IFN-gamma gene in order to establish the regulatory role of this key cytokine. In the second specific aim, we will assess the in vivo functional consequences and mechanisms of action of CXCL9, CXCL10 and CXCL11 in the living CNS. Transgenic mice will be generated with the production of each these chemokines targeted to the astrocyte. These so-called GF-CXCL transgenicmice will be assessed for spontaneous as well as disease-induced alterations in the CNS. In addition, we will elucidate the angiostatic functions of these chemokines in the CNS. For this purpose we will interbreed GF-CXCL mice with GF-IL-6transgenic mice that have chronic angiogenesis in the brain. In the final specific aim we will make use of recently developed mutant mice that lack the CXCR3 receptor to determine the role of this or other putative receptors in mediating the biological actions of CXCL10. CXCR3 deficient mice will be examined for neuropathologic outcomes following CNS viral infection or induction of MOG-EAE as well as in intercrosses with the GF-CXCL10 transgenic mice. The results from our studies will fill in large gaps in our current knowledge and provide important new information as to the CNS pathobiology of the IFN-gamma-inducible non-ELR CXC chemokines.

描述（由申请人提供）：CXCL9、CXCL10 和 CXCL11 三种趋化因子构成 IFN 诱导型非 ELR CXC 趋化因子亚组。这些趋化因子与共同受体 CXCR3 和可能的其他受体结合，参与白细胞运输，但具有其他重叠和独特的功能。在这里，我们假设，根据受体的可用性和使用以及它们自身的差异基因表达，该趋化因子亚组的成员在炎症性神经系统疾病（如多发性硬化症和病毒性脑膜脑炎）的发病机制中发挥着多种不同的作用。我们和其他人广泛研究的CXCL10是局部诱导的（例如在星形胶质细胞中）并与 多种中枢神经系统疾病中的白细胞贩运，从传染性脑膜脑炎到免疫炎症性脱髓鞘病变。尽管如此，我们对以下方面知之甚少：(1) CXCL9、CXCL10 和 CXCL11 或 CXCR3 在这些和其他 CNS 炎症性疾病病理中的协调空间和时间调节，(2) 该亚组中所有三种趋化因子可能执行的 CNS 功能范围，以及 (3) CXCR3 与介导这些趋化因子生物作用的其他假定受体的相对作用 在中枢神经系统中。因此，在本提案的第一个具体目标中，我们将定义 CXCL9、10 &l 1 和 CXCR3 在不同神经炎症病理中的协调调节和时空表达，包括：(i) LPS 诱导的内毒素血症，(ii) 病毒感染（即淋巴细胞脉络膜脑膜炎和 MHV 脑脊髓炎），以及 (iii) 髓磷脂 少突胶质细胞肽（MOG）免疫诱导的实验性自身免疫性脑脊髓炎（EAE）。此外，这些疾病范例将在缺乏 IFN-γ 基因的小鼠中进行研究，以便确定这一关键细胞因子的调节作用。在第二个具体目标中，我们将评估 CXCL9、CXCL10 和 CXCL11 在活中枢神经系统中的体内功能后果和作用机制。随着这些针对星形胶质细胞的趋化因子的产生，将产生转基因小鼠。这些所谓的 GF-CXCL 转基因小鼠将被评估中枢神经系统自发的以及疾病引起的改变。此外，我们将阐明这些趋化因子在中枢神经系统中的血管抑制功能。为此，我们将 GF-CXCL 小鼠与大脑中具有慢性血管生成的 GF-IL-6 转基因小鼠杂交。在最终的具体目标中，我们将利用最近开发的缺乏 CXCR3 受体的突变小鼠来确定该受体或其他假定受体在介导 CXCL10 生物作用中的作用。将检查 CXCR3 缺陷小鼠在 CNS 病毒感染或 MOG-EAE 诱导以及与 GF-CXCL10 转基因小鼠杂交后的神经病理学结果。我们的研究结果将填补我们当前知识的巨大空白，并提供有关 IFN-γ 诱导的非 ELR CXC 趋化因子的 CNS 病理学的重要新信息。