Chemokines and Viral-Induced Neurologic Disease

趋化因子和病毒引起的神经系统疾病

基本信息

批准号：
10090528
负责人：
Thomas E Lane
金额：
$ 32.59万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-28 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090528
关键词：
Chemokines Viral Induced Neurologic Disease

项目摘要

ABSTRACT The long-term objective of this research proposal is to focus on the functional role of chemokines and chemokine receptors in disease, protection, and repair in two well-established models of CNS disease: infection of susceptible mice with the neurotropic JHM strain of mouse hepatitis virus (JHMV) and experimental autoimmune encephalomyelitis (EAE). In both models, disease is characterized by ongoing demyelination mediated by inflammatory T cells and macrophages that is similar both clinically and histologically with the human demyelinating disease multiple sclerosis (MS). Specifically, this revised application will define how the chemokine CXCL1 as well as it’s signaling receptor CXCR2 affects neuroinflammation, demyelination and remyelination in the JHMV and EAE models of neuroinflammation and demyelination. To accomplish this, we will use mice engineered in which i) astrocyte-derived expression of the chemokine CXCL1 is inducible following doxycycline (Dox) treatment and ii) CXCR2, a signaling receptor for CXCL1, is selectively ablated upon tamoxifen (4-OHT) treatment within oligodendroglia in adult mice. We will use these animals to build on both published data and extensive preliminary data to further define how CXCL1 affects disease by attracting neutrophils into the CNS as well as influencing OPC maturation. Similarly, we will characterize how targeted ablation of CXCR2 on oligodendrocytes affects neuroinflammation and remyelination. Results from these studies will provide additional clarity to the importance of the CXCL1:CXCR2 signaling axis in both disease progression and repair and may reveal these to be relevant targets for treatment of human demyelinating diseases such as MS.

抽象的该研究计划的长期目标是关注趋化因子和趋化因子的功能作用在两种成熟的中枢神经系统疾病模型中，趋化因子受体在疾病、保护和修复中的作用：小鼠肝炎病毒（JHMV）嗜神经 JHM 株感染易感小鼠并进行实验在这两种模型中，自身免疫性脑脊髓炎（EAE）的特征都是持续脱髓鞘。由炎症 T 细胞和巨噬细胞介导，在临床和组织学上与具体来说，该修订后的申请将定义如何治疗人类脱髓鞘疾病多发性硬化症。趋化因子 CXCL1 及其信号受体 CXCR2 影响神经炎症、脱髓鞘和为了实现这一目标，我们在 JHMV 和 EAE 神经炎症和脱髓鞘模型中进行了髓鞘再生。将使用经过基因工程改造的小鼠，其中 i) 可诱导星形胶质细胞衍生的趋化因子 CXCL1 表达强力霉素 (Dox) 治疗后和 ii) CXCR2（CXCL1 的信号传导受体）被选择性消除在成年小鼠少突胶质细胞内进行他莫昔芬 (4-OHT) 治疗后，我们将使用这些动物进行研究。已发表的数据和广泛的初步数据进一步确定CXCL1如何通过吸引来影响疾病中性粒细胞进入 CNS 以及影响 OPC 成熟同样，我们将描述如何靶向。少突胶质细胞上 CXCR2 的消融会影响神经炎症和髓鞘再生。研究将进一步阐明 CXCL1:CXCR2 信号轴在这两种疾病中的重要性进展和修复，并可能揭示这些是治疗人类脱髓鞘的相关目标多发性硬化症等疾病。