Neuroimmune Communication at the Blood Brain Barrier

血脑屏障的神经免疫通讯

• 批准号: 6986200
• 负责人: Ning Quan
• 金额: $ 29.2万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986200
• 关键词: autoimmunity; blood brain barrier; cell cell interaction; cell migration; central nervous system; cytokine receptors; experimental allergic encephalomyelitis; genetically modified animals; interleukin 1; laboratory mouse; leukocytes; lipopolysaccharides; neuroimmunomodulation; neuroregulation; pathologic process; receptor expression

DESCRIPTION (provided by applicant): Neuroimmune communication has been implicated in both physiological defense against infection and pathogenic events contributing to many disorders of the central nervous system (CNS). A key mediator for this communication is interleukin-1. The following evidences indicate IL-1 acts on cells of the blood brain barrier to affect the CNS: 1) The functional 1L-1 receptor (type I IL-1 receptor, IL-1r1) is mostly expressed on CNS endothelial cells, 2) IL-1-responsive immediate early gene IkappaBalpha is induced primarily in CNS endothelium after central IL-1 injection; 3) inflammatory mediators such as the prostaglandins are induced in brain endothelial cells after both peripheral and central immune challenges; and 4) IL-1r1 is essential for mediating the recruitment of leukocytes across the BBB during the development of CNS immune responses. The central hypothesis of this proposal, therefore, is that IL-1 affects the CNS through the activation of CNS endothelial cells. This hypothesis can be tested directly in our recently created transgenic mice with which we can specifically inhibit the expression of IL-1r1 on endothelial cells. The long range goal of this application is to elucidate the role of BBB in mediating neuroimmune crosstalk. Using these transgenic animals, the following specific aims will be tested: 1) Determine the distribution of IL-1r1 protein expression in the CNS in normal and immunologically challenged mice. 2) Determine the role of endothelial IL-1r1 in mediating the activation of the neural circuits and the functional consequences induced by peripheral and central immune challenges. 3) Determine the role of endothelial IL-1r1 in the recruitment of leukocyte across the BBB. 4) Determine the role of endothelial IL-1r1 in mediating the development and progression of experimental autoimmune encephalomyelitis (EAE). The results of this project should provide a definitive analysis to determine the role of endothelial IL-1r1 in several aspects of neuroimmune interaction.

描述（由申请人提供）：神经免疫通讯与针对感染的生理防御和导致中枢神经系统（CNS）许多疾病的致病事件有关。这种通讯的关键介质是白介素-1。以下证据表明IL-1作用于血脑屏障细胞从而影响中枢神经系统：1）功能性1L-1受体（I型IL-1受体，IL-1r1）主要表达于中枢神经系统内皮细胞，2） IL-1 反应性立即早期基因 IkappaBalpha 主要在中枢 IL-1 注射后在中枢神经系统内皮细胞中被诱导； 3）在外周和中枢免疫挑战后，脑内皮细胞中会诱导炎症介质（例如前列腺素）； 4) IL-1r1 对于中枢神经系统免疫反应发展过程中介导白细胞通过 BBB 的募集至关重要。因此，该提议的中心假设是 IL-1 通过激活 CNS 内皮细胞来影响 CNS。这一假设可以直接在我们最近创建的转基因小鼠中进行测试，通过这些小鼠我们可以特异性抑制内皮细胞上 IL-1r1 的表达。该应用的长期目标是阐明 BBB 在介导神经免疫串扰中的作用。使用这些转基因动物，将测试以下具体目标： 1) 确定正常和免疫攻击小鼠中枢神经系统中 IL-1r1 蛋白表达的分布。 2) 确定内皮细胞 IL-1r1 在介导神经回路激活以及外周和中枢免疫挑战引起的功能后果中的作用。 3) 确定内皮 IL-1r1 在跨 BBB 募集白细胞中的作用。 4)确定内皮IL-1r1在介导实验性自身免疫性脑脊髓炎(EAE)发生和进展中的作用。该项目的结果应提供明确的分析，以确定内皮 IL-1r1 在神经免疫相互作用的几个方面的作用。