Microglial activation by serum factors

血清因子激活小胶质细胞

• 批准号: 6741949
• 负责人: THOMAS MOELLER
• 金额: $ 32.4万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6741949
• 关键词: CD antigens; biological signal transduction; blood brain barrier; cell death; cell motility; cell proliferation; chemotaxis; cytokine receptors; flow cytometry; gene expression; immunocytochemistry; laboratory mouse; laboratory rat; leukocyte adhesion molecules; lipopolysaccharides; lysophospholipids; messenger RNA; microglia; mitogen activated protein kinase; polymerase chain reaction; receptor expression; sphingosine; surface antigens; thrombin; thrombin receptor; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): Microglial cells are the resident immune cells of the central nervous system (CNS). They have been implicated in many acute and chronic neurological diseases, including trauma, stroke and multiple sclerosis. Upon CNS injury microglial cells are rapidly activated. Through the release of bioactive substances such as cytokines activated microglial cells can exert powerful toxic as well as protective effects on neurons. Until recently, research has mainly focused on microglial activation by cytokines. These potent peptides elicit a broad range of responses, including proliferation, motility and cytokine release itself. Nevertheless, before cytokines can activate microglia, they need to be induced, synthesized and released from neighboring cells. The reported rapid activation of microglia after CNS injury, leads to the question: Are there other, factors acting as microglial activators? One group of candidates is serum factors (SFs). SFs leak into the CNS parenchyma during insults associated with impairment of the blood-brain-barrier, such as trauma, stroke, and multiple sclerosis. Serum factors therefore could serve as immediate signals of injury and activate microglial cells without the need of intermediary, cytokine- producing "relay" cells. We hypothesize that serum factors (SF) represent a "short-cut" to microglial activation. Based on recently published reports and our preliminary findings, we propose to examine the effects of the serum factors thrombin, lysophosphatidic acid and sphingosine-1 -phospate on microglial Activation. Using molecular, immunological and imaging techniques the following issues will be addressed: 1. Determine the cellular consequences of microglial activation by SFs in vitro. 2. Determine the signal transduction mechanisms involved in SF-mediated microglial activation in vitro. 3. Determine the cellular consequences of microglial activation by SFs in a retina explant culture model in situ. In many pathological events SFs act immediately on microglial cells, long before first-phase cytokines could influence microglial behavior. Each of the receptors or signal transduction mechanisms identified may constitute a new target for therapeutic intervention in CNS injuries, which are accompanied by the break down of the blood-brain-barrier, such as trauma, multiple sclerosis or stroke.

描述（由申请人提供）：小胶质细胞是中枢神经系统（CNS）的常驻免疫细胞。它们与许多急性和慢性神经系统疾病有关，包括创伤、中风和多发性硬化症。中枢神经系统损伤后，小胶质细胞迅速激活。通过释放细胞因子等生物活性物质，激活的小胶质细胞可以对神经元产生强大的毒性和保护作用。直到最近，研究主要集中在细胞因子激活小胶质细胞上。这些有效的肽可引起广泛的反应，包括增殖、运动和细胞因子释放本身。然而，在细胞因子激活小胶质细胞之前，它们需要被邻近细胞诱导、合成和释放。据报道，中枢神经系统损伤后小胶质细胞会快速激活，这引发了一个问题：是否还有其他因素充当小胶质细胞激活剂？一组候选者是血清因子（SF）。在与血脑屏障损伤相关的损伤（如创伤、中风和多发性硬化症）期间，SFs 渗入 CNS 实质。因此，血清因子可以作为损伤的直接信号并激活小胶质细胞，而不需要中间的、产生细胞因子的“中继”细胞。我们假设血清因子（SF）代表小胶质细胞激活的“捷径”。根据最近发表的报告和我们的初步研究结果，我们建议检查血清因子凝血酶、溶血磷脂酸和 1-磷酸鞘氨醇对小胶质细胞激活的影响。使用分子、免疫学和成像技术将解决以下问题： 1. 确定体外 SF 激活小胶质细胞的细胞后果。 2. 确定体外 SF 介导的小胶质细胞激活所涉及的信号转导机制。 3. 确定视网膜外植体原位培养模型中 SF 激活小胶质细胞的细胞后果。在许多病理事件中，SFs 立即作用于小胶质细胞，早在第一阶段细胞因子影响小胶质细胞行为之前。所确定的每种受体或信号转导机制都可能构成中枢神经系统损伤治疗干预的新靶点，这些损伤伴随着血脑屏障的破坏，例如创伤、多发性硬化症或中风。