Regulation of Microglial Activation State by a Lipid Transporter

脂质转运蛋白对小胶质细胞激活状态的调节

• 批准号: 10536663
• 负责人: Erhard Bieberich
• 金额: $ 37.46万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536663
• 关键词: ATP binding cassette transporter 1; Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Anti-Inflammatory Agents; Astrocytes; Autopsy; Brain; Central Nervous System; Ceramides; Chronic; Clinical; Complex; Data; Disease; Drug Kinetics; Exposure to; Extracellular Space; Goals; Homologous Gene; Immune; Impaired cognition; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inorganic Phosphate Transporter; Investigation; Knockout Mice; Lipids; MAPT gene; Mediating; Microglia; Mus; NF-kappa B; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Onset of illness; Pathogenesis; Pathology; Pathway interactions; Peptides; Phagocytosis; Phagocytosis Induction; Phenotype; Play; Procedures; Process; Proteins; Public Health; Regulation; Reporting; Repression; Research; Role; Senile Plaques; Signal Induction; Signal Pathway; Signal Transduction; Sphingosine-1-Phosphate Receptor; Stimulus; Testing; Therapeutic; amyloid pathology; antagonist; astrogliosis; cell type; cognitive function; extracellular; genome wide association study; glial activation; improved; mouse model; neuroinflammation; neuroprotection; novel; novel therapeutic intervention; p38 Mitogen Activated Protein Kinase; pre-clinical; response; sphingosine 1-phosphate; sphingosine kinase; tau Proteins

Abstract Functional genome wide association studies have indicated that dysregulated microglia activation is a major contributing factor for neurodegeneration and cognitive decline in Alzheimer's disease (AD). Thus, regulating the microglia activation state could have profound therapeutic potential for AD. However, the underlying mechanisms by which microglia transition between different states during normal and disease conditions are largely unknown. S1P-signaling has been implicated to play important roles in AD. Yet the function of S1P in AD is not clear due to conflicting reports. On one hand, the level of S1P is reduced in postmortem AD patient brains, suggesting a protective role of S1P. On the other hand, there are also reports indicating that S1P might play the opposite. Although has been tested in Aβ-related AD mouse models, the role of FTY720 in tau pathology is elusive. Further, FTY720 can have different function depending on the cellular context and treatment procedure, which makes interpretation of S1P's role challenging. Thus, the function of S1P-signaling in AD is more complex than assumed and demands further investigation Our preliminary studies suggest that Spinster homolog 2 (Spns2), an S1P transporter, critically modulates microglial transition from inflammatory to anti-inflammatory states when treated with Aβ peptide. This data is interesting in that it reveals microglia states could be regulated through Spns2 and/or S1P. Since microglia form the first and major line of immune defense in the central nervous system, we will mainly investigate the function of Spns2 on microglia activation in this application. The role of astrocytes, the other major glial cell type, and other S1P transporters such as ABCA1, will also be evaluated. Our goal is to define the function and underlying mechanism of Spns2 in microglial responses in AD. Our goal is to define the function and underlying mechanism of Spns2 in microglial responses in AD. Our overarching hypothesis is that Spns2 contributes to AD pathogenesis by promoting microglial pro-inflammatory activation induced by AD-related stimuli. We will Test that (1) Spns2 enhances pro-inflammatory responses in microglia induced by AD-related stimuli, (2) Spns2/S1P promotes NFκB and p38 MAPK pro-inflammatory signaling induced by Aβ and tau in microglia, and (3) Spns2 deficiency ameliorates AD-related phenotypes in murine AD models. By focusing on the S1P transporter Spns2, this proposal holds a unique premise to reveal novel aspects of S1P-signaling in AD pathogenesis.

抽象的 功能基因组广泛关联研究表明，小胶质细胞激活失调 是阿尔茨海默氏病神经退行性变和认知能力下降的一个主要因素 (AD) 因此，调节小胶质细胞的激活状态可能具有深远的治疗潜力。 然而，小胶质细胞在不同状态之间转变的潜在机制。 在正常和疾病条件下，S1P 信号传导与此有关。 S1P 在 AD 中发挥重要作用，但由于报道相互矛盾，S1P 在 AD 中的功能尚不清楚。 一方面，AD 患者死后大脑中 S1P 的水平降低，这表明 另一方面，也有报道表明S1P可能起到保护作用。 尽管已在 Aβ 相关 AD 小鼠模型中进行了测试，但 FTY720 的作用却相反。 此外，FTY720 可以根据细胞的不同而具有不同的功能。 背景和治疗程序，这使得解释 S1P 的作用具有挑战性。 S1P 信号在 AD 中的功能比假设的更复杂，需要进一步研究 我们的初步研究表明，Spinster 同源物 2 (Spns2)，一种 S1P 转运蛋白，对 当治疗时调节小胶质细胞从炎症状态向抗炎状态的转变 该数据很有趣，因为它揭示了小胶质细胞状态可以通过调节。 Spns2 和/或 S1P 是中枢免疫防御的第一道也是主要防线。 神经系统中，我们将主要研究 Spns2 对小胶质细胞激活的功能 星形胶质细胞（另一种主要的神经胶质细胞类型）和其他 S1P 转运蛋白的作用。 与ABCA1一样，我们的目标也是定义功能和底层机制。 Spns2 在 AD 小胶质细胞反应中的作用 我们的目标是定义其功能和基础。 Spns2 在 AD 小胶质细胞反应中的机制 我们的首要假设是 Spns2。 通过促进小胶质细胞促炎激活来促进 AD 发病机制 我们将测试 (1) Spns2 增强小胶质细胞的促炎症反应。 由 AD 相关刺激诱导，(2) Spns2/S1P 促进 NFκB 和 p38 MAPK 促炎 小胶质细胞中 Aβ 和 tau 诱导的信号传导，以及 (3) Spns2 缺陷可改善 AD 相关疾病 通过关注 S1P 转运蛋白 Spns2，该提议成立。 这是揭示 AD 发病机制中 S1P 信号传导新方面的独特前提。