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: 9887304
• 负责人: Erhard Bieberich
• 金额: $ 37.53万
• 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/9887304
• 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; Ceramides; Chronic; Clinical; Clinical Data; Complex; Conflict (Psychology); 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; Neuraxis; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Onset of illness; Pathogenesis; Pathology; Pathway interactions; Peptides; Phagocytosis; Phenotype; Play; Procedures; Process; Proteins; Public Health; Regulation; Reporting; Research; Role; Senile Plaques; Signal Pathway; Signal Transduction; Sphingosine-1-Phosphate Receptor; Stimulus; Testing; Therapeutic; amyloid pathology; astrogliosis; cell type; cognitive function; extracellular; genome wide association study; improved; mouse model; neuroinflammation; 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 功能性基因组广泛的关联研究表明，小胶质细胞活化失调 是阿尔茨海默氏病神经退行性变化和认知下降的主要因素 （广告）。这是，测量小胶质细胞激活状态可能具有深远的治疗潜力 广告。但是，不同状态之间小胶质细胞过渡的基本机制 在正常情况下和疾病条件下，在很大程度上尚不清楚。 S1P信号已与 在广告中扮演重要角色。然而，由于报告的报道冲突，S1P在AD中的功能尚不清楚。 一方面，在验尸AD患者的大脑中降低了S1P的水平，这表明 S1P的保护作用。另一方面，也有报道表明S1P可能会播放 相反。尽管已在Aβ相关的AD小鼠模型中进行了测试，但FTY720在 tau病理是弹性的。此外，FTY720可以取决于细胞的功能 上下文和治疗程序，可以解释S1P的角色挑战。那， S1P信号在AD中的功能比假设更复杂，并且需要进一步研究 我们的初步研究表明，S1P转运蛋白的Spinster同源物2（SPNS2）至关重要 当用治疗时，调节从炎症到抗炎状态的小胶质细胞过渡 Aβ肽。该数据很有趣，因为它揭示了小胶质细胞状态可以通过 SPNS2和/或S1P。由于小胶质细胞构成了中央的第一和主要免疫防御线 神经系统，我们将主要研究SPNS2对小胶质细胞激活的功能 应用。星形胶质细胞，其他主要的神经胶质细胞类型和其他S1P转运蛋白的作用 作为ABCA1，也将进行评估。我们的目标是定义功能和基本机制 AD中的小胶质细胞反应中的Spns2。我们的目标是定义功能和基础 AD中小胶质响应中SPNS2的机理。我们的总体假设是SPNS2 通过促进由小胶质细胞促炎激活诱导的小胶质细胞发病机理 广告相关刺激。我们将测试（1）SPNS2增强小胶质细胞中的促炎反应 通过广告相关刺激诱导的（2）SPNS2/S1P促进NFκB和p38 MAPK促炎 由Aβ和TAU在小胶质细胞中诱导的信号传导，（3）SPNS2缺乏可改善与AD相关的 鼠广告模型中的表型。通过专注于S1P运输蛋白SPNS2，该提案成立 在AD发病机理中揭示S1P信号的新颖方面的独特前提。