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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

基本信息

批准号：
10112795
负责人：
Erhard Bieberich
金额：
$ 37.51万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2020-03-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112795
关键词：
ATP binding cassette transporter 1 Affect Agonist Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

摘要