Project 3: Role of Microglial α7nAChR in Diet Induced Brain Inflammation

项目 3：小胶质细胞 α7nAChR 在饮食引起的脑炎症中的作用

基本信息

批准号：
10212405
负责人：
Jose Orlando Colon-Saez
金额：
$ 20.51万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212405
关键词：
Affect Agonist Amyloid beta-Protein Animal Model Anti-Cholinergics Anti-Inflammatory Agents Area Behavioral Brain Brain region Calcium Cause of Death Cell membrane Cells Centers of Research Excellence Cholesterol Cognition Confocal Microscopy Consumption Dementia Development Diet Dietary Fats Drosophila acetylcholine receptor alpha-subunit Electrophysiology (science)Encephalitis Enzyme-Linked Immunosorbent Assay Exposure to Fatty acid glycerol esters Goals HIV HIV Envelope Protein gp120 High Fat Diet Hippocampus (Brain)Histologic Human Immune Impaired cognition Impairment In Vitro Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Kinetics Knock-out Knockout Mice Learning Light Lipids Measures Mediating Mediator of activation protein Membrane Lipids Memory Microglia Modeling Myocardial Ischemia Neurodegenerative Disorders Neuronal Injury Neuronal Plasticity Neurons Obesity Obesity Epidemic Overweight Pathway interactions Permeability Pharmacology Phase Play Predisposition Process Puerto Rico Research Rheumatoid Arthritis Risk Risk Factors Role Sepsis Serum Short-Term Memory Signal Transduction Stimulus Synapses Synaptic plasticity TNF gene Testing Therapeutic Time Transcriptional Activation Universities Wild Type Mouse alpha-bungarotoxin receptor axon regeneration cholinergic cognitive performance cytokine dietary fluorescence imaging in vivo Model macrophage mild cognitive impairment morris water maze mouse model neuroinflammation neuron loss neuroprotection neurotoxicity new therapeutic target novel obesity prevention obesity treatment prevent response tool transcription factor

项目摘要

The α7 nAChRs has emerged as a potential target in the treatment of many neurodegenerative disorders, which have been found to be associated with an inflammatory response. The α7 nAChRs are expressed in macrophages where they play a key role in the cholinergic anti-inflammatory pathway, were they have proven to be an effective target in the treatment of sepsis, myocardial ischemia, and rheumatoid arthritis. However little is known about the role that α7 nAChRs play on brain inflammation. Interestingly, it has been shown that a high fat diet on wild-type mice causes the activation of microglia resulting in impairments on working memory and in humans an elevated serum cholesterol is a risk factor for mild cognitive impairment and dementia. Suggesting that dietary fat content affects the function of the brain. Using electrophysiology and pharmacological manipulation of lipids, we demonstrated that changes in lipid levels in the plasma membrane causes dramatic changes in the function of the α7 nAChRs. To dissect the role that α7 nAChR plays on the high fat diet mediated microglia activation and subsequent development of neuroinflammation, we will generate microglia specific α7 nAChR knockout mice and compare them with control, fed either a normal or high fat diet. We will look at the activation of inflammatory responses over time, the function of neuronal α7 nAChRs, and the susceptibility of neuronal cell death caused by dietary induced changes in inflammatory response. The results will help us discern the role of α7nAChR in both microglia activation and subsequent neuronal cell death, and shed light in the possibility of targeting α7 nAChRs therapeutically in the prevention of obesity induced dementia.

α7 nAChR 已成为治疗许多神经退行性疾病的潜在靶点，已发现与炎症反应相关的α7 nAChRs 表达于其中。巨噬细胞在胆碱能抗炎途径中发挥关键作用，如果它们具有被证明是治疗脓毒症、心肌缺血和类风湿关节炎的有效靶点。然而，人们对 α7 nAChR 在脑部炎症中的作用知之甚少。研究表明，野生型小鼠的高脂肪饮食会导致小胶质细胞的激活，从而导致工作记忆受损和人类血清胆固醇升高是轻度的危险因素认知障碍和痴呆症表明饮食中的脂肪含量会影响大脑的功能。利用电生理学和脂质的药理学操作，我们证明了质膜中的脂质水平会导致 α7 nAChR 的功能发生巨大变化。 α7 nAChR 在高脂饮食介导的小胶质细胞激活及随后的过程中发挥的作用神经炎症的发展，我们将产生小胶质细胞特异性 α7 nAChR 敲除小鼠将它们与喂食正常或高脂肪饮食的对照组进行比较，我们将观察它们的激活情况。随着时间的推移，炎症反应、神经元 α7 nAChR 的功能以及神经元的易感性饮食引起的炎症反应变化引起的细胞死亡将有助于我们辨别。 α7nAChR 在小胶质细胞激活和随后的神经元细胞死亡中的作用，并揭示了治疗性靶向 α7 nAChR 预防肥胖引起的痴呆的可能性。