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

α7nAChRs已成为治疗许多神经退行性疾病的潜在靶点， 已被发现与炎症反应有关。α7 nAChR以 巨噬细胞在胆碱能抗炎途径中发挥关键作用，它们是否有 已被证明是治疗败血症、心肌缺血和类风湿性关节炎的有效靶点。 然而，人们对α7nAChRs在脑部炎症中所起的作用知之甚少。有趣的是，它有 已经证明，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高血压的危险因素 认知障碍和痴呆症。这表明饮食中的脂肪含量影响大脑的功能。 利用电生理学和脂类的药理操作，我们证明了在 质膜中的脂质水平会导致α7nAChRs功能的急剧变化。解剖 α-7nAChR在高脂饮食诱导的小胶质细胞活化中的作用 在神经炎症的发展过程中，我们将产生小胶质细胞特异性的α7nAChR基因敲除小鼠和 将他们与对照组进行比较，对照组喂以正常或高脂肪饮食。我们将研究如何激活 随时间变化的炎症反应、神经元α7nAChRs功能和神经元易感性 饮食引起的细胞死亡引起炎症反应的变化。结果将帮助我们洞察 α7nAChR在小胶质细胞激活和随后的神经细胞死亡中的作用，并揭示了 靶向α-7nAChRs在预防肥胖性痴呆中的治疗作用

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.