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

α7 nAChR已成为治疗许多神经退行性疾病的潜在靶点， 已经发现其与炎症反应有关。α7 nAChR在 巨噬细胞在胆碱能抗炎通路中发挥关键作用， 被证明是治疗脓毒症、心肌缺血和类风湿性关节炎的有效靶点。 然而，关于α7 nAChR在脑炎症中的作用知之甚少。有趣的是，它已经 已经表明，野生型小鼠的高脂肪饮食会导致小胶质细胞的激活， 在人类中，血清胆固醇升高是轻度脑损伤的危险因素。 认知障碍和痴呆症。这表明饮食中的脂肪含量会影响大脑的功能。 使用脂质的电生理学和药理学操作，我们证明了 质膜中的脂质水平引起α7 nAChR功能的显著变化。解剖 α7 nAChR在高脂饮食介导的小胶质细胞活化及随后的 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， 将它们与正常或高脂肪饮食的对照组进行比较。我们将研究 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， 由饮食诱导的炎症反应变化引起的细胞死亡。结果将帮助我们辨别 α 7 nAChR在小胶质细胞活化和随后的神经元细胞死亡中的作用，并揭示了 靶向α7 nAChR治疗预防肥胖诱导的痴呆的可能性。

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.