HCA2在帕金森病小鼠模型中的神经保护作用及其机制

Parkinson’s disease (PD) is a common and debilitating age associated human neurodegenerative disorder, and its pathogenesis is still unclear. So far, there are no effective therapies for PD. In recent years, neuroinflammation has been proven to be one of the causes of PD. Search for new anti-neuroinflammatiory target of PD therapy has been the hotspot. HCA2 is a Gi-protein-coupled receptor, which we found expressed in microglia, and inhibits inflammatory response of microglia in LPS-induced PD rat model. We’ve just discovered that HCA2 is also expressed in astrocytes and dopaminergic neurons. However, it has not been reported whether HCA2 inhibits inflammatory response in astrocytes and dopaminergic neurons, and the relationship between anti-neuroinflammatory function of HCA2 and PD. Based on our previous studies, we attempt to study the effects and its mechanisms of HCA2 on neuroinflammation, and reveal the effect of HCA2 on the progress of PD, using HCA2 knockout mice and HCA2 conditional knockout mice (selective deletion HCA2 in microglia, astrocytes or dopaminergic neurons). Our study will provide the experimental basis for the research and development of anti-inflammation drugs targeting HCA2.

帕金森病（PD）是中老年常见的神经退行性疾病，病因未明，尚无法治愈。近年来神经炎症已被证实是PD的病因之一，针对神经炎症寻找PD的治疗靶点已成为当今PD的研究热点。烟酸受体（HCA2）是一种Gi蛋白偶联的受体，本课题组前期发现HCA2能抑制小胶质细胞介导的神经炎症反应，并参与PD的发生发展。我们新近发现HCA2除了小胶质细胞外，在星形胶质细胞和多巴胺能神经元中均有表达，那么HCA2是否也能抑制星形胶质细胞和多巴胺能神经元的炎性反应，HCA2是否能通过其抗神经炎症功能对PD起到治疗作用，有待于进一步确证。因此，本项目拟应用HCA2敲除鼠以及小胶质细胞、星形胶质细胞和多巴胺能神经元HCA2条件性敲除鼠，在整体、细胞和分子水平系统的研究HCA2在神经炎症反应中的作用及其机制，揭示HCA2介导的抗神经炎症作用对PD的影响，以期为PD提供潜在的治疗靶点。

帕金森病（PD）是中老年常见的神经退行性疾病，病因未明，尚无法治愈。近年来神经炎症已被证实在PD中发挥重要作用，针对神经炎症寻找PD的靶点已成为当今PD的研究热点。烟酸受体（HCA2）作为一种Gi蛋白偶联受体，已被发现具有抗炎作用。本项目在前期研究的基础上，进一步研究了HCA2在PD中的神经保护作用及机制。首先，在PD小鼠中，研究了HCA2缺失对小鼠脑部炎症反应和PD病理的影响。结果发现，HCA2缺失增加了小鼠对炎症和PD的易感性。然后在体外培养BV2小胶质细胞系、HA1800星形胶质细胞系、SN4741神经元细胞系，研究了HCA2对神经炎症的影响及其机制。结果发现，HCA2通过AKT/PPARγ-NF-κB信号轴，调节小胶质细胞极化表型，进而抑制神经炎症，而激活HCA2能通过抗神经炎症发挥神经保护作用。最后，在特异性敲除小胶质细胞中HCA2的小鼠上研究了激活HCA2对小鼠PD症状的改善作用。结果发现, 烟酸（NA）通过激活小胶质细胞上的HCA2，改善小鼠的PD症状。本研究揭示了HCA2在PD中的神经保护作用及其机制，为HCA2作为PD的治疗靶点奠定了理论基础。