星形胶质细胞炎症信号通路在肥胖相关的脑血管内皮细胞功能紊乱中的作用及其机制

Cerebrovascular disease (CVD) is a disease with high prevalence, high disability and extremely high mortality rates. Obesity, hypertension and diabetes are among the major risk factors for CVD. The pathogenesis of CVD is closely related to cerebrovascular dysfunction. Previous work has demonstrated that inflammation plays a key role in the vascular diseases; there are low level, chronic inflammation and reactive glia in the central nervous system in obese animals. In the current research proposal, we are planning to study the role of astrocyte inflammatory signaling pathway in obesity-related CVD. Specifically, we will pursue the study in the following three aims. Aim 1, identify the brain regions in which the vascular network are more prone to dysfunction under obesity condition, by combinatorially utilizing a reporter mouse line in which the vascular cells are labeled by a fluorescent protein and high-fat diet induced obesity mouse model. Aim 2, characterize the roles of excessive inflammatory signaling pathway activation and pro-inflammation cytokine expression and secretion from astrocyte in obesity-related CVD. Aim 3, investigate the effect of inhibition of astrocyte inflammatory signaling pathway on obesity-related CVD, by using a conditional knockout mouse line in which an inflammatory signaling gene is specifically deleted in astrocyte, and antibody therapy targeting the pro-inflammatory cytokine through intracerebroventricular administration. Our proposed research will elucidate the roles of astrocyte inflammatory signaling pathway and the secreted cytokine in obesity-related CVD, and the underlying mechanism. Our research will lay foundation for targeting astrocyte inflammation in the prevention and/or treatment of obesity-related CVD.

脑血管疾病是临床常见疾病，致残、致死率较高，其病因常涉及到血管功能的紊乱，危险因素有高血压、肥胖和糖尿病等。研究显示炎症在血管疾病病理过程中起重要的作用；肥胖常伴随中枢神经系统低水平、慢性的炎症反应和胶质细胞炎性活化。在本项目中，我们计划研究星形胶质细胞来源的炎症细胞因子在肥胖相关的脑血管功能紊乱中的作用及其分子机制，包括以下三个研究内容：1. 利用标记脑血管细胞的荧光Reporter小鼠系研究血管结构或功能易受肥胖影响的脑部区域。2. 研究肥胖小鼠星形胶质细胞炎症信号通路活化、细胞因子分泌与脑血管功能紊乱的关系。3. 结合星形胶质细胞特异性炎症信号分子敲除小鼠和脑内注射抗细胞因子抗体治疗的方法，研究抑制胶质细胞炎症对于肥胖相关的脑血管功能紊乱的逆转或改善作用。开展本研究能够阐明星形胶质细胞来源的炎症因子在脑血管功能紊乱中的作用和机制，从而为靶向相关分子以预防或治疗脑血管疾病打下基础。

脑血管疾病是一类常见的神经系统疾病，致残、致死率高。近年来，研究显示肥胖与脑血管疾病的发生关系密切。在本项目中，我们研究了胶质细胞来源的炎症分子在肥胖相关的脑血管功能紊乱中的作用。我们分析了其中一个主要的动脉——基底动脉。基底动脉在解剖学上紧贴脑干，因此我们选择分析脑干部分多种细胞内Tak1的活化情况。我们的分析显示，在这一结构，Tak1主要在小胶质细胞中活化。根据上述结果，我们分析了小胶质细胞中Tak1与基底动脉血管功能的关系。我们发现，阻断脑内Tak1活性，或者选择性敲除小胶质细胞中Tak1，能够显著改善肥胖小鼠基底动脉的功能。在机制方面，我们发现，Tak1通过增加促炎症细胞因子的表达和分泌引起脑血管功能的异常。阻断该细胞因子的作用能够显著缓解肥胖相关的血管功能异常。总之，本研究发现小胶质细胞表达的Tak1在肥胖相关的脑血管内皮功能紊乱中起作用，并阐明了其作用的机制。在研期间发表论文3篇。