血管紧张素转换酶对小胶质细胞活性的调控机制

Microglia are the resident immune cells in the central nervous system. They not only participate in immune reaction of the brain, but prune the dendrites of neurons and regulate the functions of neurons. The activation and proliferation of microglia have been observed in a various of neurologic diseases, such as epilepsy, Parkinson's disease and Alzheimer's disease. Microglia will be tuned to different activation status /polarization, such as the pro-inflammatory M1 and anti-inflammatory M2, depending on the presence of available cytokines in the milieu. Therefore, how to regulate the activation/polarization of microglia is a central aim to treat neural diseases. Hypertension, especially resistant hypertension, is usually accompanied with sustained elevation of sympathetic nerve activity. The recent studies showed that hypertension is associated with neuroinflammation, and the M1 activation of microglia is the major cause of neuroinflammation and sympathetic nerve overactivity. Angiotensin converting enzyme (ACE) is one of the main pharmacological targets of anti-hypertension. The recent immunological studies unveiled that ACE expression is correlated with activities of macrophages and microglia. Thus, we hypothesize here that ACE will positively regulate microglia to foster neuroinflammation so as to promote the progression of hypertension. This grant proposal is to address the mechanism of ACE in the central regulation of microglia and sympathetic nerve activity. We will study the mice having null, normal and high level of ACE expression in microglia. Moreover, we will study the roles of the two catalytic domains of ACE in microglial biology. Finally, we will investigate a plethora of bioactive peptides which are physiologically regulated by ACE. This proposal is set to understand the cellular and molecular mechanisms of neuroinflammation associated with hypertension. The successful completion of these aims will provide new targets and strategies for a better modulation of microglia in a variety of neural diseases.

高血压发病率在我国成年人群中超过30%，其发生是其它心脑血管疾病以及神经退行性病变的主要诱因。约20%的高血压患者在积极治疗后血压仍得不到有效控制，成为顽固性高血压。鉴于顽固性高血压通常伴随肾交感神经的持续升高、以及中枢慢性炎症，本申请旨在研究高血压的中枢发病机制。既往的研究显示：血管紧张素转换酶（ACE）参与调控脑内小胶质细胞的激活，而小胶质细胞作为脑内主要的免疫细胞决定了中枢的炎症状态。在此我们提出假说：ACE激活小胶质细胞，导致中枢炎症，进而促进高血压进展。我们将使用转基因小鼠研究特异性ACE缺失和 高表达的小胶质细胞在血压和自主神经功能上的调控；同时研究ACE作为一个肽酶如何通过调控水解底物，进而调控小胶质细胞活性的分子机制。本标书从中枢神经系统炎症反应为切入点，在细胞和分子水平深入研究原发性高血压的发病机制。本课题是对既往工作的延伸和拓展，同时为治疗高血压提供新颖的靶点和途径。

高血压作为沉默性杀手，在我国成年人群的发病率高达30%，是导致心血管以及神经退行性疾病的独立危险因素。顽固性高血压的两大特征为持续升高的交感张力和慢性无菌炎症。本项目聚焦这两大特征，研究脑内固有免疫细胞小胶质细胞（MG）通过旁分泌调控下丘脑室旁核交感神经元（PVN）活性，影响交感张力和心血管功能。既往研究着眼于调控PVN神经元环路，鲜有对其内源性电生理活性调控的报道。本课题组前期数据指出：MG作为脑内主要分泌PDGFB细胞类型，通过旁分泌影响PVN交感神经元中编码K+电流的基因表达；高血压诱导后MG内的PDGFB表达显著性下调；提示PDGFB作为分泌型因子参与了神经元电生理活性的调控。本课题将从脑内微环境的角度出发，探究高血压如何通过改变MG中PDGFB的表达，进而干预神经元的兴奋性。在挖掘原发性高血压机制的基础上，为相关神经退行性疾病的干预提高新思路和靶点。