神经炎症调控自主神经功能以及血压稳态之机制

Hypertension is the most prevalent disease in China with 30% of incidents in adults. It is the major risk factor of stroke, heart failure and neural degenerative diseases. Despite its high prevalence, 90-95% are primary hypertension with unknown etiology. 15-20% patients have resistant hypertension which is defined by the failure of three-drug combination therapy. Therefore, it is imperative to understand the mechanism of hypertension and seek more effective treatment. It has been recently uncovered that hypertension is accompanied with neuroinflammation which is the major factor of sympathetic nerve over-activity and blood pressure increase. As the essential immune cells in the nervous system, microglia are the major participants in the neuroinflammation associated with hypertension, as manifested by morphology change and elevated expression of pro-inflammatory cytokines. Specifically, removing activated microglia could alleviate neuroinflammation and the progression of hypertension. This grant application is focusing on the cellular and molecular mechanisms of neurogenic hypertension. First, we will explore the relationship between the activation status of microglia and sympathetic nerve excitation. Second, we will investigate the mechanism of maintaining central nerve homeostasis; here, we will focus on the pathway of TGFβ since TGFβ expression has direct effects on microglial activity, neuroinflammation and blood pressure regulation. Finally, we will study the molecular character of neuroinflammation associated with hypertension. The successful completion of these aims will not only disclose the neurogenic mechanism of hypertension, but also potentially provide new targets and strategies for a better modulation of hypertension.

高血压在中国成年人群中的发病率高达30%，其发生是脑梗、心衰以及神经退行性病变等疾病的重要危险因素。最新的研究进展表明高血压伴随升高的交感神经活性和神经炎症。然而对于神经炎症导致的高血压进展机制目前尚不清楚。小胶质细胞是脑内主要的免疫细胞，特异性去除激活的小胶质细胞可以缓解高血压的进展以及神经炎症首先，我们将探索小胶质细胞的活化状态与交感神经兴奋性的关系。同时，我们将探讨中枢系统稳态维持和小胶质细胞活性调控机制；在此我们将着眼在TGF的调控通路，因为TGF的表达直接与小胶质细胞活性、神经炎症和血压调控相关。最后，我们将研究高血压相关的中枢系统炎症的分子特征。这一系列研究不仅能进一步揭示高血压发病的中枢机制，还能为治疗高血压提供新的靶点和策略。

高血压在全球范围内成年人群中的发病率高达30%以上，是导致心血管以及神经退行性疾病的独立危险因素。顽固性高血压的病理特征表现为持续升高的交感张力和慢性低度无菌性炎症。本课题聚焦脑内固有免疫细胞小胶质细胞对脑内自主神经元活性的调控机制。目前结果揭示小胶质细胞最为脑内主要分泌PDGFB的细胞类型，通过旁分泌影响自主神经元电活性，该作用通过维持神经元中编码外向钾电流（IA）的Kcnd3基因表达，维持对该神经元的活性的抑制。本课题揭示了小胶质细胞通过非免疫作用对神经元活性的调控机制，为血压的调控提供了全新的机制研究。