Gasdermin D介导的巨噬细胞炎症反应在 动脉粥样硬化进程中的作用及机制研究

Gasdermin D (GSDMD) is an important member of the Gasdermin family of protein，and the latest study confirms that GSDMD controls the secretion of IL-1β and the inflammatory response. Our pre-experiments showed that GSDMD expression was significantly increased in atherosclerosis (AS) plaque and mainly expressed in macrophages. Inflammation stimulated macrophages in vitro, expression of GSDMD, IL-1β and other inflammatory factors were significantly increased, silencing GSDMD significantly inhibited its expression. We speculated that GSDMD as a target for intervention can reduce the vascular inflammation and AS process. In order to confirm the hypothesis, we proposed to detect the dynamic changes of GSDMD in the peripheral circulation blood and AS plaque. 2. We will evaluate the effect of GSDMD on the AS plaques by establishing the GSDMD-/-ApoE-/- double knock out mouse model. 3. We will detect the effect of GSDMD on the the inflammatory reaction， macrophage polarization and the formation of foamed cells by silence or overexpression of GSDMD macrophages in vitro. This study will contribute to perfect the role and mechanism of GSDMD in the development of AS and inflammatory reaction, and may provide a new target for the experimental basis and treatment of AS.

Gasdermin D（GSDMD）是Gasdermin家族蛋白的重要成员，其调控着细胞因子IL-1β的分泌和相关炎症反应。我们的预实验表明，GSDMD在动脉粥样硬化（atherosclerosis,AS）斑块中表达显著升高，且主要表达于巨噬细胞；体外巨噬细胞炎症刺激后，GSDMD表达以及IL-1β等炎症因子分泌显著增高，沉默GSDMD则显著抑制其表达。我们推测以GSDMD为靶点进行干预可调控血管炎症反应及AS的进程。为证实假说，我们拟1.检测AS 形成过程中外周血、斑块中 GSDMD 表达变化；2.建立GSDMD-/-ApoE-/-双敲小鼠，评估GSDMD对斑块形成的影响；3.体外培养腹腔巨噬细胞，沉默或过表达GSDMD检测其对炎症反应、巨噬细胞极化和泡沫化细胞形成的影响。通过本课题研究，阐明GSDMD在AS中的作用及机制，为进一步完善 AS 炎症反应学说及防治提供新的的实验依据和理论。

动脉粥样硬化（atherosclerosis, AS） 性心血管疾病具有较高发病率和致死率， 其引发的心血管并发症对个人和社会都带来严重的经济负担 ， 寻求有效抑制 AS 形成的治疗措施一直是世界公共卫生亟待解决的重要且艰巨的问题。因此深入研究 AS 的形成机制， 为抑制斑块形成提供更为有效的方法， 具有重要的医学价值和深远的社会意义。现代研究证实， AS 是一种慢性炎症性疾病， 炎症反应贯穿 AS 的始终， 由巨噬细胞分泌的炎症因子在斑块形成的过程中发挥着重要作用。Gasdermin D（GSDMD）是Gasdermin家族蛋白的重要成员，其调控着细胞因子IL-1β的分泌和相关炎症反应。我们的研究证实GSDMD在动脉粥样硬化（atherosclerosis,AS）斑块中表达显著升高，且主要表达于巨噬细胞；体外巨噬细胞炎症刺激后，GSDMD表达以及IL-1β ；建立GSDMD-/-ApoE-/-双敲小鼠，敲除 GSDMD 减轻 AS 免疫炎症反应并 阻止或延缓 AS 进程。通过本课题研究，阐明GSDMD在AS中的作用及机制，为进一步完善 AS 炎症反应学说及防，治提供新的的实验依据和理论。以 GSDMD 为靶点进行干预可调控血管炎症反应及 AS 的进程， GSDMD 增加可能促进巨噬细胞内 IL-1β和 IL-18 等炎症因子的分泌， 引发血管的局部炎症反应， 促进 AS 形成，抑制GSDMD的表达显著抑制了动脉粥样硬化斑块的形成。