Galectin-9诱导耐受型树突状细胞分化在心肌梗死后心室重塑中的作用机制研究

Excessive inflammatory reactions play a deleterious role in post infarction ventricular remodeling. As an inhibitor of the immune response, Galectin-9 was significantly contributed to the pathophysiology of various diseases, such as autoimmune diseases, cancer, and HIV infection. Our previous study showed that serum Galectin-9 levels were decreased in the acute myocardial infarction (AMI) patients. Our preliminary studies showed that Galectin-9 inhibited the maturation of DCs. We speculate that Galectin-9 can regulate immune response and ventricular remodeling after AMI via inducing tolerogenic DC differentiation. To confirm this hypothesis, we plan to: first, Galectin-9 levels were measured in animal model and cell model of AMI; second, the tolerogenic DC differentiation was induced by Galectin-9 via binding the HAVCR2 receptor and then targeting to block the activation of NLRP3 inflammasome in cultured BMDC; third, the effect of recombinant adeno-associated virus rAAV9-Galectin-9 was evaluated in the process of ventricular remodeling after AMI. In this study, we may clarify the role of Galectin-9-HAVCR2-NLRP3 inflammasome pathway in tolerogenic DC differentiation and provide a novel therapeutic strategy to improve ventricular remodeling and cardiac function after AMI.

过度的炎症反应在急性心肌梗死（AMI）后心室重塑中发挥极其有害的作用。半乳凝素-9（Galectin-9）作为免疫抑制分子，在自身免疫性疾病、癌症以及HIV感染中具有重大意义。我们前期研究显示，Galectin-9在AMI患者血浆中表达降低。我们预实验发现，Galectin-9能够抑制DC的成熟。我们推测，Galectin-9能诱导耐受型DC（tDC）分化从而调控炎症反应及心梗后心室重塑。因此，拟1.以心梗模型鉴定Galectin-9在心梗后的表达变化；2.以体外培养BMDC细胞模型阐明Galectin-9通过HAVCR2受体靶向抑制DC中NLRP3炎症小体活化，进而诱导tDC分化；3.靶向设计过表达腺病毒rAAV9-Galectin-9，注射AMI动物模型后评估其对心室重塑的保护作用。本研究拟阐明Galectin-9诱导tDC分化的作用机制，为治疗AMI后心室重塑提供理论依据与药物靶点。

急性心肌梗死（acute myocardial infarction，AMI）是指冠状动脉急性、持续性缺血缺氧所引起的心肌坏死，由于其具有高致残率和高致死率的特点，目前已成为全球范围内重大的公共卫生问题。最新研究表明，心室重塑（ventricular remodeling，VR）开始于AMI发病后数小时内，并贯穿慢性心功能不全整个过程，是慢性心功能不全发生发展的关键因素之一，同时也是导致 AMI 患者最终死亡的主要病因。因此，深入阐明AMI后心室重塑的病理生理过程是本领域关键的科学问题之一。. 过度的炎症反应在急性心肌梗死（AMI）后心室重塑中发挥极其有害的作用。半乳凝素-9（Galectin-9）作为免疫抑制分子，在自身免疫性疾病、癌症以及HIV感染中具有重大意义。我们前期研究显示，Galectin-9在AMI患者血浆中表达降低。在这个项目中我们发现，在AMI动物模型中相比于假手术组，Galectin-9在RNA与蛋白水平表达均下降，血清Galectin-9蛋白含量也降低。Galectin-9能够改善小鼠MI术后28天内的生存率及心功能。同时，Galectin-9能够减轻心梗后1周小鼠心脏的炎症反应。心梗后7天，与野生型小鼠对比，HAVCR2基因敲除小鼠心功能降低，而心脏组织炎症反应更重。与此同时，Galectin-9对HAVCR2基因敲除小鼠的心功能改善作用以及心脏组织炎症小体的抑制作用均得到消除。我们还证明了Galectin-9蛋白靶向HAVCR2受体抑制NLRP3炎症小体激活参与诱导tDC分化，以及rAAV9-Galectin-9能够负向调控MI后心室重塑。. 本研究阐明了Galectin-9诱导tDC分化的作用机制，能为治疗AMI后心室重塑提供理论依据与药物靶点。