Rnd3抑制NF-κB信号活化负性调控心肌梗死后炎症反应的作用机制研究

心肌梗死（MI）后适度的炎症反应是心脏愈合所必需的，然而持续过度的炎症反应会加重梗死的程度并引起心脏重塑。NF-κB是炎症反应的上游调控中枢，NF-κB的异常激活往往导致放大的炎症反应以及MI不良结局的发生。课题组前期研究发现Rnd3基因缺陷小鼠的心肌细胞中NF-κB的激活增强并在MI后发展为过度的炎症反应，进一步的预实验表明Rnd3能够结合p65的二聚化结构域而影响p65/p50异二聚体的形成。由此，本项目假设心肌梗死情况下Rnd3通过占据p65的二聚化结构域，破坏p65和p50之间的异源二聚化而抑制NF-κB的激活引起的心脏炎症反应，从而发挥控制MI后心脏炎症反应的心肌保护作用。本项目拟从体内、体外两个层面研究Rnd3影响NF-κB活性及其在心梗后炎症损伤中的作用并探讨其分子机制，这不仅为NF-κB信号通路的调控机制增加了新的视角，并为MI和其他炎性疾病的防治提供新靶点与新策略。

Cardiac inflammatory response after myocardial infarction (MI) is essential for cardiac healing, while excessive and prolonged inflammation extends the infarction and promotes adverse cardiac remodeling. NF-κB is the pivot regulator upstream of inflammatory response. Aberrant NF-κB activation exaggerates inflammation and subsequently promotes detrimental outcomes of MI. Our previous studies have found that Rnd3-deficient mice showed increased NF-κB activation in the heart and developed excessive inflammation after MI. furthermore, the preliminary data suggested that Rnd3 interacted with the dimerization domain of p65 and subsequently interrupted p65/p50 heterodimer level. In this proposal, we hypothesize that Rnd3 negatively regulates inflammatory response post myocardial infarction by suppressing NF-κB activation, which is due to Rnd3 occupies the dimerization surface of p65 and therefore disrupts the heterodimerization between p65 and p50. These findings uncover Rnd3as an essential cardioprotective factor in mediating post-MI inflammation. In this project, we aim to explore the effects of Rnd3 inhibiting the NF-κB activation in cardiomyocytes after MI as well as the molecular mechanism combining in vitro and in vivo experiments. The findings add a new regulatory layer to the negative regulatory machinery of NF-κB signaling, and manipulation of Rnd3 could be as a potential therapeutic approach for MI and other inflammatory diseases.