布鲁顿酪氨酸激酶抑制剂致心房颤动机制和干预研究

Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, is a breakthrough in the treatment of B-cell lymphoma, 5%-10% of patients developed new-onset atrial fibrillation (AF), the underlying mechanisms are unclear. Previous studies have demonstrated that over-activation of CaMKII plays a key role in the occurrence and development of atrial fibrillation that is associated with calcium handling disorder in cardiac myocytes and structural remodeling in the atrium. Our group has established ibrutinib-induced atrial fibrillation mouse model, preliminary data showed that ibrutinib can stimulate ROS production in atrial myocytes and subsequently activate CaMKII signaling pathway, thus we proposed that ROS-CaMKII axis activation may be the molecular mechanism for the atrial fibrillation induced by ibrutinib. This project has 3 aims. Aim 1 will verify our hypothesis by multiple state-of-the-art techniques including patch clamp, calcium imaging, the molecular biology technique at different levels spanning from in vivo whole-animals to the single cell. Aim 2 will test whether the intervention of ROS-CaMKII axis can prevent and treat ibrutinib-induced atrial fibrillation. Aim 3 will explore whether the second generation of BTK inhibitors can cause atrial fibrillation. The proposed work will elucidate a novel mechanism for ibrutinib-induced atrial fibrillation and provide a scientific evidence for the prevention and treatment of ibrutinib-induced atrial fibrillation and the development of a new generation of BTK inhibitors without the side effect of atrial fibrillation.

布鲁顿酪氨酸激酶（BTK）抑制剂依鲁替尼是治疗B细胞淋巴瘤的突破性新药，但治疗期间5%-10%的患者新发房颤，且机制不明。研究显示CaMKII过度激活所致的心房细胞钙转运紊乱和心房重构在房颤发生和发展过程中起关键作用。本课题组已构建依鲁替尼致房颤小鼠模型，并发现该药可刺激心房肌细胞产生ROS，进而激活CaMKII信号通路。故我们推测ROS-CaMKII轴激活可能是依鲁替尼致房颤的分子机制。本研究拟在依鲁替尼致房颤小鼠模型上，采用电生理、活细胞荧光成像和分子生物学等技术，从整体-组织-细胞三个层次，围绕心房肌细胞钙转运和心房重构证实假说，并探索第二代BTK抑制剂是否致房颤及其与ROS-CaMKII轴的关系；在此基础上研究干预ROS-CaMKII轴能否有效防治依鲁替尼所致房颤。本项目将阐明依鲁替尼致房颤的全新分子机制，为其房颤副作用的防治以及BTK抑制剂的进一步研发提供科学依据。

布鲁顿酪氨酸激酶（BTK）抑制剂依鲁替尼是治疗B细胞淋巴瘤的突破性新药，但治疗期间5%-10%的患者新发房颤，且机制不明。研究显示CaMKII过度激活所致的心房细胞钙转运紊乱和心房重构在房颤发生和发展过程中起关键作用。本课题组已构建依鲁替尼致房颤小鼠模型，并发现该药可刺激心房肌细胞产生ROS，进而激活CaMKII信号通路。故我们推测ROS-CaMKII轴激活可能是依鲁替尼致房颤的分子机制。本研究拟在依鲁替尼致房颤小鼠模型上，采用电生理、活细胞荧光成像和分子生物学等技术，从整体-组织-细胞三个层次，围绕心房肌细胞钙转运和心房重构证实假说，并探索第二代BTK抑制剂是否致房颤及其与ROS-CaMKII轴的关系；在此基础上研究干预ROS-CaMKII轴能否有效防治依鲁替尼所致房颤。本项目将阐明依鲁替尼致房颤的全新分子机制，为其房颤副作用的防治以及BTK抑制剂的进一步研发提供科学依据。