不良心室重构是导致心衰的关键机制，而心室重构涉及到许多未知基因、蛋白、信号分子的动态变化过程，目前临床上针对心室重构的干预性措施对防治心衰并未取得理想的效果，因此阐明心室重构及寻求新的干预靶点仍是心血管研究的新挑战。最近发现心肌Fms样酪氨酸激酶3（Flt3）是抑制心室重构的新靶点，但其机制尚未阐明。本课题拟通过心脏后负荷性心衰动物模型（TAC）和细胞培养，应用分子生物学、膜片钳及共聚焦等技术，以Flt3受体-信号通路-功能为主要研究内容：①明确Flt3激活对TAC心室重构及心衰的作用；②阐明Flt3-PI3K/Akt抑制线粒体凋亡通路的机制；③阐明Flt3-PI3K/Akt/NOS/NO调控CaMKIIδ的作用及NO负性调控CaMKIIδ的S-亚硝基化位点。深入研究Flt3激活对压力负荷性心室重构和心衰的保护作用及其新机制，为阐述心衰机制及其临床治疗提供新的理论依据和潜在药物靶点。

Abnormal ventricular remodeling is the key mechanism of heart failure. Ventricular remodeling involves many unknown gene, protein, dynamic change process of signaling molecules.Currently,the intervention measures of the ventricular remodeling for clinical prevention and treatment of heart failure did not achieve the ideal effects, thus elucidating ventricular remodeling and seeking new intervention target are still a new challenge of cardiovascular research. Most recently, it was found that Fms-like tyrosine kinase-3 receptor (Flt3) is a new target of inhibition of ventricular remodeling, however, its mechanisms have not yet been elucidated.This study using molecular biology, patch clamp and confocal techniques,will study the effects and mechanisms of Flt3 activation in cardiac pressure overload induced heart failure animal by transverse aortic contricttion (TAC) and cell model. (1) to clear the effects of Flt3 receptor on TAC ventricular remodeling and heart failure; (2) to clarify inhibiting mechanisms of Flt3/PI3K/Akt on mitochondrial apoptotic pathways;(3)to clarify the regulation mechanisms of Flt3/PI3K/Akt/NOS/NO to CaMKIIδ, and how to modify CaMKIIδ by NO via s-nitrosylation. This will provide an interpretation for heart failure and the new theoretical foundation and potential drug targets for clinical treatment of heart failure.