KBP微管转运在心肌分化成熟，重塑和心血管神经支配中的作用机制

kinesin结合蛋白KBP调控细胞内微管动态，分子和线粒体转运，在细胞增殖，迁移分化和轴突生长中发挥作用。人类KBP变异可导致中枢和肠道神经发育障碍综合症。心肌细胞KBP与线粒体和微管共定位，但作用不明。我们建立了多种KBP敲除小鼠模型。KBP全身敲除小鼠生后死亡，部分伴心肌发育不良。心肌和神经嵴细胞特异性KBP敲除小鼠能够存活，但后者感觉神经生长障碍伴肢端水肿坏死。假设：通过调控细胞微管动态，关键分子和线粒体转运和代谢，KBP调控了心肌分化成熟和神经轴突生长。利用上述小鼠模型，通过免疫生化，转录和表观组学分析，将阐明KBP在心肌细胞分化成熟，增殖和再生中的作用机制；揭示KBP在心肌病，心梗和心衰等病理重塑中的作用；阐明KBP在外周神经系统形成和心脏血管支配中的作用，探讨神经血管互作在血管结构和功能维护中的作用。本研究将为心肌重塑以及神经血管的互作机制提供新见解。

KBP is kinesin-binding protein that plays important roles in regulation of microtubule dynamics and intracellular cargo trafficking and mitochondrial localization. Mutations of KBP in humans underlie developmental anomalies in Goldberg–Shprintzen syndrome, characterized by defects in the central and enteric nervous system. KBP is highly expressed in cardiomyocytes, where it is co-localized with microtubule and mitochondria, however, its role in cardiac development and function remains unknown. We generated several KBP knockout mouse lines, include global KBP knockout (KO) and mice with KBP being specifically ablated in cardiomyocyte (Tnt-Cre;KBP) or neural crest cell (Wnt1-Cre;KBP) lineages. Preliminary study revealed that KBP-KO mice died shortly after birth with phenotypes of cardiomyopathy. Ablation of KBP in neural crest resulted in defects in sensory neuron axon growth and innervation. We hypothesis that, by regulating intracellular trafficking and localization of proteins and organelles including mitochondria, and mitochondrial biogenesis and metabolism, KBP is essential for myocardial proliferation, differentiation, maturation, and remodeling. KBP is required for peripheral nervous system development and vascular innervation. By using these KBP mouse lines, we will study roles of KBP in: 1) perinatal cardiomyocyte polarity and maturation, and in maintenance of cardiac structure and function; 2) cardiac proliferation and regeneration; 3) the pathogenesis of cardiomyopathy, myocardial infarction and heart failure; 4) Peripheral neuronal differentiation and vascular innervation, as well as neurovascular interaction. Results of the proposed studies will give novel mechanistic insights into related cardiovascular diseases and provide potential targets for better therapeutic intervention.