Cardiac lymphatic vessels in heart development and regeneration.

项目摘要 冠状动脉和心脏淋巴管构成心脏的脉管系统， 为心脏发育和心肌再生提供支持环境。 冠状动脉在维持心脏功能方面起着关键作用， 持续的氧气和营养供应。淋巴管系统是一种专门的 从组织中排出液体并使免疫细胞得以运输的血管网络， 整个身体的监视。尽管最近的临床观察表明， 淋巴管阻塞可能与心脏病和心肌水肿有关 降低心输出量并可导致间质纤维化， 心脏淋巴系统在很大程度上被低估。目前尚不清楚心脏如何 淋巴管在心脏发育、修复和再生过程中形成并发挥作用。 我们以斑马鱼为模型， 因为它们非凡的再生能力在本提案中，我们将检验假设 冠状动脉可以为淋巴管的形成提供指导， Cxcr4a和Ackr3a阳性， 消极地调节这些过程。我们将确定Ackr3a的功能， 冠状动脉和心脏淋巴管发育和心脏再生。使用新颖 我们产生的斑马鱼CRISPR突变体，我们将分析新的候选基因， 冠状动脉和心脏淋巴管发育。以这些斑马鱼为工具， 将评估心脏淋巴管是否会影响心脏再生， 调节体液平衡和免疫细胞清除。我们的研究计划不会 仅提供对冠状动脉和心脏淋巴管的分子机制的见解， 在心脏发育过程中以及对心脏损伤的反应中， 从而为未来的治疗方法提供有希望的靶点。

Project Summary Coronary and cardiac lymphatic vessels constitute the vasculature of the heart and provide a supporting environment for heart development and myocardial regeneration. Coronary arteries play critical roles in maintaining heart functions by providing a continuous supply of oxygen and nutrients. The lymphatic vasculature is a specialized network of vessels that drains fluid from tissues and enables immune-cell trafficking and surveillance throughout the body. Although recent clinical observations suggest that lymphatic obstruction might be associated with heart diseases and myocardial edema decreases cardiac output and can cause interstitial fibrosis, the importance of the cardiac lymphatic system has been largely underappreciated. It is not clear how cardiac lymphatic vessels form and function during heart development, repair, and regeneration. We have characterized cardiac lymphatic vessel formation using zebrafish as a model for their remarkable regenerative capacity. In this proposal, we will test the hypothesis that coronary arteries can provide guidance for the formation of lymphatic vessels during zebrafish heart development and regeneration and Cxcr4a and Ackr3a positively and negatively regulate these processes. We will determine the functions of Ackr3a in coronary and cardiac lymphatic vessel development and heart regeneration. Using novel zebrafish CRISPR mutants we generated, we will analyze new candidate genes in coronary and cardiac lymphatic vessel development. With these zebrafish as tools, we will assess whether cardiac lymphatic vessels can affect heart regeneration by modulating fluid homeostasis and immune cell clearance. Our proposed research will not only provide insights into the molecular mechanisms of coronary and cardiac lymphatic vessel formation during heart development and in response to cardiac injury, it might lead to promising targets for future therapeutic approaches.