Cardiac Lymphatics in Heart Failure

 描述(由申请人提供)：淋巴管在维持全身间质液体平衡方面起着重要作用。它们也是运输和成熟免疫细胞的管道。由于手术、放疗/化疗或器官损伤导致的淋巴管功能障碍会导致病理性淋巴水肿以及随后的间质纤维沉积和炎症。心脏包含一个密集的淋巴管网络，随着心肌的每次收缩，淋巴管呈现协调流动。然而，淋巴功能障碍是否有助于心肌缺血后心脏损伤的病理生理进展仍不清楚。此外，我们对缺血性心脏病后心肌水肿对心功能的影响缺乏充分的了解。因此，这项研究计划的总体目标是开发复杂的外科和遗传学小鼠模型工具，以解决心脏淋巴管在心脏病中的功能和调节。基于我们在淋巴管生物学方面的专业知识以及我们对肾上腺髓质素多肽的心脏保护功能的兴趣，我们认为我们处于独特的有利地位，可以分别解决心脏淋巴管增加或淋巴管不足对缓解或加重心肌水肿的影响。我们的研究结果将从概念上为心脏淋巴管在心肌水肿中的作用提供新的见解。

 DESCRIPTION (provided by applicant): Lymphatic vessels serve an essential function in maintaining interstitial fluid balance throughout the body. They also serve as a conduit for the trafficking and maturation of immune cells. Functional disruption of lymphatic vessels by either surgery, radiation/chemotherapy or organ damage results in pathological lymphedema and subsequent interstitial fibrous deposition and inflammation. The heart contains a dense network of lymphatic vessels that exhibit coordinated flow with each contraction of the myocardium. However, whether lymphatic dysfunction contributes to the pathophysiological progression of heart injury following myocardial ischemia remains unknown. Furthermore, we lack a full understanding of the consequences of myocardial edema on heart function following ischemic heart disease. Therefore the overall goal of this research proposal is to develop sophisticated surgical and genetic mouse model tools to address the function and modulation of cardiac lymphatic vessels in heart disease. Based on our expertise in lymphatic vessel biology and our interest in the cardioprotective functions of adrenomedullin peptide, we feel that we are uniquely well- positioned to address the effects of either increased cardiac lymphatics or lymphatic insufficiency on the resolution or exacerbation of myocardial edema, respectively. Results from our studies will provide conceptually novel insights into the largely unexplored role of cardiac lymphatic vessels in myocardial edema.