Molecular Mechanisms Controlling Lymphatic Vascular Function in Health and Disease

摘要 淋巴系统在调节组织液平衡和肠道脂肪摄取方面是必不可少的。重要的是 病态肥胖患者淋巴功能障碍与体重指数呈正相关 淋巴系统在维持代谢动态平衡中的重要性。作为支持，缺乏一个等位基因的小鼠 Prox1(淋巴分化的主要调节者)因淋巴功能缺陷而导致成人发作性肥胖 船只。淋巴管功能障碍如何加重代谢综合征，反之，肥胖如何损害代谢综合征 淋巴功能是一个知之甚少但与医学高度相关的问题。这一点从以下事实中突显出来 接受淋巴清扫术的肥胖乳腺癌患者患乳腺癌的几率是对照组的3.6倍 继发性淋巴水肿者多于非肥胖乳腺癌患者。我们的长期目标是发现分子 在健康和疾病中调节淋巴管功能的机制以及确定关键的调节因子 希望提供潜在的新治疗靶点来对抗毁灭性的代谢紊乱。我们有 确定了两个协同调节促淋巴管生成VEGFR3信号通路的分子。 使用新的小鼠模型，我们将确定操纵这些分子是否会加强修复 以及淋巴管在淋巴清扫和高脂饮食等挑战后的再生反应。 我们将使用敏感的成像方法和临床相关的小鼠模型来解决我们的问题。 具体来说，我们将确定FOXC2调节成年小鼠淋巴功能的分子机制 明确了淋巴管内皮细胞FOXC2和epsin表达的调控机制 细胞。最后，我们将测试靶向FOXC2或epsin在淋巴功能障碍中的治疗潜力。在……里面 总结，我们的发现可以转化为治疗淋巴功能障碍和新陈代谢的创新方法 精神错乱。

ABSTRACT The lymphatic system is essential in mediating tissue fluid homeostasis and intestinal lipid uptake. Importantly, lymphatic dysfunction positively correlates with body-mass index in morbidly obese patients accentuating the importance of the lymphatic system in maintaining metabolic homeostasis. In support, mice lacking one allele of Prox1 (a master regulator of lymphatic differentiation) develop adult onset obesity due to defective lymphatic vessels. How dysfunctional lymphatics aggravates metabolic syndrome, and conversely, how obesity impairs lymphatic function are poorly understood but highly medical relevant questions. This is highlighted by the fact that obese breast cancer patients undergoing lymphadenectomy are 3.6 times more prone to develop secondary lymphedema than non-obese breast cancer patients. Our long-term goal is to uncover molecular mechanisms governing lymphatic vascular function in health and disease and to identify critical regulators in hopes of offering potential new therapeutic targets to combat devastating metabolic disorders. We have identified two molecules that cooperatively regulate the pro-lymphangiogenic VEGFR3 signaling pathway. Using novel mouse models, we will determine whether manipulating these molecules will enhance the repair and regenerative response of lymphatic vessels after challenges such as lymphadenectomy and high fat diet. We will use sensitive imaging approaches and clinically relevant mouse models to address our questions. Specifically, we will determine molecular mechanism by which Foxc2 regulates lymphatic function in adult mice and define the regulatory machinery controlling the expression of Foxc2 and epsin in lymphatic endothelial cells. Finally, we will test the therapeutic potential of targeting Foxc2 or epsin in lymphatic dysfunctions. In summary, our findings could translate into innovative approaches to treat lymphatic dysfunctions and metabolic disorders.