A Critical Role for Hypoxia-Inducible Factors in Lymphedema

项目摘要/摘要 淋巴水肿是一种慢性的、使人衰弱的疾病，目前还没有得到批准的药物治疗。淋巴 由炎症和淋巴内皮细胞(LEC)功能障碍引起的引流不足是主要的 促进淋巴水肿进展的因素。LEC来源的缺氧诱导因子-2α是必需的 淋巴正常发育和动态平衡；淋巴水肿时观察到的LEC HIF-2α下降可能是 直接参与了疾病的发展。在实验模型中，减少缺氧诱导因子-2α的表达会加剧 淋巴引流不足，加重积聚的间质液体。抗炎酮洛芬 最近发现治疗淋巴水肿有效，治疗后患者的LEC HIF-2α升高。 在他们的皮肤活检中表达。这项拨款中提议的研究旨在解决基本问题。 淋巴水肿中LEC HIF-2α减少的原因及其对淋巴的影响 排水系统。格兰特假说是抑制炎症介质引起的LEC HIF-2α表达， 通过促进LEC表型转化和异常细胞能量学来损害淋巴引流。 具体目的1是探讨炎症抑制LEC HIF-2α表达和MAP的机制 低氧诱导因子-2α调控的晶状体上皮细胞基因网络。AIM 2将调查LEC HIF-2α减少如何导致LEC 表型转化，促进淋巴管重塑，加重淋巴引流 不够用。目标3将研究LEC HIF-2α减少如何通过促进淋巴结构和功能 细胞代谢异常。总的来说，拟议的研究可望促进对 低氧诱导因子-2α在淋巴水肿中的作用，其理论基础是所获得的知识可以促进许多- 需要治疗方面的发展。

PROJECT SUMMARY / ABSTRACT Lymphedema is a chronic and debilitating condition currently without approved medical therapies. Lymphatic drainage insufficiency, caused by inflammation and lymphatic endothelial cell (LEC) dysfunction, is the main factor promoting the progression of lymphedema. LEC-derived hypoxia-inducible factor (HIF)-2α is required for proper lymphatic development and homeostasis; the decline of LEC HIF-2α, observed in lymphedema, may be directly involved with disease progression. In experimental models, reducing HIF-2α expression aggravates lymphatic drainage insufficiency and exacerbates accumulating interstitial fluid. Anti-inflammatory ketoprofen therapy was recently shown to be effective in lymphedema, and treated patients show increased LEC HIF-2α expression in their skin biopsies. The studies proposed in this grant are designed to address fundamental questions about why LEC HIF-2α is decreased in lymphedema and how this reduction influences lymphatic drainage. The grant hypothesis is that suppressed LEC HIF-2α expression, caused by inflammatory mediators, impairs lymphatic drainage by promoting LEC phenotypic transformation and abnormal cellular energetics. Specific Aim 1 is to explore the mechanisms by which inflammation inhibits LEC HIF-2α expression and map HIF-2α-regulated gene networks in LECs. Aim 2 will investigate how LEC HIF-2α reduction may cause LEC phenotypic transformation, promote lymphatic vascular remodeling, and aggravate lymphatic drainage insufficiency. Aim 3 will study how LEC HIF-2α reduction affects lymphatic structure and function by promoting abnormal cellular metabolism. Collectively, the proposed studies are expected to advance the understanding of the role that HIF-2α plays in lymphedema with the rationale that the knowledge gained can facilitate much- needed therapeutic development.