A Critical Role for Hypoxia-Inducible Factors in Lymphedema

项目总结/摘要 淋巴水肿是一种慢性和使人衰弱的疾病，目前没有批准的药物治疗。淋巴 由炎症和淋巴管内皮细胞（LEC）功能障碍引起的引流功能不全是主要的 促进水肿进展的因子。LEC衍生的缺氧诱导因子（HIF）-2α是 淋巴管的正常发育和体内平衡;在水肿中观察到的LEC HIF-2α的下降，可能是 与疾病进展直接相关。在实验模型中，降低HIF-2α表达 淋巴引流功能不全，加重组织液积聚。抗炎酮洛芬 最近的研究表明，这种疗法对水肿有效，治疗后的患者显示LEC HIF-2α水平升高， 在他们的皮肤活检中表达。该补助金中提出的研究旨在解决基本的 关于为什么LEC HIF-2α在水肿中减少以及这种减少如何影响淋巴 排水.格兰特假说认为，抑制LEC HIF-2α的表达，由炎症介质引起， 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表达的机制， LEC中HIF-2α调控的基因网络。目的2将研究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 不足目的3研究LEC HIF-2α减少如何通过促进淋巴结转移影响淋巴结结构和功能 细胞代谢异常总的来说，拟议的研究预计将促进对以下问题的理解： HIF-2α在脑水肿中的作用，其原理是所获得的知识可以促进许多- 需要进行治疗性开发。

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.