Targeting Angiogenesis Pathways for Therapeutic Protection against Dengue

登革热病毒的四种血清型在100多个国家传播，估计造成9000万病例。在这些登革热患者中，有急性毛细血管渗透性导致体内液体流失的患者，如果不加以纠正，可能导致休克、出血和死亡。结果，登革出血热/登革休克综合征（DHF/DSS），广泛归因于病理药理学介质，因为严重的内皮损伤持续数小时并迅速逆转。及早发现失水患者，应适当补充水分，以稳定病情。鉴于有症状的登革热在世界上造成的巨大负担，出现治疗失败也就不足为奇了——据估计，每年有2万人死于登革热。对人类的研究揭示了伴随休克综合征的血管生成因子的模式。其中包括血管内皮生长因子（VEGF）和血管生成素(Ang)- 1/Ang-2。我们实验室开发的一个小鼠模型，被其他人广泛使用，概括了DHF/DSS，包括毛细血管渗漏导致血液浓缩，休克和死亡。我们的初步数据显示，DENV感染小鼠的VEGF和Ang-2水平升高，用一种靶向VEGF通路的小分子药物治疗小鼠，可以保护小鼠免受DENV致命的攻击，VEGF通路参与调节内皮细胞的稳定性和屏障功能。基于这些数据，我们假设靶向VEGF和/或Ang-1/Ang-2通路将保护小鼠免受DENV疾病发病机制的影响。为了验证这一假设，我们提出以下具体目标：探讨抑制VEGF通路是否对DENV发病机制有保护作用。2. 探讨操纵ang1 / ang2通路是否能保护宿主免受DENV疾病的发病机制。

The four serotypes of dengue virus (DENV) circulate in more than 100 countries, resulting in an estimated 90 million cases of disease. Among these persons with dengue disease are patients who develop acute capillary permeability resulting in internal fluid losses that if not corrected may lead to shock, hemorrhage, and death. The outcome, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), is widely attributed to pathological pharmacologic mediators, as serious endothelial damage lasts for a matter of hours and is rapidly reversed. Early identification of individuals suffering from fluid loss should lead to appropriate fluid replacement that stabilizes the situation. Given the immense burden of symptomatic dengue in the world, it is not surprising that there are treatment failures—an estimated 20,000 persons die of dengue each year. Research in humans has revealed a pattern of angiogenic factors that accompany the shock syndrome. Among these are vascular endothelial growth factor (VEGF) and angiopoietin (Ang)- 1/Ang-2. A mouse model, developed in our laboratory, and widely used by others, recapitulates DHF/DSS, including capillary leakage leading to hemoconcentration, shock and death. As shown by our preliminary data, DENV-infected mice have elevated levels of VEGF and Ang-2, and treatment of mice with a small molecule drug that targets the VEGF pathway, which is involved in regulating endothelial cell stability and barrier function, protects mice from lethal DENV challenge. Based on these data, we hypothesize that targeting the VEGF and/or Ang-1/Ang-2 pathway will protect mice against DENV disease pathogenesis. To test this hypothesis, we propose the following Specific Aims: 1. To investigate whether inhibition of the VEGF pathway protects the host against DENV disease pathogenesis. 2. To investigate whether manipulation of the Ang-1/Ang-2 pathway protects the host against DENV disease pathogenesis.