Tie2-driven vascular control in critical illness

项目总结 败血症每年影响数百万美国人，是重症监护应用的主要原因。目前没有 存在针对异常宿主反应的治疗方法，这种异常反应被广泛认为是导致多器官功能障碍的原因 严重感染导致的功能障碍和死亡。申请人已获得持续的R01支持 NHLBI自2007-2008年来研究败血症时宿主血管的反应。我们小组已经确定了Tie2 受体及其配体血管生成素作为内皮细胞的重要开关可能调控 败血症时血管反应的基本要素。我们已经提出血管生成素-2，一种拮抗剂 在脓毒症期间诱导的Tie2，加强了血管渗漏，从而促进了急性呼吸道 脓毒症及相关情况引起的痛苦。由于血管生成素-2可以在外周测量，我们 还提出其循环浓度可预测脓毒症的不良结局的风险和 可以使临床医生能够以定量和独立于操作员的方式跟踪宿主血管反应。 最后，我们最近发现的证据表明，TIE2基因座本身的多态可能会影响 基因表达，反过来，一个人的血管对脓毒症压力的反应是好是坏。 我们和其他许多人现在为这项工作做出的贡献表明，我们正处于 开发基于脓毒症宿主血管反应的突破性个性化药物治疗方法。 这些进步可能会使我们ICU提供的护理发生革命性变化。 这个应用程序试图发展核心假设，即Tie2轴可能是 脓毒症中宿主血管反应通过以下三个主题：(1)建立人源化的小鼠模型 Tie2轴使用尖端基因组工程来模拟人类宿主血管反应，及其 生理背景下的遗传决定因素；(2)确定Tie2和Tie2的主要机制 内皮调节脓毒症的止血；以及(3)研究微循环和血管内皮之间的串扰。 代谢活跃的器官，以了解宿主血管反应和代谢障碍是如何协同作用的 导致多器官功能障碍。 我们团队在Tie2领域、遗传流行病学、血栓研究和 新陈代谢为我们提供了前所未有的、完整的脓毒症分子观点 血管视角，不仅对脓毒症研究中的挑战高度响应，而且 全球领导者，但可能从根本上改变ICU的患者护理模式。

PROJECT SUMMARY Sepsis affects millions of Americans annually and is a leading cause for intensive care utilization. Currently no therapies exist to target the abnormal host response that is widely acknowledged to contribute to multi-organ dysfunction and death from severe infection. The applicant has received continuous R01 support from the NHLBI since 2007-2008 to research the host vascular response in sepsis. Our group has identified the Tie2 receptor and its ligands, the Angiopoietins, as an important switch in the endothelium that may govern essential elements of the vascular response to sepsis. We have proposed that Angiopoietin-2, an antagonist of Tie2 that is induced during sepsis, potentiates vascular leakage and thereby contributes to acute respiratory distress arising from sepsis and related conditions. Since Angiopoietin-2 can be measured peripherally, we have also proposed that its circulating concentration may predict the risk of adverse outcomes from sepsis and may enable clinicians to track the host vascular response in a quantitative and operator-independent fashion. Finally, we have recently found evidence that polymorphisms at the TIE2 locus itself may inform the level of gene expression, and in turn, how well or poorly an individual's blood vessels respond to the stress of sepsis. This body of work to which we and many others have now contributed suggests that we are on the cusp of developing breakthrough personalized medicine approaches based on the host vascular response in sepsis. Such advances could revolutionize the care delivered in our ICUs. This application seeks to develop the core hypothesis that the Tie2 axis may be a crucial determinant of the host vascular response in sepsis through the following three themes: (1) create humanized mouse models of the Tie2 axis using cutting-edge genome engineering to model the human host vascular response, and its genetic determinants, in a physiological context; (2) identify major mechanisms by which Tie2 and the endothelium regulate hemostasis in sepsis; and (3) study the crosstalk between the microcirculation and metabolically active organs to understand how the host vascular response and dysmetabolism collaborate to drive multi-organ dysfunction. The outstanding qualifications of our team in the Tie2 field, genetic epidemiology, thrombosis research, and metabolism uniquely position us to deliver an unprecedented and integrated molecular view of sepsis from the perspective of blood vessels that is not only highly responsive to the challenges in sepsis research identified by global leaders, but could fundamentally alter paradigms of patient care in the ICU.