Tie2-driven vascular control in critical illness

家长奖R35-HL139424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。申请人已连续获得NHLBI的R01支持 自2007-2008年来研究脓毒症时宿主血管的反应。我们的团队已经发现了Tie2受体 及其配体，血管生成素，作为内皮细胞的重要开关，可能控制必要的元素 对败血症的血管反应。我们提出了血管生成素-2，一种Tie2的拮抗剂，被诱导 在脓毒症期间，会加剧血管渗漏，从而导致以下原因引起的急性呼吸窘迫 败血症及相关情况。由于血管生成素-2可以在外周测量，我们也提出了 其循环浓度可预测脓毒症不良结局的风险，并可使临床医生 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 发现证据表明，TIE2基因座本身的多态可能影响基因表达水平，进而， 一个人的血管对败血症压力的反应是好是坏。我们所从事的这项工作 而许多其他人现在也做出了贡献，这表明我们正处于发展突破的边缘 脓毒症患者基于宿主血管反应的个体化用药方法。这样的进步可能 彻底改变我们ICU提供的护理服务。 这项申请寻求发展核心假设，即Tie2轴可能是宿主的关键决定因素 脓毒症的血管反应通过以下三个主题：(1)建立人源化的Tie2小鼠模型 Axis使用尖端基因组工程来模拟人类宿主血管反应，及其遗传 生理环境中的决定因素；(2)确定Tie2和内皮细胞的主要机制 调节脓毒症的止血；以及(3)研究微循环和代谢活性之间的串扰。 器官了解宿主血管反应和代谢障碍如何协同驱动多器官 功能障碍。

PROJECT SUMMARY FOR PARENT AWARD R35-HL139424 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.