Tie2-driven vascular control in critical illness

危重疾病中 Tie2 驱动的血管控制

• 批准号: 10611529
• 负责人: Samir M Parikh
• 金额: $ 81.64万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-16 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10611529
• 关键词: Acute Respiratory Distress Syndrome; Affect; American; Angiopoietin-2; Angiopoietins; Blood Vessels; Caring; Cessation of life; Collaborations; Communities; Critical Illness; Elements; Endothelium; Extravasation; Functional disorder; Gene Expression; Genetic Determinism; Genetic Polymorphism; Genome engineering; Hemostatic function; Human; Immune response; Individual; Infection; Intensive Care; Intensive Care Units; Ligands; Measures; Metabolic; Metabolism; Microcirculation; Modeling; Molecular; National Heart, Lung, and Blood Institute; Organ; Pathway interactions; Patient Care; Peripheral; Physiological; Positioning Attribute; Qualifying; Research; Sepsis; Stress; TEK gene; TIE-2 Receptor; Thrombosis; adverse outcome; antagonist; genetic epidemiology; genetic risk factor; humanized mouse; individualized medicine; mouse model; personalized medicine; public health relevance; response; risk prediction

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.

项目概要 败血症每年影响数百万美国人，是使用重症监护室的主要原因。目前没有 存在针对异常宿主反应的治疗方法，这种反应被广泛认为会导致多器官疾病 严重感染导致功能障碍和死亡。申请人已获得R01持续支持 NHLBI自2007-2008年开始研究脓毒症中宿主血管反应。我们小组已经确定了 Tie2 受体及其配体，血管生成素，作为内皮细胞中的一个重要开关，可能控制 脓毒症血管反应的基本要素。我们提出血管生成素-2（Angiopoietin-2），一种拮抗剂 脓毒症期间诱导的 Tie2 会增强血管渗漏，从而导致急性呼吸系统疾病 败血症和相关病症引起的痛苦。由于 Angiopoietin-2 可以在外周测量，我们 还提出其循环浓度可以预测脓毒症和不良后果的风险 可以使临床医生以定量且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 基因座本身的多态性可能会影响 基因表达，进而影响个体血管对脓毒症应激的反应程度。 我们和许多其他人现在所做的工作表明，我们正处于 基于脓毒症宿主血管反应开发突破性的个性化医疗方法。 这些进步可能会彻底改变我们 ICU 提供的护理。 该应用程序旨在发展核心假设，即 Tie2 轴可能是 通过以下三个主题来研究脓毒症中的宿主血管反应：（1）创建人源化小鼠模型 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 内皮细胞在脓毒症中调节止血； (3) 研究微循环和 代谢活跃的器官，以了解宿主血管反应和代谢障碍如何协同作用 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、以及 新陈代谢使我们能够从分子角度提供前所未有的脓毒症综合分子观点 血管的观点不仅对脓毒症研究中确定的挑战高度敏感 全球领先者，但可以从根本上改变 ICU 患者护理的模式。