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.

项目摘要 败血症每年影响数百万美国人，是重症监护利用的主要原因。目前没有 存在疗法以靶向异常的宿主反应，该反应被广泛承认有助于多器官 严重感染的功能障碍和死亡。申请人已获得连续的R01支持 NHLBI自2007年至2008年以来研究败血症中的宿主血管反应。我们的小组已经确定了Tie2 受体及其配体，即血管生成素，作为内皮的重要开关 血管反应对败血症的基本要素。我们提出了拮抗剂Angiopoietin-2 败血症期间诱导的TIE2，增强血管泄漏，从而导致急性呼吸道 败血症和相关条件引起的困扰。由于可以外围测量血管生成素-2，我们 还建议其循环浓度可以预测败血症和 可以使临床医生能够以定量和操作员独立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为 基因表达，反过来，一个人的血管对败血症的压力有何反应。 我们和许多其他人现在贡献的工作表明我们正在 根据败血症中宿主血管反应开发突破性的个性化药物方法。 这样的进步可能会彻底改变我们的ICU中提供的护理。 该应用程序旨在提出核心假设，即TIE2轴可能是关键的决定因素 通过以下三个主题，败血症中的宿主血管反应：（1）创建人源化的鼠标模型 使用尖端的基因组工程设计的TIE2轴对人类宿主血管反应进行建模，及其 在生理背景下的遗传决定因素； （2）确定TIE2和TIE2和 内皮调节败血症的止血； （3）研究微循环和 代谢有活跃的器官，以了解宿主血管反应和飞行代谢如何合作 驱动多器官功能障碍。 我们团队在TIE2领域，遗传流行病学，血栓形成研究和 代谢独特地定位我们从 血管的观点不仅对败血症研究的挑战高度反应 全球领导者，但从根本上可以改变ICU患者护理的范例。