Tie2-driven vascular control in critical illness

危重疾病中 Tie2 驱动的血管控制

• 批准号: 10705391
• 负责人: Samir M Parikh
• 金额: $ 9.31万
• 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/10705391
• 关键词: ANGPT1 gene; ANGPT2 gene; Acute Renal Failure with Renal Papillary Necrosis; Acute Respiratory Distress Syndrome; Affect; American; Angiopoietin-2; Angiopoietins; Applications Grants; Award; Bacterial Artificial Chromosomes; Biochemical; Biological Assay; Biology; Blood Vessels; Caring; Cells; Cessation of life; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Critical Illness; Data; Elements; Endothelium; Energy Metabolism; Event; Extravasation; Functional disorder; Future; Gene Expression; Gene Family; Genetic; Genetic Determinism; Genetic Polymorphism; Genome engineering; Hemostatic function; Heritability; Hospitalization; Human; Immune response; Individual; Infection; Intensive Care; Knowledge; Ligands; Measurable; Measures; Metabolic; Metabolism; Microcirculation; Modeling; Mus; National Heart, Lung, and Blood Institute; Organ; Parents; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Physiological; Qualifying; Research; Risk; Sepsis; Signal Transduction; Stress; Syndrome; TEK gene; TIE gene; TIE-2 Receptor; Thrombosis; Variant; adverse outcome; antagonist; biobank; clinical heterogeneity; genome-wide; humanized mouse; improved; in vivo; intravital imaging; mortality risk; mouse model; novel; personalized medicine; precision medicine; prevent; response; risk prediction; vascular endothelial protein tyrosine phosphatase

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.

PALENTIA AWARD R35-HL 139424项目总结 脓毒症每年影响数百万美国人，是重症监护使用的主要原因。目前没有 存在靶向异常宿主应答的疗法，所述异常宿主应答被广泛认为有助于多器官疾病， 功能障碍和严重感染导致的死亡。申请人已获得NHLBI的持续R 01支持 自2007-2008年以来，研究脓毒症中的宿主血管反应。我们的团队已经鉴定出Tie 2受体 及其配体，血管生成素，作为内皮细胞中的重要开关，可以控制必需元素 败血症的血管反应我们已经提出，血管生成素-2，一种Tie 2的拮抗剂， 在脓毒症期间，增强血管渗漏，从而导致急性呼吸窘迫， 败血症和相关病症。由于血管生成素-2可以在外周测量，我们还提出， 它的循环浓度可以预测败血症的不良后果的风险，并使临床医生能够 以定量和独立于操作者的方式跟踪宿主血管反应。最后，我们最近 发现TIE 2基因座本身的多态性可以告知基因表达水平的证据，反过来， 一个人的血管对脓毒症压力的反应是好是坏。我们所从事的这项工作 和其他许多人的贡献表明，我们正处于发展突破的尖端， 基于脓毒症中宿主血管反应的个性化药物治疗方法。这种进步可以 彻底改变我们重症监护室的医疗服务。 本申请旨在发展核心假设，即Tie 2轴可能是宿主的关键决定因素 通过以下三个主题研究脓毒症血管反应：（1）建立人源化小鼠Tie 2模型 轴使用尖端的基因组工程来模拟人类宿主血管反应， 决定因素，在生理背景下;（2）确定Tie 2和内皮细胞的主要机制， 调节脓毒症止血;（3）研究微循环和代谢活性之间的串扰 了解宿主血管反应和代谢异常如何协同驱动多器官 功能障碍