Tie2-driven vascular control in critical illness

危重疾病中 Tie2 驱动的血管控制

基本信息

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
项目类别：
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

项目摘要

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.

家长奖 R35-HL139424 的项目摘要脓毒症每年影响数百万美国人，是重症监护室使用的主要原因。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申请人已获得 NHLBI 的持续 R01 支持。自 2007 年至 2008 年以来，我们研究败血症时的宿主血管反应，并鉴定出 Tie2 受体。及其配体血管生成素，作为内皮细胞中可能控制必需元素的重要开关我们提出了血管生成素-2（Angiopoietin-2），它是 Tie2 的拮抗剂。在脓毒症期间，会加剧血管渗漏，从而导致急性呼吸窘迫由于 Angiopoietin-2 可以在外周进行测量，因此我们还提出：它的循环可以预测脓毒症不良后果的风险，并可以使注意力集中最后，我们最近以定量且独立于操作员的方式跟踪宿主血管反应。发现证据表明 TIE2 基因座本身的多态性可能会影响基因表达水平，进而，一个人的血管对脓毒症压力的反应有多好或有多差。和许多其他人现在做出的贡献表明我们正处于发展突破的风口浪尖基于脓毒症宿主血管反应的个性化医疗方法可能会取得进展。彻底改变我们 ICU 提供的护理。本申请旨在提出核心假设，即 Tie2 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中的血管反应：（1）创建 Tie2 人源化小鼠模型轴使用尖端基因组工程来模拟人类宿主血管反应及其遗传 (2) 确定 Tie2 和内皮细胞相互作用的主要机制调节脓毒症的止血；(3) 研究微循环和代谢活性之间的相互作用器官以了解宿主血管反应和代谢障碍如何协作驱动多器官功能障碍。