Role of heparin binding growth factors in vascular leakage and fatal bleeding

肝素结合生长因子在血管渗漏和致命性出血中的作用

• 批准号: 8963247
• 负责人: PATRICIO E RAY
• 金额: $ 43万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963247
• 关键词: A Mouse; Affect; Angiopoietin-1; Angiotensin II; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulants; Arteries; Biological Assay; Biological Markers; Blood Circulation; Blood Pressure; Blood Vessels; Capillary Leak Syndrome; Capillary Permeability; Cardiopulmonary Bypass; Child; Clinical; Coagulants; Critically ill children; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Data; Development; Disease; Early identification; Early treatment; Endothelial Cells; Equilibrium; Event; Extracorporeal Membrane Oxygenation; Extravasation; Fibroblast Growth Factor 2; Functional disorder; Growth Factor; Hemorrhage; Heparin; Heparin Binding; Heparin Binding Growth Factor; Hypotension; Inflammatory; Intervention; Intestines; Knowledge; Mesentery; Mus; Nitric Oxide; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Plasma; Play; Postoperative Period; Procedures; Process; Regulation; Resistance; Risk; Role; Sampling; Signal Pathway; Signal Transduction; Testing; Urine; Vascular Endothelial Growth Factors; Vascular Permeabilities; base; cytokine; high risk; improved; inhibitor/antagonist; mouse model; novel; prevent; prospective; public health relevance; research study; rho

 DESCRIPTION (provided by applicant): Critically ill children treated with heparin during extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass (CPB), are at high risk of developing severe capillary leak syndromes (CLS) and excessive bleeding (EB). These events are attributed to multifactorial causes, including inflammatory cytokines and the anti-coagulant activity of heparin. Very little is known, however, about the role that heparin-binding angiotenic growth factors (HBGFs), acting in synergy with heparin-like drugs, play in this process. A nonsurgical intervention that can effectively control postoperative vascular leakage and bleeding is needed. This proposal is based on our novel observation that Fibroblast Growth Factor-2 (FGF-2), a heparin binding angiogenic growth factor, plays a critical role precipitating lethal bleeding disorders in mice treated with heparin-like drugs. In addition, we found that Angiopoietin-1 (Ang-1), an anti-permeability-anti-inflammatory angiogenic growth factor, can prevent lethal bleeding complications in mice without normalizing their anticoagulant status. Based on these findings, we hypothesize that FGF-2 and other HBGFs, tip the balance to precipitate CLS and EB by inducing changes in vascular tone and permeability in combination with heparin-like drugs. Furthermore, we propose that blocking the permeability signaling pathways induced by heparin + FGF-2 will prevent these complications. Finally, we hypothesize that FGF-2 and other HBGFs will become reliable biomarkers to identify children at high risk of developing CLS and EB. Three aims will be explored. In aim 1, will test the hypothesis that heparin, in synergy with FGF-2, induce vascular leakage and bleeding complications by affecting the vascular activity of Angiotensin II (Ang II), VEGF-A, and nitric oxide (NO). In aim 2 we will identify the basic mechanisms through with Ang-1 prevents the development of severe bleeding complications induced by heparin + FGF-2, and test the hypothesis that blocking the Rho-A, Src, Tek (Tie-2) and other signaling - inflammatory pathways will prevent lethal bleeding complications in mice. In aim 3, we will follow the clinical outcome of children treated with ECMO and CPB, and define the clinical value of FGF-2 and other HBGFs as biomarkers to identify children at risk of developing severe CLS and EB. These experiments will generate new knowledge and treatments to prevent CLS and EB in children treated with ECMO and CPB, and establish the new notion that blocking the early capillary permeability changes induced by heparin + FGF-2 will prevent CLS and EB in these patients without normalizing their anti-coagulant status.

 描述（由申请人提供）：在体外膜肺氧合 (ECMO) 和体外循环 (CPB) 期间接受肝素治疗的危重儿童，发生严重毛细血管渗漏综合征 (CLS) 和出血过多 (EB) 的风险很高。然而，我们对肝素结合血管紧张素的作用知之甚少。生长因子 (HBGF) 与肝素类药物协同作用，在此过程中需要一种能够有效控制术后血管渗漏和出血的非手术干预措施，该建议基于我们对成纤维细胞生长因子 2 的新观察。 FGF-2）是一种肝素结合血管生成生长因子，在使用肝素类药物治疗的小鼠中发挥着促进致命性出血性疾病的关键作用。此外，我们还发现 Angiopoietin-1。 (Ang-1) 是一种抗渗透性抗炎血管生成生长因子，可以预防小鼠致命性出血并发症，而无需使其抗凝状态正常化。基于这些发现，我们发现 FGF-2 和其他 HBGF 可以平衡这一平衡。通过与肝素样药物联合诱导血管张力和通透性变化来促进 CLS 和 EB 此外，我们建议阻断肝素 + FGF-2 诱导的通透性信号通路。最后，我们认为 FGF-2 和其他 HBGF 将成为识别 CLS 和 EB 高风险儿童的可靠生物标志物。目标 1 将探讨肝素协同作用的假设。与 FGF-2 一起使用，通过影响血管紧张素 II (Ang II)、VEGF-A 和一氧化氮 (NO) 的血管活性来诱发血管渗漏和出血并发症。在目标 2 中，我们将确定Ang-1 的基本机制可防止肝素 + FGF-2 引起的严重出血并发症的发生，并检验阻断 Rho-A、Src、Tek (Tie-2) 和其他信号传导 - 炎症途径将防止致命的假设在目标 3 中，我们将跟踪接受 ECMO 和 CPB 治疗的儿童的临床结果，并确定 FGF-2 和其他 HBGF 作为生物标志物的临床价值，以识别有发生严重 CLS 和 CLS 风险的儿童。这些实验将产生新的知识和治疗方法，以预防接受 ECMO 和 CPB 治疗的儿童的 CLS 和 EB，并建立新的概念，即阻断肝素 + FGF-2 诱导的早期毛细血管通透性变化将预防这些患者的 CLS 和 EB。而不使它们的抗凝血状态正常化。