Mitigators of Radiation-Induced Endovascular Injury: Targeting Tie2 and Thrombocytopenia

放射引起的血管内损伤的缓解剂：针对 Tie2 和血小板减少症

• 批准号: 9385521
• 负责人: Nelson J. Chao
• 金额: $ 55.65万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-06 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9385521
• 关键词: ANGPT1 gene; Acute; Acute Lung Injury; Address; Agonist; Angiopoietin-2; Binding; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; Bone Marrow; Chemicals; Chronic; Development; Effectiveness; Endothelial Cells; Endothelium; Event; Exposure to; Extravasation; Fibrinogen; Fibrosis; Functional disorder; Growth; Hematopoiesis; Hemostatic function; Hour; Human; Impairment; Inflammation; Injury; Ligands; Lung; Mediating; Mediator of activation protein; Medical; Mission; Morbidity - disease rate; National Institute of Allergy and Infectious Disease; Nuclear; Organ; Outcome; Pathologic; Pathway interactions; Pharmacology; Pharmacology and Toxicology; Pre-Clinical Model; Process; Pulmonary Fibrosis; Radiation; Radiation Injuries; Radiation exposure; Radiation induced damage; Receptor Protein-Tyrosine Kinases; Recruitment Activity; Resources; Role; Sepsis; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Testing; Thrombocytopenia; Toxic effect; Transfusion; Vascular Diseases; Vascular Endothelium; Whole-Body Irradiation; animal efficacy; body system; efficacy study; imaging study; improved; improved outcome; lung injury; mortality; mouse model; nanoparticle; novel; novel therapeutics; prevent; programs; radiation effect; radiation mitigator; radiation-induced injury; repaired; safety study; small molecule; small molecule inhibitor; vascular endothelial protein tyrosine phosphatase

PROJECT SUMMARY Radiation exposure from a large-scale nuclear incident could have catastrophic consequences. Significant morbidity and mortality may result from damage to the vascular endothelium. Endothelial cells are central to all organs, and radiation-induced endovascular injury may result in both acute and delayed organ toxicity, such as acute lung injury, pulmonary fibrosis, and impaired hematopoiesis. These outcomes result from several pathological effects on the endothelium, which begin with endothelial barrier disruption and vascular leak. Endothelial integrity and barrier function are regulated in large part by the endothelial receptor tyrosine kinase Tie2. Tie2 activation by its agonist ligand, angiopoietin-1 (Ang-1), promotes vascular integrity, preventing vascular leak induced by inflammation. In contrast, Ang-2, a Tie2 antagonist, inhibits the stabilizing effects of Ang-1, thereby promoting vascular leak in a variety of pathological conditions, such as sepsis and chemical- induced lung injury. Importantly, Ang-2 expression is increased in endothelial cells after exposure to radiation, suggesting that decreased Tie2 activity is an important factor in radiation-induced endovascular injury. In addition to Ang-2, Tie2 is negatively regulated by vascular endothelial-protein tyrosine phosphatase (VE-PTP). Our group has tested a highly selective small molecule inhibitor of VE-PTP, AKB-9785, which acts as a pharmacological Tie2 activator, and shown that it promotes endothelial barrier function in preclinical models. By targeting this pathway, we may increase Tie2 activity, prevent vascular leak after radiation, and improve outcomes. In addition to Tie2, platelets also regulate endothelial barrier function by occupying gaps in the endothelial lining; releasing soluble factors (including Ang-1) to enhance barrier function; promoting the growth of endothelial cells; and maintaining the endothelial ultrastructure. Paucity of platelets (i.e., radiation-induced thrombocytopenia) may mediate vascular leak and other downstream effects. Though thrombocytopenia may be addressed via transfusion, donor platelets are limited in supply and may not be available in a mass radiation event. To meet this need, we have developed fibrinogen-coated nanoparticles (FCN) as a novel therapeutic strategy. Imaging studies suggest that FCN bind to endothelial cells, serving a physical presence (i.e., plugging gaps), and recruit the remaining platelets to sites of need. Thus, FCN may have both direct effects (improved hemostasis) and indirect effects (Ang-1/Tie2 activation) on the endothelium, and preliminary studies in murine models of radiation-induced thrombocytopenia suggest that FCN improve survival. While AKB-9785 and FCN may appear to target different pathways, the role of Ang-1 is an important point of overlap. Therefore, we propose to further characterize the acute and delayed effects of radiation on endothelial cells in the lung and bone marrow, focusing on the endothelial Tie2 signaling pathway and thrombocytopenia as likely mediators of radiation damage. We also propose study to novel countermeasures (AKB-9785, FCN) targeting these pathways to mitigate the effects of radiation-induced endothelial injury.

项目概要 大规模核事故的辐射暴露可能会造成灾难性后果。重要的 血管内皮损伤可能导致发病和死亡。内皮细胞是所有细胞的核心 器官和辐射引起的血管内损伤可能会导致急性和迟发性器官毒性，例如 急性肺损伤、肺纤维化和造血功能受损。这些结果源于几个 对内皮的病理影响，首先是内皮屏障破坏和血管渗漏。 内皮完整性和屏障功能很大程度上由内皮受体酪氨酸激酶调节 领带2。 Tie2 通过其激动剂配体血管生成素-1 (Ang-1) 激活，可促进血管完整性，预防血管生成 炎症引起的血管渗漏。相比之下，Tie2 拮抗剂 Ang-2 会抑制 Tie2 的稳定作用 Ang-1，从而促进多种病理条件下的血管渗漏，例如脓毒症和化学- 诱发肺损伤。重要的是，暴露于辐射后，内皮细胞中的 Ang-2 表达增加， 表明Tie2活性降低是辐射引起的血管内损伤的重要因素。在 除了 Ang-2 之外，Tie2 还受到血管内皮蛋白酪氨酸磷酸酶 (VE-PTP) 的负调节。 我们小组测试了一种高度选择性的 VE-PTP 小分子抑制剂 AKB-9785，它作为 药理学 Tie2 激活剂，并表明它在临床前模型中促进内皮屏障功能。 通过靶向该通路，我们可以增加 Tie2 活性，防止放疗后血管渗漏，并改善 结果。除 Tie2 外，血小板还通过占据内皮屏障间隙来调节内皮屏障功能。 内皮层；释放可溶性因子（包括Ang-1）以增强屏障功能；促进生长 内皮细胞；并维持内皮超微结构。血小板缺乏（即辐射引起的 血小板减少症）可能介导血管渗漏和其他下游效应。虽然血小板减少症可能 通过输血来解决，供体血小板的供应有限，并且可能无法在大规模放射治疗中获得 事件。为了满足这一需求，我们开发了纤维蛋白原涂层纳米粒子（FCN）作为一种新型治疗方法 战略。成像研究表明 FCN 与内皮细胞结合，提供物理存在（即堵塞 间隙），并将剩余的血小板募集到需要的部位。因此，FCN 可能具有两种直接效果（改进 止血）和对内皮的间接影响（Ang-1/Tie2 激活），以及小鼠的初步研究 辐射引起的血小板减少症模型表明 FCN 可提高生存率。而AKB-9785和FCN 尽管Ang-1的作用可能出现不同的靶点，但其作用是一个重要的重叠点。因此，我们 提议进一步表征辐射对肺内皮细胞的急性和延迟影响 骨髓，重点关注内皮 Tie2 信号通路和血小板减少症作为可能的介质 辐射损伤。我们还建议研究针对这些的新对策（AKB-9785，FCN） 减轻辐射引起的内皮损伤影响的途径。