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: 10170277
• 负责人: Nelson J. Chao
• 金额: $ 53.01万
• 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 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170277
• 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; Mission; Morbidity - disease rate; National Institute of Allergy and Infectious Disease; Nuclear Accidents; Organ; Outcome; Pathologic; Pathway interactions; Pharmacology; Pharmacology and Toxicology; Pre-Clinical Model; Process; Pulmonary Fibrosis; Radiation; Radiation Accidents; Radiation Injuries; Radiation exposure; Radiation induced damage; Receptor Protein-Tyrosine Kinases; Resources; Role; Sepsis; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; TIE-2 Receptor; Testing; Thrombocytopenia; Toxic effect; Transfusion; Vascular Diseases; Vascular Endothelium; Whole-Body Irradiation; animal efficacy; body system; effectiveness evaluation; efficacy study; imaging study; improved; improved outcome; lung injury; medical countermeasure; mortality; mouse model; nanoparticle; novel; novel therapeutic intervention; nuclear countermeasure; prevent; programs; radiation countermeasure; radiation effect; radiation mitigator; radiation-induced injury; recruit; 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.

项目摘要 大规模核事件的辐射暴露可能会带来灾难性的后果。重要的 发病率和死亡率可能是由于对血管内皮的损害而造成的。内皮细胞是所有人的核心 器官以及辐射引起的内血管内损伤可能导致急性和延迟器官毒性，例如 急性肺损伤，肺纤维化和造血受损。这些结果来自几个 对内皮的病理作用，始于内皮屏障破坏和血管泄漏。 内皮完整性和屏障功能在很大程度上受到内皮受体酪氨酸激酶的调节 TIE2。 TIE2由其激动剂配体Angiopoietin-1（Ang-1）激活，促进血管完整性，防止 炎症引起的血管泄漏。相反，TIE2拮抗剂Ang-2抑制了稳定作用 Ang-1，从而在多种病理状况（例如败血症和化学条件）中促进血管泄漏 诱发肺损伤。重要的是，暴露于辐射后的内皮细胞中ANG-2表达增加， 表明降低TIE2活性是辐射引起的血管内损伤的重要因素。在 除ANG-2外，TIE2受血管内皮蛋白酪氨酸磷酸酶（VE-PTP）负面调节。 我们的小组已经测试了高度选择性的小分子抑制剂AKB-9785，该抑制剂充当 药理学领带激活剂，并表明它促进了临床前模型中的内皮屏障功能。 通过针对此途径，我们可能会增加TIE2活性，防止辐射后血管泄漏并改善 结果。除TIE2外，血小板还通过占据差距来调节内皮屏障功能 内皮衬里；释放可溶性因子（包括ANG-1）以增强屏障功能；促进增长 内皮细胞；并保持内皮超微结构。血小板的较弱（即辐射诱导的 血小板减少症）可能介导血管泄漏和其他下游作用。尽管血小板减少症可能 可以通过输血来解决，供体血小板的供应量有限，并且可能无法在质量辐射中使用 事件。为了满足这种需求，我们已经开发了纤维蛋白原涂层的纳米颗粒（FCN）作为一种新型治疗 战略。成像研究表明，FCN与内皮细胞结合，具有物理存在（即堵塞） 差距），并将剩余的血小板招募到需要的站点。因此，FCN可能具有直接效应（改善 止血）和间接效应（ANG-1/TIE2激活）对内皮以及鼠的初步研究 辐射诱导的血小板减少症的模型表明FCN可以提高生存率。而AKB-9785和FCN 似乎靶向不同的途径，Ang-1的作用是重叠的重要点。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作用 骨髓，专注于内皮TIE2信号通路和血小板减少症 辐射损坏。我们还建议对针对这些的新型对策（AKB-9785，FCN）进行研究 减轻辐射引起的内皮损伤的影响的途径。

项目成果

Fibrinogen-Coated Albumin Nanospheres Prevent Thrombocytopenia-Related Bleeding.

• DOI: 10.1667/rade-20-00016
• 发表时间: 2020-08-01
• 期刊: Radiation research
• 影响因子: 3.4
• 作者: Sung AD;Yen RC;Jiao Y;Bernanke A;Lewis DA;Miller SE;Li Z;Ross JR;Artica A;Piryani S;Zhou D;Liu Y;Vo-Dinh T;Hoffman M;Ortel TL;Chao NJ;Chen BJ
• 通讯作者: Chen BJ