The Protein C Pathway in Mitigation of Radiation-Induced Endothelial and Vascular Dysfunction

减轻辐射引起的内皮和血管功能障碍的蛋白 C 途径

• 批准号: 9384928
• 负责人: Marjan Boerma
• 金额: $ 62.49万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-05 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9384928
• 关键词: Accidents; Acute; Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulants; Apoptosis; Biological Markers; Blood Vessels; Bone Marrow; Brain; Catalogs; Cell Extracts; Cell Survival; Chronic; Data; Development; Disease; Endothelial Cells; Endothelium; Exposure to; Extensive Radiation; FDA approved; Functional disorder; Future; Gene Expression; Gene Expression Profiling; Granulocyte Colony-Stimulating Factor; Health; Heart; Human; Immune response; Impairment; In Vitro; Injury; Knowledge; Lead; Mediating; Medical; Metabolic; Metabolic Pathway; Mission; Molecular; Molecular Profiling; Molecular Target; Monitor; Morphology; Mus; National Institute of Allergy and Infectious Disease; Nuclear; Nuclear Accidents; Organ; Outcome; Pathway interactions; Peptide Hydrolases; Phosphorylation; Plasma; Play; Property; Protein C; Radiation; Radiation Injuries; Radiation Toxicity; Radiation exposure; Radiation induced damage; Radiation-Induced Change; Radiology Specialty; Receptor Signaling; Recombinants; Research; Role; Sampling; Small Intestines; Staining method; Stains; Structure; Surface; System; Technology; Terrorism; Testing; Therapeutic; Thrombomodulin; Triage; Variant; Vascular Diseases; Vascular Endothelium; Whole-Body Irradiation; Wild Type Mouse; activated Protein C; activated protein C receptor; base; body system; endothelial dysfunction; in vivo; insight; irradiation; mass casualty; metabolomics; mouse model; mutant; novel; novel marker; preclinical study; programs; protective effect; radiation response; receptor; response; senescence; transcriptome sequencing; treatment response

PROJECT SUMMARY/ABSTRACT The threat of nuclear accidents or attacks makes it critical to develop medical countermeasures. Preclinical studies have shown a relation between vascular dysfunction and chronic organ radiation damage, but little is known about the underlying protective mechanisms. Hence, to identify targets for mitigation, research is needed to elucidate pathways involved in radiation-induced vascular dysfunction and vascular protection. Radiation-induced endothelial dysfunction is associated with detrimental alterations in the protein C pathway. Loss of endothelial surface thrombomodulin (Thbd) leads to reduced levels of activated protein C (APC), a critical component in plasma that has anticoagulant and anti-inflammatory properties and that enhances endothelial cell survival. We have previously shown that recombinant APC is an effective mitigator of acute radiation injury when administered 24 h after total-body irradiation in a mouse model. We will further explore the paradigm that the protein C pathway plays a central role in radiation-induced vascular dysfunction and that APC is an effective mitigator of both acute and late radiation toxicity in multiple organs. In vitro studies with wild-type and recombinant APC using irradiated human endothelial cells in culture will determine which structural features of APC and which endothelial APC receptors are critical for enhancing post-radiation endothelial function. In vivo studies with wild-type mice, Thbd-deficient mice, and mice with enhanced vascular responses to radiation in the small intestine, heart and brain—three organ systems critical in the endogenous levels of APC will determine the role of the Thbd–protein C pathway in both the acute and the late delayed response to radiation. Gene expression profiling focused on endothelial cells extracted from mice will identify radiation-induced changes in the translatome and the effects of APC on those gene expression profiles. Plasma samples from the same mice will be used to identify metabolite profiles indicative of radiation injury and reflective of how APC alters host responses. Such metabolic data may lead to novel biomarkers, as well as enlightening us about how radiation and radiomitigation affect various metabolic pathways. In summary, these studies will provide novel insights into mechanisms by which the Thbd–protein C pathway components, i.e., APC and its endothelial receptors, achieve endothelial radiomitigation. Studies of endothelial gene expression profiles will provide insights into which endothelial regulatory systems are significantly altered by radiation and rescued by APC. Basic knowledge from this project will provide key data required for thoughtful development of countermeasures addressing radiation-induced endovascular injury.

项目摘要/摘要 核事故或攻击的威胁使发展医学对策是批判性的。 研究表明，血管功能障碍与慢性器官辐射损伤之间有关系，但几乎没有 关于基本保护机制的了解。 需要阐明涉及辐射引起的血管功能障碍和血管保护的途径。 辐射诱导的实质功能障碍与蛋白质C途径的有害改变有关。 造影型外表面血栓形成蛋白（THBD）的丧失导致活化蛋白C（APC）的水平降低 具有抗凝剂和抗炎特性的血浆中的关键成分，并增强 内皮细胞存活。 辐射损伤在小鼠模型中总体照射后24小时进行损伤。 蛋白质途径在辐射引起的血管功能障碍中起着核心作用的范例，并且 APC是多个器官中急性辐射毒性的有效缓解剂。 使用辐照的人内皮凯尔特尔使用野生型和重组APC将确定哪个 APC的结构特征和哪些触及APC受体对于增强后辐射至关重要 与与之有关 小肠，心脏和大脑 - 树器官系统中对辐射的血管反应至关重要 内源水平的APC水平将THBD蛋白C途径在晚期和晚期中的作用 对辐射的反应延迟。 鉴定辐射诱导的翻译组的变化以及APC对这些基因表达的影响 剖面。 伤害和反映APC如何改变宿主的反应。 以及启发我们的辐射和放射线如何影响各种代谢途径 总而言之，这些研究将提供有关THBD C的机制的新见解。 成分，即APC及其内皮受体，可实现造影辐射。 基因表达曲线将提供有关其他定期系统的见解 通过APC救出的辐射。 对辐射引起的血管内损伤的对策进行了周到的对策。