The Therapeutic Potential of Cold Stored Platelets in Regulating Vascular Instability in Trauma

冷藏血小板调节创伤血管不稳定的治疗潜力

基本信息

批准号：
10652299
负责人：
Shibani Pati
金额：
$ 40.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-05 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10652299
关键词：
Adherens Junction Age Alpha Granule Angiopoietin-2 Antibodies Biological Biological Assay Blood - brain barrier anatomy Blood Banks Blood Platelets Blood Vessels Brain Brain Injuries Cause of Death Cell Communication Cerebral Edema Circulation Coagulation Process Cytoskeleton Data Endothelial Cells Endothelium Functional disorder Glycocalyx Goals Growth Factor Hemorrhage Hemostatic function Hippocampus Histones Immune system In Vitro Incubators Individual Inflammation Injury Intracranial Hemorrhages Investigation Lesion Molecular Morphology Mus Neurocognitive Neurocognitive Deficit Organ failure Outcome Pathway interactions Permeability Platelet Transfusion Regulation Risk Rodent Model Role Scanning Electron Microscopy Signal Pathway Signal Transduction TBI Patients TIE-2 Receptor Temperature Testing Therapeutic Therapeutic Effect Therapeutic Intervention Transmission Electron Microscopy Trauma Trauma patient Traumatic Brain Injury Traumatic injury Vascular Endothelial Cell Vascular Endothelium Vascular Permeabilities Visualization antibody inhibitor blood product blood-brain barrier permeabilization cadherin 5 comparison group cremaster muscle cytokine design experimental study improved improved outcome in vivo inhibitor intravital imaging intravital microscopy mortality mouse model neuroinflammation neuron loss neuroprotection novel therapeutics platelet storage preservation prevent protective effect receptor severe injury vascular endothelium permeability vascular injury

项目摘要

The Therapeutic Potential of Cold Stored Platelets in Regulating Vascular Stability in Trauma Trauma is the leading cause of death world-wide in individuals between the ages of 1-44, with traumatic brain injury (TBI) being the number one cause of death after trauma. Platelet transfusion and balanced ratios of blood products have been shown to increase survival in severely injured bleeding trauma patients. In the current US blood-banking practice, platelets (Plts) are stored in incubators at 22°C for up to 5 days. Storage of Plts at 22°C for 5 days is associated with a storage lesion, increased infectious risk, and an overall decline in hemostatic function. 4°C storage of Plts has been proposed as an equivalent and in some cases superior alternative to 22 °C storage. Therapeutically, in addition to their critical role in hemostasis, Plts are known to safeguard the integrity of the vascular endothelium. Vascular instability is a hallmark effect of traumatic injury leading to vascular permeability, inflammation, coagulation disturbances and end organ failure. In TBI, intracranial hemorrhage (ICH) and cerebral edema are the leading causes of mortality, which are potentially addressable by Plt transfusion. Our previous data demonstrate that 4°C Plts regulate vascular stability and inhibit endothelial cell (EC) permeability similar to 22°C Plts. This proposal will aim to elucidate the therapeutic effects of platelets and cold stored (4oC) platelets on vascular stability in traumatic brain injury (TBI) with the thought that platelets can be used as a first line therapeutic intervention in TBI to decrease cerebral edema, ICH, neuroinflammation and improve outcomes in TBI patients. Aim 1 is a mechanistic aim designed to investigate the structural, molecular and cellular signaling effects of 4°C storage on Plts and on Plt-endothelial cell interactions and coagulation. Inhibitors of relevant Plt and EC signaling pathways will be utilized to tease apart what pathways are relevant to Plt effects on endothelial permeability. Aim 2 is designed to provide a deeper understanding of the effects of 4°C Plts on the vascular endothelium by using state of the art intravital imaging in the cremaster muscle and brain, to visualize the effects of 4°C Plts on vascular permeability, clot formation and preservation of the endothelial glycocalyx. Aim 3 is designed to test out our primary hypothesis that 4°C Plts can be used to regulate vascular stability in TBI hence improving hemostasis, decreasing neuroinflammation and neuronal cell loss. In this revised proposal we have demonstrated our full capabilitiy to execute the proposed studies and have refined our experiments to successfully answer the questions posed.

冷藏血小板调节血管稳定性的治疗潜力创伤创伤是全球 1-44 岁人群死亡的主要原因，其中创伤性脑损伤（TBI）是创伤后血小板输注后死亡的第一大原因。血液制品的平衡比例已被证明可以提高严重受伤者的生存率在美国目前的血库实践中，血小板 (Plts) 储存在出血性创伤患者中。 22°C 培养箱最多可保存 5 天 22°C 培养箱可保存 5 天。病变、感染风险增加以及 Plts 4°C 储存的止血功能总体下降。已被提议作为 22°C 存储的等效替代方案，并且在某些情况下是更好的替代方案。在治疗上，除了止血方面的关键作用外，众所周知，Plt 还可以保护血液血管内皮的完整性。血管不稳定是创伤的标志性影响。损伤导致血管通透性、炎症、凝血障碍和终末器官 TBI 失败的主要原因是颅内出血 (ICH) 和脑水肿。死亡率，我们之前的数据表明，这可以通过 Plt 输血来解决。 4°C Plts 调节血管稳定性并抑制内皮细胞 (EC) 通透性，类似于 22°C Plts. 该提案旨在阐明血小板和冷藏的治疗效果 (4oC) 血小板对创伤性脑损伤 (TBI) 中血管稳定性的影响，认为血小板可用作 TBI 的一线治疗干预，以减少脑水肿、ICH、目标 1 是设计的机械目标。研究 4°C 储存对 Plts 和细胞的结构、分子和细胞信号传导影响 Plt-内皮细胞相互作用和相关 Plt 和 EC 信号传导的抑制剂。将利用这些途径来梳理哪些途径与 Plt 对内皮细胞的影响相关目标 2 旨在更深入地了解 4°C Plts 对渗透性的影响。通过在提睾肌中使用最先进的活体成像来观察血管内皮细胞大脑，可视化 4°C Plts 对血管通透性、凝块形成和保存的影响目标 3 旨在检验我们的主要假设：4°C Plts。可用于调节 TBI 中的血管稳定性，从而改善止血，减少在这个修订后的提案中，我们展示了我们的神经炎症和神经元细胞损失。完全有能力执行拟议的研究并完善我们的实验以成功回答提出的问题。