Resuscitation Strategies for Achieving Thrombo-inflammatory Homeostasis

实现血栓炎症稳态的复苏策略

基本信息

批准号：
10397402
负责人：
Mitchell Cohen
金额：
$ 219.86万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-20 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397402
关键词：
Acidosis Acute Address Affect Affinity Affinity Chromatography Age Agonist Alteplase Animal Experiments Animal Model Animals Area Binding Biochemistry Bioinformatics Biological Assay Blood Blood Coagulation Disorders Blood Coagulation Factor Blood specimen Bradykinin Catabolism Cause of Death Cells Citric Acid Cycle Complement Complement 3a Complement 5a Conflict (Psychology)Databases Dependence Distal Early-life trauma Endothelium Enzyme Precursors Enzyme-Linked Immunosorbent Assay Etiology Event Factor XII Fibrinolysis Floods Functional disorder Future Gene Expression Gene Expression Regulation Health Hemorrhage Hemorrhagic Shock Hemostatic Agents Hemostatic function Homeostasis Hour Human Hypotension Immune Inflammation Inflammation Mediators Inflammatory Inflammatory Response Infrastructure Injury Kininogens Kinins Knowledge Liver Liver X Receptor Mammals Mass Spectrum Analysis Measures Mediating Mediator of activation protein Metabolic Methods Molecular Morbidity - disease rate Natural Immunity Nuclear Nuclear Receptors Outcome Pathway interactions Patients Peptide Hydrolases Personal Growth Phase Phenotype Physiological Plasma Plasma Proteins Plasmin Plasminogen Activator Plasminogen Activator Inhibitor 1 Proteins Proteomics Purines RXR Rattus Receptor Signaling Resuscitation Role Sampling Scientist Sea Secure Serine Protease Sex Differences Signal Transduction Succinates Testing Thrombelastography Thrombin Tissues Trauma Trauma patient Traumatic Shock Trust Vascular Permeabilities Venous Vision aged animal data antagonist base cohort crystalloid cytotoxicity design genomic locus hemodynamics human data improved in vivo injured innovation lung injury metabolomics mortality multidisciplinary novel organ injury outcome prediction post-trauma preventable death protein expression protein metabolite receptor recruit response severe injury sexual dimorphism sexual role stable isotope steroid metabolism thromboinflammation trauma induced coagulopathy

Acidosis Acute Address Affect Affinity Affinity Chromatography Age Agonist Alteplase Animal Experiments Animal Model Animals Area Binding Biochemistry Bioinformatics Biological Assay Blood Blood Coagulation Disorders Blood Coagulation Factor Blood specimen Bradykinin Catabolism Cause of Death Cells Citric Acid Cycle Complement Complement 3a Complement 5a Conflict (Psychology)Databases Dependence Distal Early-life trauma Endothelium Enzyme Precursors Enzyme-Linked Immunosorbent Assay Etiology Event Factor XII Fibrinolysis Floods Functional disorder Future Gene Expression Gene Expression Regulation Health Hemorrhage Hemorrhagic Shock Hemostatic Agents Hemostatic function Homeostasis Hour Human Hypotension Immune Inflammation Inflammation Mediators Inflammatory Inflammatory Response Infrastructure Injury Kininogens Kinins Knowledge Liver Liver X Receptor Mammals Mass Spectrum Analysis Measures Mediating Mediator of activation protein Metabolic Methods Molecular Morbidity - disease rate Natural Immunity Nuclear Nuclear Receptors Outcome Pathway interactions Patients Peptide Hydrolases Personal Growth Phase Phenotype Physiological Plasma Plasma Proteins Plasmin Plasminogen Activator Plasminogen Activator Inhibitor 1 Proteins Proteomics Purines RXR Rattus Receptor Signaling Resuscitation Role Sampling Scientist Sea Secure Serine Protease Sex Differences Signal Transduction Succinates Testing Thrombelastography Thrombin Tissues Trauma Trauma patient Traumatic Shock Trust Vascular Permeabilities Venous Vision aged animal data antagonist base cohort crystalloid cytotoxicity design genomic locus hemodynamics human data improved in vivo injured innovation lung injury metabolomics mortality multidisciplinary novel organ injury outcome prediction post-trauma preventable death protein expression protein metabolite receptor recruit response severe injury sexual dimorphism sexual role stable isotope steroid metabolism thromboinflammation trauma induced coagulopathy

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项目摘要

ABSTRACT Annually 40,000 die of unintentional trauma in USA, from potentially preventable complications after hemorrhagic shock. Guided damage control resuscitation (DCR) within the early golden hours improves hemostasis and metabolic homeostasis (Gonzalez, Ann Surg. 2016; 263:1051-9). Our long term vision for this proposal is to develop the knowledge infrastructure necessary to take DCR to the next level in 5-10 years to reduce post traumatic morbidity and mortality drastically (25%). The objective of this RM1 is to restrict thrombo inflammation without losing hemostasis or innate immune defense. The central hypothesis is that plasma can be tailored to achieve thrombo-inflammatory homeostasis. Our rationale is that plasma contains soluble, innate immune components that while perfectly normal can promote lethal thrombo-inflammation and organ injury in trauma patients. Our specific aims test the hypotheses that Trauma and Hemorrhagic shock (T/HS) Aim 1 Resuscitating hemorrhage-induced coagulopathy and immuno-inflammation: will explore the activation of thrombo-inflammatory serine protease cascades that increase vascular permeability, Aim 2 Allosteric modulation of fibrinolysis mediators: multi-domain Ser-proteases (plasmin interactome): will define and identify the released novels regulators of fibrinolysis into the plasma, Aim 3 LXR signaling and hemorrhagic shock rapidly alter the fibrinolytic phenotype: will define the involvement of liver nuclear responses regulating hemostasis in animals and Aim 4 Metabolic reprogramming drives deranged hemostatic and inflammatory responses after T/HS: will characterize the metabolites that perturb innate immunity. This contribution is significant because it provides animal and human data necessary for future FDA approvals while considering the role of sex differences. The proposed approaches are innovative on a number of areas: First, we evaluate complementopathy and kininopathy, which have not been well studied in the context of trauma, acidosis and coagulopathy. Secondly, we identify new regulators of plasmin. Thirdly, the switching of fibrinolysis from one phenotype to another through activation or antagonism of specific nuclear receptors is novel. Lastly, we have identified a number of metabolites that are associated with and induce organ injury/dysfunction, especially lung injury, and are investigating methods to inhibit their accumulation and effects. We have built a multidisciplinary team to study the scope of DCR since 2010. Over the years, we have engaged and supported experts in proteomics, metabolomics, and bioinformatics to analyze earliest patient plasma, discovering hemostatic phenotypes that predict outcomes. We have been amongst the first to test prehospital DCR in the field, and first to obtain detailed TEG and biochemistry of humans in post-traumatic shock. Over the years, we have refined optimal team dynamics 1) recruiting and sustaining suitable experts, 2) assigning responsibility according to specific expertise, and 3) building trust and resolving conflict by emphasizing personal growth.

抽象的在美国，每年40,000人死于无意的创伤，来自出血后的潜在预防并发症震惊。损害控制复苏（DCR）在早期的黄金小时内改善了止血和代谢稳态（Gonzalez，AnnSurg。2016; 263：1051-9）。我们对此建议的长期愿景是建立在5 - 10年内将DCR提升到一个新水平所需的知识基础设施以减少职位创伤性发病率和死亡率急剧（25％）。该RM1的目的是限制势头炎症不会失去止血或先天免疫防御。中心假设是血浆可以量身定制实现血栓炎性稳态。我们的理由是等离子体包含可溶的，先天的免疫虽然完全正常的成分可以促进创伤中致命性血栓炎和器官损伤患者。我们的具体目的测试了创伤和出血性休克（T/HS）目标1的假设1 复苏的出血引起的凝血病和免疫炎症：将探索激活的激活增加血管渗透性的血栓炎性丝氨酸蛋白酶级联反应，目标2变构纤维蛋白溶解介质的调节：多域Ser-蛋白酶（质蛋白质相互作用）：将定义和将纤维蛋白溶解的释放小说调节因子识别为血浆，AIM 3 LXR信号和出血休克迅速改变纤溶表型：将定义调节肝脏核反应的参与动物的止血和瞄准4代谢重编程驱动驱动器会造成止血和炎症 T/HS之后的反应：将表征扰乱先天免疫力的代谢产物。这个贡献是意义重大，因为它为未来FDA批准所需的动物和人类数据提供了考虑性别差异的作用。提出的方法在许多领域都是创新的：首先，我们评估互补病和律学，在创伤，酸中毒和凝血病。其次，我们确定纤溶酶的新调节剂。第三，从一个通过特定核受体的激活或拮抗作用是另一种表型是新颖的。最后，我们有确定了许多与器官损伤/功能障碍相关的代谢产物，尤其是肺伤害，正在研究抑制其积累和影响的方法。我们已经建立了一个多学科自2010年以来研究DCR范围的团队。多年来，我们从事并支持专家蛋白质组学，代谢组学和生物信息学分析最早的患者血浆，发现止血预测结果的表型。我们一直是第一个在该领域测试院前DCR的人之一，首先在创伤后休克中获得人类的详细TEG和生物化学。多年来，我们已经完善了最佳团队动态1）招募和维持合适的专家，2）根据特定的专业知识以及3）通过强调个人成长来建立信任和解决冲突。