FXI and Sepsis

FXI 和败血症

基本信息

批准号：
9127988
负责人：
FLOREA LUPU
金额：
$ 44.77万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9127988
关键词：
Acute Affect Afibrinogenemia Animal Model Antibodies Anticoagulation Blood Coagulation Disorders Blood Coagulation Factor Blood Coagulation Factor VII Blood Platelets Blood Vessels Blood coagulation Cardiopulmonary Cardiovascular system Cessation of life Clinical Trials Coagulation Process Consumption Development Disease Disease Outcome Disseminated Intravascular Coagulation Edema Endothelial Cells Event F2R gene Factor XII Factor XIIa Failure Fibrin Functional disorder Generations Goals Health Hemorrhage Hemostatic Agents Hemostatic function Hospital Mortality Hour Human Hypotension Immune response In Vitro Infection Inflammation Inflammatory Response Injury Lead Left Life Cycle Stages Listeriosis Medical Modeling Molecular Molecular Target Mus Natural Immunity Organ Outcome Pathogenesis Pathologic Pathway interactions Patient-Focused Outcomes Patients Peptidoglycan Perfusion Peritonitis Platelet Activation Play Polyphosphates Primates Research Research Project Grants Role Sepsis Series Signal Transduction Stroke Surface Syndrome Testing Therapeutic Thrombin Thrombosis Thrombus Tissues Translating Translations Vascular Diseases Vasodilation Venous Thrombosis Virulence Yersinia activated Protein C combat design drotrecogin alfa effective therapy endothelial dysfunction improved in vivo inhibitor/antagonist mortality novel novel therapeutics outcome forecast pathogen patient subsets prevent research study septic

项目摘要

DESCRIPTION (provided by applicant): Our research project is designed to test our central hypothesis that activation of the contact factor pathway contributes to pathologic mechanisms that lead to vascular dysfunction, thrombin generation, and inflammatory responses during sepsis induced by specific infectious pathogens. Sepsis is a sequel of molecular and cellular events that perpetually change over the course of this life threatening disease condition. Failure of vasoregulation, poor tissue perfusion, edema, and systemic hypotension are hallmarks of severe sepsis, and, by triggering a cardiopulmonary and vascular collapse, leads to death when left untreated. Severe sepsis may be accompanied by disseminated intravascular coagulation (DIC) that aggravates the vasodilation and edema-associated tissue perfusion insufficiency. DIC can lead to the failure of hemostasis, and subsequent bleeding due to the consumption of coagulation factors and platelets. We focus on the contact activation pathway, because 1) there appears to be a causal relationship between pathological activation of the coagulation factor XII and the poor prognosis of some forms of sepsis, and 2) targeting the contact activation pathway as a therapeutic approach is unlikely to have detrimental consequences for the host. We will define the role of the molecular steps in the contact pathway of coagulation in the development and outcomes of severe sepsis. We will define the roles of FXII (Aim 1) and its procoagulant substrate FXI (Aim 2), and will translate our mechanistic in vitro and ex vivo studies to define th pathological role of activation of the contact pathway in 2 distinct primate models of severe sepsis. The potential translational relevance of our project will be the identification of safe and druggable molecular targets and mechanisms within the contact activation pathway. Our research may ultimately provide rationale for the development of selective contact activation pathway inhibitors that could benefit sepsis patients infected with pathogens that exploit the contact activation pathway for virulence. Importantly, this approach would not do harm to patients whose infection is controlled by endogenous extrinsic pathway-dependent fibrin formation as part of the innate immune response.

描述（由适用提供）：我们的研究项目旨在检验我们的中心假设，即接触因子途径的激活有助于导致特定感染性病原体引起的脓毒症期间导致血管功能障碍，凝血酶产生和炎症反应的病理机制。败血症是分子和细胞事件的续集，在这种危及生命的疾病状况的过程中，它们会永久改变。血管调节，组织灌注不良，水肿和全身性低血压的失败是严重败血症的标志，并且通过触发心肺和血管塌陷，在未经治疗时会导致死亡。严重的败血症可以通过分布的血管内凝血（DIC）来完成，该凝血（DIC）聚集了血管舒张和与水肿相关的组织灌注不足。 DIC可能导致止血失败，并且由于食用凝血因子和血小板而导致随后的出血。我们关注接触激活途径，因为1）在凝结因子XII的病理激活与某些形式的败血症的不良进展之间似乎存在因果关系，而2）将接触式激活途径作为治疗方法作为治疗方法是不可能对宿主带来不利的后果。我们将定义分子步骤在凝血接触途径中的作用，在严重败血症的发育和结果中。我们将定义FXII（AIM 1）及其Procagulant底物FXI（AIM 2）的作用，并将转化我们在体外的机械和实体研究，以定义在2个不同的严重败血症的2个不同私人模型中接触途径激活的病理学作用。我们项目的潜在翻译相关性将是确定安全和接触激活途径内的可药物分子靶标和机制。我们的研究最终可能为开发选择性接触激活途径抑制剂的发展提供理由，这些抑制剂可能使感染病原体的败血症患者受益于病毒的接触激活途径。重要的是，这种方法不会损害由内源性外途径依赖性纤维蛋白形成作为先天免疫反应的一部分的患者。