FXI and Sepsis

FXI 和败血症

• 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
• 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

 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(申请人提供)：我们的研究项目旨在验证我们的中心假设，即接触因子途径的激活有助于在特定感染病原体诱导的脓毒症期间导致血管功能障碍、凝血酶生成和炎症反应的病理机制。脓毒症是分子和细胞事件的续集，在这种威胁生命的疾病的过程中，这些事件会永久改变。血管调节功能障碍、组织灌流不良、浮肿和全身性低血压是严重脓毒症的特征，如果不进行治疗，会引发心肺和血管崩溃，导致死亡。严重的脓毒症可能伴有弥散性血管内凝血(DIC)，这会加重血管扩张和水肿相关的组织灌注量不足。DIC可导致止血失败，继而因凝血因子和血小板的消耗而出血。我们将重点放在接触激活途径上，因为1)凝血因子XII的病理性激活与某些形式的脓毒症预后不良之间似乎存在因果关系，以及2)将接触激活途径作为一种治疗途径不太可能对宿主产生有害后果。我们将明确凝血接触途径中的分子步骤在严重脓毒症的发展和结局中的作用。我们将确定FXII(目标1)及其促凝底物FXI(目标2)的作用，并将转化我们的体外和体外机制研究，以确定在两个不同的灵长类动物严重脓毒症模型中接触通路激活的病理作用。我们项目的潜在翻译相关性将是识别SAFE和 接触激活途径中的可用药分子靶点和机制。我们的研究可能最终为开发选择性接触激活途径抑制剂提供理论基础，这些抑制剂可以使感染病原体的脓毒症患者受益，这些病原体利用接触激活途径来实现毒力。重要的是，这种方法不会对感染由内源性外源性途径依赖的纤维蛋白形成作为先天免疫反应一部分控制的患者造成伤害。