Contact Activation and Infection

接触激活和感染

基本信息

批准号：
10676088
负责人：
FLOREA LUPU
金额：
$ 55.31万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-23 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676088
关键词：
Acute Respiratory Distress Syndrome Adverse event Animals Antibiotic Therapy Antibiotics Antibodies Antibody Affinity Attenuated Bacteremia Bacterial Infections Bacterial Model Binding Blood Coagulation Disorders Blood Platelets Blood Vessels Bradykinin Cardiopulmonary Cardiovascular system Caring Cause of Death Cessation of life Clinical Clinical Trials Coagulation Process Complement Complement Activation Complement Factor H Complex Consumption Contact Inhibition Data Development Disease Disease Progression Disseminated Intravascular Coagulation Dose Drug Targeting Edema Endothelial Cells Endothelial Plasminogen Activator Inhibitors Enzymes Escherichia coli Evaluation Event Exposure to FDA approved Factor XII Failure Feedback Fibrinolysis Functional disorder Generations Genetic Goals Hemodialysis Hemorrhage Hospitals Hour Hypotension Immune response In Vitro Industry Infection Inflammation Inflammatory Inflammatory Response Infusion procedures Intervention Investments Kallikrein-Kinin System Kininogens Life Medical Medicine Modeling Molecular Molecular Target Morbidity - disease rate Multiple Organ Failure Mus Organ Organ failure Outcome Papio Pathogenesis Pathologic Patients Perfusion Pharmaceutical Preparations Phase II Clinical Trials Play Prekallikrein Prevalence Primates Prognosis Research Research Project Grants Role Sepsis Septic Shock Shock Solid Staphylococcus aureus Support System Syndrome System Systemic infection Testing Therapeutic Thrombin Thrombosis Tissues Translating Vascular Diseases Virulent antibody inhibitor antimicrobial drug bacterial resistance combat complement C5b cytokine release syndrome design drug development drug market druggable target effective therapy granulocyte healthy volunteer improved in vivo infection risk inhibitor microbial molecular dynamics mortality multiorgan damage nonhuman primate novel organ growth pathogen pathogenic bacteria pharmacologic phase I trial prevent research and development response translational potential

项目摘要

Project Summary Our research project is designed to test our central hypothesis that the contact activation system contributes to pathologic mechanisms that lead to vascular dysfunction, thrombin generation, and inflammatory responses during systemic bacterial challenge by specific pathogens. Despite the availability of effective antibiotics, sepsis remains a prevalent clinical syndrome and significant cause of severe in-hospital morbidity and mortality, brought about by a sequence of rapidly advancing dynamic molecular and cellular events that occur upon exposure to and subsequent systemic infection by certain pathogens. Complicating the problem is the increasing prevalence of multiresistant bacterial pathogens. At present, after more than half a century of research, drug development, and countless clinical trials, there are still no FDA-approved marketed drugs specifically indicated for the treatment of sepsis. Sepsis can lead to multiple organ system failure, including failure of vasoregulation, poor tissue perfusion, edema, and systemic hypotension, which are hallmarks of severe sepsis. By triggering cardiopulmonary and vascular collapse, it is often lethal even with available supportive and antibiotic treatments. Sepsis may be accompanied by disseminated intravascular coagulation (DIC), which can lead to both thrombosis and bleeding due to the consumptive coagulopathy. We focus on the contact activation system, because 1) there appears to be a causal relationship between activation of coagulation factor XII and the poor prognosis of some forms of sepsis, and 2) targeting the contact activation system as a therapeutic approach is unlikely to have detrimental consequences for the host such as bleeding. We will study the role of the molecular steps in the contact activation system in the development and outcome of experimental bacterial infection, in vivo. We will define the roles of FXII (Aim 1) and its procoagulant substrate FXI (Aim 2), and translate our mechanistic in vitro studies to characterize the pathological role of contact activation in two distinct baboon models of bacterial infection. The potential translational relevance of our project will be the identification of safe and druggable molecular targets and mechanisms within the contact activation system. Our research may ultimately provide rationale for the development of selective contact activation inhibitors that could safely benefit patients that have or are at risk of infections by pathogens that can cause contact system activation.

项目概要我们的研究项目旨在测试我们的中心假设，即接触激活系统有助于导致血管功能障碍、凝血酶生成和的病理机制特定病原体对全身细菌攻击期间的炎症反应。尽管有有效的抗生素，脓毒症仍然是一种普遍的临床综合征，并且具有重要意义。一系列快速进展的疾病导致严重的院内发病率和死亡率暴露于和随后的全身感染后发生的动态分子和细胞事件某些病原体。多重耐药细菌的日益流行使问题变得更加复杂病原体。目前，经过半个多世纪的研究、药物开发，无数临床试验中，目前尚无 FDA 批准的专门用于治疗的上市药物败血症。脓毒症可导致多器官系统衰竭，包括血管调节失败、组织不良灌注、水肿和全身性低血压，这是严重脓毒症的标志。通过触发心肺和血管衰竭，即使有可用的支持和抗生素，通常也是致命的治疗。脓毒症可能伴有弥散性血管内凝血（DIC），这可能导致消耗性凝血病导致的血栓形成和出血。我们专注于联系激活系统，因为 1) 凝血因子 XII 的激活之间似乎存在因果关系以及某些形式的脓毒症的不良预后，以及 2）将接触激活系统作为目标治疗方法不太可能对宿主产生有害后果，例如出血。我们将研究接触激活系统中分子步骤在发展和结果中的作用体内实验性细菌感染。我们将定义 FXII（目标 1）及其促凝血剂的作用底物 FXI（目标 2），并将我们的体外机制研究转化为表征 FXI 的病理作用两种不同的狒狒细菌感染模型中的接触激活。我们项目的潜在转化相关性将是确定安全且可成药的药物接触激活系统内的分子靶点和机制。我们的研究最终可能为开发可以安全受益的选择性接触激活抑制剂提供理论依据患有或有感染可能导致接触系统激活的病原体感染风险的患者。