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Contact Activation and Infection

接触激活和感染

基本信息

批准号：
10269038
负责人：
FLOREA LUPU
金额：
$ 52.6万
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/10269038
关键词：
Adult Respiratory Distress Syndrome Adverse event Aftercare 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 Cleaved cell 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 XI Factor XII Failure Feedback Fibrinolysis Functional disorder Gap Junctions Generations Genus staphylococcus Goals Hemodialysis Hemorrhage Hospitals Hour Hypotension Immune response In Vitro Industry Infection Inflammation Inflammatory Inflammatory Response Infusion procedures Intervention Kallikrein-Kinin System Kininogens Lead 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 Pharmacology Phase II Clinical Trials Play Prekallikrein Prevalence Primates Prognosis Research Research Project Grants Role Sepsis Septic Shock Shock Solid Support System Syndrome System Systemic infection Testing Therapeutic Thrombin Thrombosis Tissues Translating Vascular Diseases Virulent antibody inhibitor antimicrobial drug combat complement C5b cytokine release syndrome design drug development drug market druggable target effective therapy granulocyte healthy volunteer improved in vivo infection risk inhibitor/antagonist microbial mortality multiorgan damage nonhuman primate novel organ growth pathogen pathogenic bacteria phase I trial prevent research and development response

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.

项目总结