Complement C5 inhibition as sepsis therapy

补体 C5 抑制作为脓毒症治疗

基本信息

批准号：
10569623
负责人：
FLOREA LUPU
金额：
$ 63.34万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-09 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10569623
关键词：
Affect Amplifiers Anaphylatoxins Animal Model Animals Antibiotics Anticoagulants Anticoagulation Antimicrobial Effect Aspartate Transaminase Attenuated Bacillus Bacillus anthracis Bacteremia Bacteria Basic Science Biological Markers Blood Circulation Blood Coagulation Disorders Blood Urea Nitrogen C5a anaphylatoxin receptor Cause of Death Cell Death Cessation of life Coagulation Process Combined Modality Therapy Complement Complement 3 Convertase Complement 3b Complement 5a Complement Activation Complement Membrane Attack Complex Complement component C5 Complex Contact Inhibition Creatinine Data Development Disease Disease Progression Early treatment Escherichia Escherichia coli Functional disorder Genus staphylococcus Goals Gram-Negative Bacteria Hemolysis Host Defense Hour Immune Tolerance Immune response Impairment Individual Infection Inflammation Inflammatory Response Intensive Care Units Kidney Failure Lead Lethal Dose 50 Life Lipopolysaccharides Mediating Mediator Modeling Multiple Organ Failure Myocardial dysfunction Organ Organ failure Papio Pathogenesis Pathway interactions Patients Peptidoglycan Phagocytosis Plasma Play Prothrombin time assay Recovery Reperfusion Injury Role Sepsis Septicemia Shock Signal Transduction Staphylococcus aureus Syndrome System Testing Therapeutic Thrombosis Time Tissues Vascular Diseases activation product antagonist clinically relevant complement pathway effective therapy hypoperfusion improved improved outcome inhibiting antibody inhibitor innovation microbial nonhuman primate novel novel therapeutics pathogen pre-clinical research preservation prevent receptor response septic septic patients systemic inflammatory response targeted treatment

项目摘要

PROJECT SUMMARY Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. Sepsis is a leading cause of death in intensive care units. The contact of pathogens with the intravascular compartment of the host leads to systemic inflammation, wherein activation of the complement and coagulation systems plays critical roles. The objectives of this proposal are to investigate the role of complement activation and its crosstalk with inflammation and coagulation to sepsis progression and multiple organ failure (MOF) and, whether blocking complement activation at the C5 level could prevent MOF and improve the outcome of sepsis. We will use clinically relevant models of sepsis caused by two of the most common pathogens, Escherichia coli and Staphylococcus aureus to: (i) determine the contribution of complement and coagulation to pathogenesis of microthrombosis, vascular dysfunction, organ failure and death; (ii) test stage-specific therapies targeting the complement and coagulation cascades to provide organ protection and survival benefit in sepsis-induced progressive MOF. Successful completion of these aims will determine: (i) whether timed complement inhibition at the C5 level could be used as an effective therapy for sepsis-induced MOF; (ii) if inhibition of C5a receptor-1 signaling could attenuate disease progression and provide organ protection; (iii) if combination therapies employing early treatment with an anticoagulant and a delayed treatment with a C5 inhibitor will provide synergistic protection in cases of high septic bacteremia/shock. Altogether, our project will combine basic and preclinical research to verify novel hypotheses on the pathophysiology of both Gram-negative and Gram-positive sepsis, and test innovative approaches, which in the long-term may save lives from this deadly disease with no specific cure.

项目摘要败血症是一种威胁生命的器官功能障碍，这是由于宿主对感染的反应失调引起的。败血症是重症监护病房的主要死亡原因。病原体与血管内室的接触宿主会导致系统性炎症，其中补体和凝结系统的激活播放关键角色。该提案的目标是调查补体激活的作用及其与炎症和凝血对败血症的进展和多器官衰竭（MOF），以及是否阻塞 C5水平的补体激活可以防止MOF并改善败血症的结果。我们将使用由两种最常见的病原体大肠杆菌引起的与临床相关的败血症模型金黄色葡萄球菌对：（i）确定补体和凝结对发病机理的贡献微栓塞，血管功能障碍，器官衰竭和死亡；（ii）针对针对的测试阶段特异性疗法补充和凝血级联反应可提供脓毒症引起的器官保护和生存益处渐进式MOF。这些目标的成功完成将确定：（i）是否定时补体抑制在C5级别可以用作败血症诱导的MOF的有效疗法；（ii）如果抑制C5A受体-1信号传导可以减轻疾病进展并提供器官保护；（iii）如果结合疗法提早采用用抗凝剂治疗和用C5抑制剂延迟治疗将提供协同保护在败血性菌血症/休克较高的情况下。总的来说，我们的项目将结合基本和临床前研究，以验证有关的新假设革兰氏阴性和革兰氏阳性败血症的病理生理，以及测试创新方法长期可以从这种致命的疾病中挽救生命，无法治愈。