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：
10420351
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/10420351
关键词：
Affect Amplifiers Anaphylatoxins Animal Model Animals Antibiotics Anticoagulants Anticoagulation Antimicrobial Effect Aspartate Transaminase Attenuated 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 Creatinine Data Development Disease Disease Progression Early treatment Escherichia Escherichia coli Functional disorder Genus staphylococcus Goals 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 of activation protein 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 Savings Sepsis Septicemia Shock Signal Transduction Staphylococcus aureus Syndrome System Testing Therapeutic Time Tissues Vascular Diseases activation product antagonist base 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.

项目概要脓毒症是一种由宿主对感染反应失调引起的危及生命的器官功能障碍。败血症是一种重症监护病房死亡的主要原因。病原体与血管内室的接触宿主导致全身炎症，其中补体和凝血系统的激活发挥作用关键角色。该提案的目的是研究补体激活的作用及其与补体激活的串扰炎症和凝血对脓毒症进展和多器官衰竭 (MOF) 的影响，以及是否阻断 C5 水平的补体激活可以预防 MOF 并改善脓毒症的结果。我们将使用由两种最常见病原体大肠杆菌引起的脓毒症的临床相关模型和金黄色葡萄球菌：(i) 确定补体和凝血对发病机制的贡献微血栓形成、血管功能障碍、器官衰竭和死亡； (ii) 测试针对特定阶段的疗法补体和凝血级联在脓毒症引起的情况下提供器官保护和生存益处渐进式 MOF。成功完成这些目标将决定：(i) 是否在 C5 水平进行定时补体抑制可作为脓毒症引起的 MOF 的有效治疗方法； (ii) 抑制 C5a 受体 1 信号传导是否可以减缓疾病进展并提供器官保护； (iii) 如果早期采用联合疗法抗凝剂治疗和 C5 抑制剂延迟治疗将提供协同保护在严重败血症菌血症/休克的情况下。总而言之，我们的项目将结合基础研究和临床前研究来验证关于革兰氏阴性和革兰氏阳性败血症的病理生理学，并测试创新方法，其中从长远来看，这种致命疾病没有特效治疗方法，可能会挽救生命。