Contact Activation and Infection
接触激活和感染
基本信息
- 批准号:10269038
- 负责人:
- 金额:$ 52.6万
- 依托单位:
- 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:
- 关键词:Adult Respiratory Distress SyndromeAdverse eventAftercareAnimalsAntibiotic TherapyAntibioticsAntibodiesAntibody AffinityAttenuatedBacteremiaBacterial InfectionsBacterial ModelBindingBlood Coagulation DisordersBlood PlateletsBlood VesselsBradykininCardiopulmonaryCardiovascular systemCaringCause of DeathCessation of lifeCleaved cellClinicalClinical TrialsCoagulation ProcessComplementComplement ActivationComplement Factor HComplexConsumptionContact InhibitionDataDevelopmentDiseaseDisease ProgressionDisseminated Intravascular CoagulationDoseDrug TargetingEdemaEndothelial CellsEndothelial Plasminogen Activator InhibitorsEnzymesEscherichia coliEvaluationEventExposure toFDA approvedFactor XIFactor XIIFailureFeedbackFibrinolysisFunctional disorderGap JunctionsGenerationsGenus staphylococcusGoalsHemodialysisHemorrhageHospitalsHourHypotensionImmune responseIn VitroIndustryInfectionInflammationInflammatoryInflammatory ResponseInfusion proceduresInterventionKallikrein-Kinin SystemKininogensLeadLifeMedicalMedicineModelingMolecularMolecular TargetMorbidity - disease rateMultiple Organ FailureMusOrganOrgan failureOutcomePapioPathogenesisPathologicPatientsPerfusionPharmaceutical PreparationsPharmacologyPhase II Clinical TrialsPlayPrekallikreinPrevalencePrimatesPrognosisResearchResearch Project GrantsRoleSepsisSeptic ShockShockSolidSupport SystemSyndromeSystemSystemic infectionTestingTherapeuticThrombinThrombosisTissuesTranslatingVascular DiseasesVirulentantibody inhibitorantimicrobial drugcombatcomplement C5bcytokine release syndromedesigndrug developmentdrug marketdruggable targeteffective therapygranulocytehealthy volunteerimprovedin vivoinfection riskinhibitor/antagonistmicrobialmortalitymultiorgan damagenonhuman primatenovelorgan growthpathogenpathogenic bacteriaphase I trialpreventresearch and developmentresponse
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
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('FLOREA LUPU', 18)}}的其他基金
Discovery and Characterization of Novel Sepsis Proteome Biomarkers
新型脓毒症蛋白质组生物标志物的发现和表征
- 批准号:
10364288 - 财政年份:2021
- 资助金额:
$ 52.6万 - 项目类别:
COBRE: OK MED RES FOUND: CORE I: IN VITRO MICROSCOPY CORE
COBRE:确定医学研究成果:核心 I:体外显微镜核心
- 批准号:
8168454 - 财政年份:2010
- 资助金额:
$ 52.6万 - 项目类别:
EPCR, TAFI as Regulators of PMN/Endothelial Interaction
EPCR、TAFI 作为 PMN/内皮相互作用的调节剂
- 批准号:
7939125 - 财政年份:2009
- 资助金额:
$ 52.6万 - 项目类别:
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