Development of a carbon monoxide scavenging hemoprotein as a novel antidotal therapy to treat inhaled CO poisoning
开发一氧化碳清除血红蛋白作为治疗吸入性一氧化碳中毒的新型解毒疗法
基本信息
- 批准号:10387161
- 负责人:
- 金额:$ 7.68万
- 依托单位:
- 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:2022-02-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:Accident and Emergency departmentAerobicAffinityAmbulancesAmino AcidsAnimal ModelAntidotesAreaBehavior monitoringBindingBiochemicalBiologyBiophysicsBlood PressureCarbon MonoxideCarbon Monoxide PoisoningCarboxyhemoglobinCardiacCathetersCessation of lifeChemistryDataDevelopmentDiagnosisDiseaseEmergency department visitErythrocytesEscherichia coliExhibitsFunctional disorderGoalsHealthHemeHemeproteinsHemoglobinHumanHyperbaric OxygenIn VitroInhalationIntravenousInvestigationKnowledgeLaboratoriesLeadershipLigandsMediatingMedicineMentorsMetabolismMethodsMicrobeModelingMolecular CloningMorbidity - disease rateMusNeurocognitiveOrganOutcomeOxidation-ReductionOxygenPatient-Focused OutcomesPatientsPersonsPhysiciansPhysiologicalPoisoningPrincipal InvestigatorPropertyProtein EngineeringProteinsRecombinant ProteinsRecombinantsResearchSafetyScientistSignal TransductionSiteSite-Directed MutagenesisSoilSpectrum AnalysisSurvivorsTechnical ExpertiseTestingTherapeuticToxic effectTrainingUnited StatesVariantWorkautooxidationbasecareercareer developmentchemical stabilityclinically relevantconventional therapydrug developmentexperienceheart rate monitorhemodynamicshuman diseasehuman modelimprovedin vivolong-term sequelaemicrobialmortalitymouse modelnanomolarnovelnovel therapeuticspoint of carepre-clinicalpreventprotein metabolismskillstranscription factortranslational medicine
项目摘要
PROJECT SUMMARY/ABSTRACT
Accidental carbon monoxide (CO) poisoning is the leading cause of human poisoning in the United States,
resulting in approximately 50,000 cases and at least 1,500 deaths annually. No point-of-care antidotal therapy
exists for CO poisoning to date, and conventional treatments are limited to inhalation of 100% normobaric oxygen
or hyperbaric oxygen. While these therapies enhance CO clearance, delays in patient diagnosis and transport
contribute to excess morbidity and mortality. Consequently, a fast-acting CO scavenger that can be deployed in
the field, ambulance, or emergency room could significantly increase survival and long-term outcomes for
patients. Given that CO binds tightly to ferrous heme, our lab seeks to develop a hemoprotein-based CO
scavenger that can bind and eliminate CO as a novel therapy for CO poisoning. Based on preliminary studies
of recombinant hemoproteins, we have identified four key criteria for a safe and efficacious hemoprotein-based
CO scavenger: (1) high (nanomolar) CO affinity to maximize CO scavenging from physiological heme sites, (2)
CO selectivity to minimize competitive inhibition by oxygen binding, (3) thermal and chemical stability to
prevent heme release and adverse reactivity, and (4) redox stability of the Fe(II) heme to prevent autooxidation
to the inactive, Fe(III) heme state. Early investigations of the regulator of CO metabolism (RcoM) protein, a CO-
sensing transcription factor from soil microbes, suggest that this protein exhibits high CO affinity and
unprecedented selectivity for CO over oxygen. The primary objective of this proposal is to develop RcoM into a
safe and efficacious CO scavenger that will serve as an improved therapeutic treatment for CO poisoning. In
Aim 1, we will utilize in vitro spectroscopic methods developed in our lab to identify 1) the minimum functional
RcoM subunit, and 2) key amino acid residues that confer high CO affinity, selectivity, and heme stability. In
addition to characterizing basic biochemical properties, we will assess the ability of recombinantly expressed
RcoM variants to scavenge CO from hemoglobin in CO-saturated red blood cells in vitro. In Aim 2, we will
evaluate the safety and efficacy of two recombinant RcoM truncates in vivo. We will assess systemic and organ-
specific effects of intravenous RcoM delivery in healthy mice in vivo and quantify the ability of RcoM to reverse
hemodynamic collapse and prevent death in a preclinical mouse model of CO poisoning previously developed
in our laboratory. Completion of the proposed aims will advance our fundamental understanding of hemoprotein
ligand selectivity while also advancing the translational development of a novel antidotal therapy to treat inhaled
CO poisoning. These outcomes, in addition to career development, mentored training, and didactic coursework,
will ultimately provide me with the technical expertise, background knowledge, and leadership skills necessary
to accomplish my long-term academic career goal of directing a research team to study CO-dependent signaling
mechanisms relevant to human health and disease.
项目总结/文摘
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Matthew Ryan Dent其他文献
Matthew Ryan Dent的其他文献
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{{ truncateString('Matthew Ryan Dent', 18)}}的其他基金
Optimization of a carbon monoxide (CO) sensing hemoprotein for applications as an antidote for CO poisoning and a biosensor for CO detection in living cells
优化一氧化碳 (CO) 传感血红蛋白作为 CO 中毒解毒剂的应用和用于活细胞中 CO 检测的生物传感器
- 批准号:
10643257 - 财政年份:2023
- 资助金额:
$ 7.68万 - 项目类别:
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