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Novel Imaging and host-directed therapy in pediatric CNS TB

Novel Imaging and host-directed therapy in pediatric CNS TB
儿童中枢神经系统结核的新型影像学和宿主导向治疗
批准号:
10158397
负责人:
Elizabeth Winans Tucker
金额:
$19.87万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-06-05 至 2024-05-31
关键词:
AddressAdolescentAdultAdvisory CommitteesAffectAnimal ModelAntioxidantsAstrocytesAttenuatedAutopsyAwardBiodistributionBiological AssayBiometryBiopsyBrainBrain InjuriesCause of DeathCentral Nervous System AgentsCentral Nervous System InfectionsCentral Nervous System TuberculosisCerebrospinal FluidCerebrospinal Fluid ProteinsCessation of lifeChildChildhoodChronicClinical TrialsColony-forming unitsCommunicable DiseasesCritical CareCysteineDataDendrimersDevelopmentDevelopment PlansDiseaseDisease ProgressionDoseDrug Delivery SystemsDrug KineticsFoundationsFutureGoalsHumanImageImaging technologyImmune responseImmunohistochemistryImmunologicsImmunologyInfectionInflammationInflammatory ResponseKnowledgeLeadLesionLifeLinezolidMass Spectrum AnalysisMeasuresMedicineMeningeal TuberculosisMeningitisMentorsMentorshipMicrogliaModelingMonitorMultidrug-Resistant TuberculosisMultimodal ImagingMycobacterium tuberculosisNational Institute of Allergy and Infectious DiseaseNervous System TraumaNeuraxisNeurologicNeurological outcomeNeuronal InjuryOryctolagus cuniculusOutcomeOxidative StressPathogenesisPathologyPatientsPenetrationPharmaceutical PreparationsPharmacologyPlasmaPositioning AttributePositron-Emission TomographyPrognosisPulmonary TuberculosisRadiology SpecialtyResearchResearch PersonnelResourcesRifampinRoleSafetySamplingScientistSecondary toSiteSpatial DistributionSteroidsStrategic PlanningTherapeuticTimeTracerTrainingTranslationsTuberculomaTuberculosisUniversitiesWorkantimicrobialantimicrobial drugbasecareer developmentclinical translationcytokinedesigndisabilitydrug developmentdrug distributionexperiencefirst-in-humanhuman diseaseimmunopathologyimprovedimproved outcomein vivoineffective therapiesinsightmetabolomicsmortalitymotor deficitmultimodalitynanodevicenanomedicinenanotherapeuticneurobehavioralneuroimmunologyneuroinflammationneuropathologynon-invasive imagingnovelpharmacokinetic modelpharmacometricsprofessorresponseside effectskillssuccesstargeted treatmenttomographytooltranslational physiciantreatment durationtreatment optimizationtreatment responsetreatment strategytuberculosis drugswhite matter

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中文摘要
翻译
项目摘要:中枢神经系统(CNS)结核(TB),最常见的是结核性脑膜炎(TBM)
英文摘要
PROJECT SUMMARY: Central nervous system (CNS) tuberculosis (TB), most often TB meningitis (TBM), is the most severe form of TB and disproportionately affects children, causing death or neurologic disability in over half despite treatment. Current treatment is inadequate – it is based on pulmonary TB, is not optimized for CNS penetration and does not sufficiently ameliorate the neuroinflammation causing neurologic injury. The K08 award will provide Dr. Tucker, a pediatric intensivist at Johns Hopkins University, the essential time, training, resources and mentorship to achieve her goals. Her long-term goal is to become an independent clinician scientist to better understand the host immune response resulting in brain injury in TBM, to inform antimicrobial and adjunctive therapeutic strategies, and to design therapeutic monitoring tools in order to improve treatment and prognosis of children with this devastating disease. In the current proposal, Dr. Tucker will use a juvenile TBM rabbit model to investigate the following aims: (1) optimize dosing of new TB antimicrobial drugs at the site of infection, (2) determine whether the degree of bacterial burden, inflammation or antimicrobial penetration at the site of infection correlates most with neurologic outcomes using multi-modality position emission tomography (PET) imaging, and (3) determine if adjunctive host-directed, anti-oxidative therapy (dendrimer-N-acetyl-L- cysteine[NAC]) targeted to activated microglia attenuates neuroinflammation and improves neurologic injury. To achieve her long-term goals and complete her K08 aims, Dr. Tucker has assembled an interdisciplinary mentorship team of experienced investigators committed to her success. Her mentors are experts in their fields; Dr. Sujatha Kannan is a Professor of Pediatric Critical Care Medicine, whose research focuses on investigating the role of neuroinflammation in the developing brain and utilization of nanotherapeutics, and Dr. Sanjay Jain is a Professor of Pediatric Infectious Disease and Radiology who is an expert in TBM and development of novel PET imaging tracers. Additionally, her advisory committee strengthens her mentorship with expertise in nanomedicine, mass spectrometry and pharmacometrics to provide a strong foundation for her training. The five- year career development plan will provide training in neuropathology, immunology, pharmacology, metabolomics and biostatistics in order to complete these aims and lead to future R01 applications to investigate therapeutic strategies that will improve the prognosis of children with TBM. Completion of the proposed research will significantly advance our knowledge of the dynamic interactions between bacterial burden, host immune response and antimicrobial penetration at the site of infection and provide new insights into TBM’s pathogenesis. Additionally, this research will provide a foundation for clinical translation to optimize treatment in CNS infections with pharmacokinetic modeling and dendrimer nanodevices to enhance CNS drug delivery as well as novel noninvasive imaging to monitor treatment response. Several novel PET tracers and dendrimer-NAC are already undergoing first-in-human studies or clinical trials which enhances translation to patients.
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Novel Imaging and host-directed therapy in pediatric CNS TB
  • 批准号:
    10620286
  • 项目类别:
  • 资助金额:
    $19.87万
  • 财政年份:
    2019
  • 负责人:
    Elizabeth Winans Tucker
  • 依托单位:
Novel Imaging and host-directed therapy in pediatric CNS TB
  • 批准号:
    10402847
  • 项目类别:
  • 资助金额:
    $19.87万
  • 财政年份:
    2019
  • 负责人:
    Elizabeth Winans Tucker
  • 依托单位:
海外基金