Translational Modeling of Brain Injury Rehabilitation to Maximize Recovery.
脑损伤康复转化模型以最大限度地恢复。
基本信息
- 批准号:10341226
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-01 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAcheAcuteAnimal ModelAnimalsAnisotropyAutopsyBlindedBloodBrainBrain InjuriesBrain MassBrain-Derived Neurotrophic FactorBranched-Chain Amino AcidsCaringChronicClinicalClinical ManagementClinical ResearchCognitionCognitive deficitsComaCommunitiesDataData CollectionDiagnosticDietary SupplementationDiffuseDiffuse Axonal InjuryDiffusion Magnetic Resonance ImagingDoctor of PhilosophyElectrophysiology (science)EnrollmentEnvironmentEtiologyEvaluationExerciseFamily suidaeFatigueFoundationsFrequenciesFutureGaitGeneral PopulationGoalsHeadHistopathologyHumanImmunohistochemistryIndividualInjuryInterventionInvestigationInvestmentsK-Series Research Career ProgramsKnowledgeLifeLongitudinal StudiesMedical centerMentorsMentorshipMissionModelingMonitorNerve DegenerationNervous System TraumaNeurologicOutcomeOutputPathologyPathway interactionsPatientsPennsylvaniaPhasePhiladelphiaPhysical ExercisePlacebosPre-Clinical ModelProtocols documentationRandomizedRecoveryRecovery of FunctionRehabilitation therapyResearchResearch PersonnelResolutionResourcesRodent ModelRotationSample SizeSerumServicesSeveritiesSignal TransductionSleepSleep DeprivationSleep disturbancesSliceStructureSystemTestingTherapeuticTimeTranslationsTraumatic Brain InjuryTraumatic Brain Injury recoveryUnconscious StateUnit of MeasureUniversitiesVeteransactigraphyamino acid therapybrain sizecareerclinically relevantcognitive enhancementcognitive recoverycognitive testingdiet and exercisedietarydriving forceeffective therapyefficacy testingexercise rehabilitationexperienceimprovedin vivointerestlong-term rehabilitationmembermilitary veteranmultimodalityneurobehavioralneuroimagingneurological rehabilitationneuroprotectionnovel therapeuticspatient variabilityporcine modelpre-clinicalprognosticrehabilitation researchrehabilitation strategyresearch and developmentrestorationsevere injurysleep qualitytherapeutic targettherapy developmenttractographytranslational modeltreadmilltreatment group
项目摘要
The motivating force driving me to build an independent research enterprise has been my personal desire to
maximize functional recovery after traumatic brain injury (TBI). Experiences in my life have solidified this
research goal as one of primary purpose, and my career trajectory and accomplishments through adversity
stand as evidence of my devotion to that purpose and ability to acheive it. This mission brought me to the
Philadelphia CMC VA Medical Center (CMC-VAMC), where I have found that my own research goals align
perfectly with those of the Rehabilitation R&D (RR&D) Service and the needs of our Veterans. To make the
greatest impact on TBI rehabilitation, I will utilize a unique large animal model to accurately replicate the
mechanisms and manifestations of human TBI: the swine rotational acceleration system applied to great effect
by my mentor, D. Kacy Cullen, PhD, and other researchers in his Center for Neurotrauma, Neurodegeneration,
and Restoration at the CMC-VAMC and University of Pennsylvania. In addition to diffuse axonal injury, this
model results in damage to the ascending reticular activating system (ARAS) as observed in moderate TBI in
humans, leading to temporary loss of consciousness and lasting effects on sleep, fatigue, and cognition that are
major factors during recovery from TBI. Due to their small brain size, our commonly used rodent models
cannot be used to reproduce these aspects of the human injury or their manifestations, as the damage is a
product of rotational acceleration and brain mass. In this project I propose to build on the swine model,
extending beyond the acute injury period following moderate TBI to establish the first translational model of
moderate TBI Rehabilitation and Recovery at long-term time points most relevant for our Veteran population.
Such a high-fidelity preclinical model will provide the rigor and control necessary to directly test the efficacy of
individual ingredients of rehabilitation therapies (e.g. diet, exercise) and conduct detailed mechanistic
investigations to inform adjustments to existing therapies and development of new therapies that improve
efficacy. I will christen this vessel of bidirectional translation with a blinded, randomized investigation of the
efficacy and mechanisms of action of dietary branched-chain amino acid (BCAA) therapy for enhancing
cognitive recovery over a three-month study period (including investigation of Veteran-relevant delayed therapy
administration). Our studies will benefit greatly from clinically-relevant advanced neuroimaging, a gamut of
clinically-inspired neurobehavioral and neurological testing, extensive histopathological and
immunohistochemical analyses, and high-resolution post-mortem diffusion tensor imaging with anisotropy,
diffusivity, and tractography to quantify changes in brain connectivity that are a hallmark of human TBI. I will
also utilize this model to test the mechanisms and efficacy of regular exercise rehabilitation or exercise plus
BCAAs for improving recovery trajectory over a six-month period (also with Veteran-relevant delayed
treatment). Previous studies suggest that exercise and BCAA therapies share common mechanisms of action
and effects, and therefore I will effectively be testing the overarching hypothesis that enhancing neurotrophic
signaling and improving sleep quality after injury can improve cognitive recovery and reduce ARAS pathology
following moderate TBI. Beyond the advancements that this project will provide for our mission to maximize
functional recovery from brain injury in our Veterans, I will be gathering invaluable knowledge and expertise
from a dedicated, world-class mentorship team and carving a niche for my future career as an independent VA
investigator. Due to the swine model and the community of researchers gathered around it, the CMC-VAMC
and University of Pennsylvania are at the epicenter of translational TBI research. The greatest environment in
the world to achieve my research goals in TBI rehabilitation is within this community, and I intend to become an
integral member throughout my career. I will achieve independence through this Career Development Award
and provide considerable return on investment through a highly productive VA research career.
驱使我建立一个独立的研究型企业的动力一直是我个人的愿望
项目成果
期刊论文数量(0)
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会议论文数量(0)
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John Charles O'Donnell其他文献
John Charles O'Donnell的其他文献
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{{ truncateString('John Charles O'Donnell', 18)}}的其他基金
Translational Modeling of Brain Injury Rehabilitation to Maximize Recovery.
脑损伤康复转化模型以最大限度地恢复。
- 批准号:
10557786 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Translational Modeling of Brain Injury Rehabilitation to Maximize Recovery.
脑损伤康复转化模型以最大限度地恢复。
- 批准号:
10183457 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Mitochondrial dynamics in astrocytic processes after transient ischemia
短暂性缺血后星形胶质细胞过程中的线粒体动力学
- 批准号:
8921078 - 财政年份:2014
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