Investigating Autonomic Dysfunction as an Early Pathologic Feature of Huntington’s Disease
研究自主神经功能障碍作为亨廷顿病的早期病理特征
基本信息
- 批准号:10212681
- 负责人:
- 金额:$ 18.05万
- 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:2021-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:18 year oldAdrenergic beta-AntagonistsAdultAgeAge of OnsetAnteriorAreaAtrophicAutonomic DysfunctionAutonomic nervous systemBackBaroreflexBiometryBlood PressureBody TemperatureBrainBrain regionCardiovascular systemCarotid ArteriesCerebrovascular CirculationCerebrovascular systemChildChronicComplicationCorpus striatum structureDiseaseDisease ProgressionEnsureEquilibriumEtiologyExhibitsFamilyFunctional Magnetic Resonance ImagingFunctional disorderFundingGene therapy trialGenesGoalsGrantHeart RateHomeostasisHuntington DiseaseHuntington geneHuntington proteinHypertensionInsula of ReilIowaK-Series Research Career ProgramsLocationMagnetic Resonance ImagingMeasuresMentorsMentorshipMethodsModificationMotorNational Institute of Neurological Disorders and StrokeNerve DegenerationNervous System PhysiologyNeurobiologyNeurodegenerative DisordersOutcomeParticipantPathologicPatient RecruitmentsPatientsPharmaceutical PreparationsPharmacistsPharmacologyPhysiologicalPlasmaPositioning AttributePrefrontal CortexPrincipal InvestigatorPublishingRecording of previous eventsReportingResearchResearch PersonnelResearch TrainingRestRiskSamplingSeedsSignal TransductionSpin LabelsStructureSympathetic Nerve BlockSympathetic Nervous SystemSymptomsTestingTherapeuticThinnessTimeTrainingTraining ProgramsTrinucleotide RepeatsVascular Systemagedarterial stiffnessbasebeta-adrenergic receptorblood oxygen level dependentcareercareer developmentcingulate cortexexperienceexperimental studygene therapyheart rate variabilityimprovedmutantneurodevelopmentneurofilament protein Lneuroimagingnew therapeutic targetnovelnovel therapeuticspatient orientedpatient populationpreventsuccesstargeted biomarkertherapeutic targettranslational scientist
项目摘要
Project Summary/Abstract
The purpose of this Mentored Patient-Oriented Career Development Award (K23) is to support my short-term
career objective of determining if dysfunction of the autonomic nervous system (ANS) is an early pathological
feature of HD by quantitatively characterizing functional connections between brain regions that regulate the
ANS in children with the gene expansion that causes HD using magnetic resonance imaging (MRI). I will also
investigate unique physiologic measures of ANS function and early effects on the vascular system in these
participants. ANS dysfunction has been described in adult patients with HD, but it has been thought that this is
a secondary complication of neurodegeneration. However, I recently discovered that children carrying the HD
gene expansion that causes HD (GE children) exhibit symptoms consistent with enhanced sympathetic tone
decades prior to their predicted motor onset. These findings indicate that ANS dysfunction may be one of the
earliest manifestations of neurodegeneration in HD. As a result, the ANS may be a therapeutic target for disease
modification of HD, but more information is required. The ANS is highly regulated by cortical brain regions that
comprise the Central Autonomic Network (CAN), and cortical thinning and atrophy have been well-described in
HD. However, there are no published reports that have objectively characterized the integrity of the functional
connections in the CAN in HD. I will perform resting-state and tasked functional MRI on GE children to
characterize the function of the CAN at different stages of the disease. This experiment will test the specific
hypothesis that quantitative changes in functional integrity of the CAN are apparent decades prior to the predicted
motor onset of HD. Additionally, I will explore physiologic measure of ANS dysfunction including baroreflex
sensitivity (BRS) and how this relates to the function of the vascular system early in the disease course of HD.
Specifically, I will measure aortic stiffness and carotid artery compliance while also measuring cerebral blood
flow using arterial spin labeling to test the hypotheses that relative to healthy control children, GE children will
demonstrate increased aortic stiffness, decreased BRS, and decreased cerebral blood flow. These experiments
will provide vital information regarding when ANS dysfunction occurs in HD, the underlying mechanisms
causing the dysfunction, and if these changes have negative effects on the cardiovascular system early
in the disease course. I have a unique background that positions me well to be a successful translational
scientist. Further training is required in sophisticated neuroimaging methods, neurodevelopment and
neurobiology, as well as biostatistics. The proposed integrated research, world-class mentorship team, and
didactic training programs will ensure my short-term and long-term success. Additionally, the proposed research
and training plans support my long-term career goal to be an independent translational pharmacist studying the
structure and function of the brain in patients with HD to advance therapeutic strategies.
Project Summary/Abstract
The purpose of this Mentored Patient-Oriented Career Development Award (K23) is to support my short-term
career objective of determining if dysfunction of the autonomic nervous system (ANS) is an early pathological
feature of HD by quantitatively characterizing functional connections between brain regions that regulate the
ANS in children with the gene expansion that causes HD using magnetic resonance imaging (MRI). I will also
investigate unique physiologic measures of ANS function and early effects on the vascular system in these
participants. ANS dysfunction has been described in adult patients with HD, but it has been thought that this is
a secondary complication of neurodegeneration. However, I recently discovered that children carrying the HD
gene expansion that causes HD (GE children) exhibit symptoms consistent with enhanced sympathetic tone
decades prior to their predicted motor onset. These findings indicate that ANS dysfunction may be one of the
earliest manifestations of neurodegeneration in HD. As a result, the ANS may be a therapeutic target for disease
modification of HD, but more information is required. The ANS is highly regulated by cortical brain regions that
comprise the Central Autonomic Network (CAN), and cortical thinning and atrophy have been well-described in
HD. However, there are no published reports that have objectively characterized the integrity of the functional
connections in the CAN in HD. I will perform resting-state and tasked functional MRI on GE children to
characterize the function of the CAN at different stages of the disease. This experiment will test the specific
hypothesis that quantitative changes in functional integrity of the CAN are apparent decades prior to the predicted
motor onset of HD. Additionally, I will explore physiologic measure of ANS dysfunction including baroreflex
sensitivity (BRS) and how this relates to the function of the vascular system early in the disease course of HD.
Specifically, I will measure aortic stiffness and carotid artery compliance while also measuring cerebral blood
flow using arterial spin labeling to test the hypotheses that relative to healthy control children, GE children will
demonstrate increased aortic stiffness, decreased BRS, and decreased cerebral blood flow. These experiments
will provide vital information regarding when ANS dysfunction occurs in HD, the underlying mechanisms
causing the dysfunction, and if these changes have negative effects on the cardiovascular system early
in the disease course. I have a unique background that positions me well to be a successful translational
scientist. Further training is required in sophisticated neuroimaging methods, neurodevelopment and
neurobiology, as well as biostatistics. The proposed integrated research, world-class mentorship team, and
didactic training programs will ensure my short-term and long-term success. Additionally, the proposed research
and training plans support my long-term career goal to be an independent translational pharmacist studying the
structure and function of the brain in patients with HD to advance therapeutic strategies.
项目成果
期刊论文数量(0)
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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Jordan Schultz其他文献
Jordan Schultz的其他文献
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{{ truncateString('Jordan Schultz', 18)}}的其他基金
Investigating Autonomic Dysfunction as an Early Pathologic Feature of Huntington’s Disease
研究自主神经功能障碍作为亨廷顿病的早期病理特征
- 批准号:
10360540 - 财政年份:2021
- 资助金额:
$ 18.05万 - 项目类别:
Investigating Autonomic Dysfunction as an Early Pathologic Feature of Huntington’s Disease
研究自主神经功能障碍作为亨廷顿病的早期病理特征
- 批准号:
10620644 - 财政年份:2021
- 资助金额:
$ 18.05万 - 项目类别: