The role of myocardial BDNF signaling in myocardial physiology and myocardial response to pathological stress
心肌 BDNF 信号在心肌生理和心肌对病理应激反应中的作用
基本信息
- 批准号:9337496
- 负责人:
- 金额:$ 2.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2017-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAgonistBiochemicalBioenergeticsBiogenesisBrainBrain-Derived Neurotrophic FactorCardiacCardiac MyocytesCause of DeathCreatine KinaseDataDeteriorationExerciseExercise PhysiologyGeneticGrowth FactorHealthcareHeartHeart failureHomeostasisHumanImpairmentMagnetic Resonance SpectroscopyMeasuresMediatingMitochondriaModelingMusMyocardialMyocardiumNamesNatural regenerationNeuronsPPAR gammaPathologicPathway interactionsPatientsPhosphocreatinePhosphotransferasesPhysiologicalPhysiologyPlayProductionProtein IsoformsPublic HealthPublicationsRelaxationReportingReservationsRespirationRespiratory physiologyRoleSignal TransductionSkeletal MuscleStressTestingTransgenic MiceTransgenic OrganismsTropomyosinUp-RegulationWorkbaseconstrictionendurance exerciseenhancing factorexercise capacityimage guidedimprovedin vivoindexingknock-downmouse modelneurogenesisneurotrophic factorneurotropinnew therapeutic targetnovelnovel therapeuticsoverexpressionpressurepreventprotective effectreceptorresponsesmall molecule
项目摘要
Project summary/Abstract
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates energy homeostasis,
mitochondrial bioenergetics and mediates exercise-induced neurogenesis in the brain. Both BDNF and its
receptor Tropomyosin related kinase receptor B (TrkB) are present in the myocardium. However, the role of
BDNF/TrkB signaling in myocardial physiology and the myocardial response to pathological stress is largely
unknown. My recent first author publication in PNAS found that constitutive myocardial BDNF/TrkB signaling is
required for normal cardiac contraction and relaxation. In new preliminary data, we found exercise induced BDNF
expression in the heart, whereas BDNF expression was decreased in myocardium from human heart failure
patients and mouse heart failure models. The mice with transgenic myocardial BDNF over-expression showed
preserved cardiac function against pressure overload induced by transaortic constriction (TAC). Conversely,
cardiac specific TrkB-/- mice (cTrkB-/-) displayed accelerated heart failure progression under pressure overload.
Moreover, a small molecule TrkB agonist prevented progression of heart failure in mice, suggesting the
BDNF/TrkB pathway could be a novel therapeutic target. Importantly, we found the expression of Peroxisome
proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), a master regulator of mitochondrial
biogenesis and mitochondrial respiratory function, was decreased in pressure overload in mice, while over-
expression of BDNF restored the impaired PGC1α expression in the stressed hearts. In addition, we also found
that the expression of myofibrillar isoform of creatine kinase (CK) was decreased in myocardium after TAC, and
recovered in cBDNF-tg mice. CK plays a critical role in energy reservation by ATP regeneration through
conversion of creatine phosphate (pCr) and ADP. Thus I will test the hypothesis that BDNF/TrkB activation is
critical for exercise physiology and protects against pathological stress by improving cardiac bio-energetics, via
PGC1α dependent mitochondrial function enhancement and CK mediated ATP regeneration. This hypothesis
will be addressed in three specific aims leveraging our novel transgenic mice models: 1) Determine the
importance of myocardial BDNF/TrkB on exercise capacity and exercise induced adaptive response; 2) Test
whether myocardial BDNF/TrkB signaling protects against pressure overload by activating PGC1α; 3) Test
whether myocardial BDNF/TrkB signaling protects against pressure overload by augmenting creatine kinase
mediated ATP regeneration
项目总结/文摘
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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Ning Feng其他文献
Ning Feng的其他文献
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{{ truncateString('Ning Feng', 18)}}的其他基金
The role of transcription factor Ying-Yang 1 in the cardiac bioenergetics regulation
转录因子Ying-Yang 1在心脏生物能调节中的作用
- 批准号:
10688160 - 财政年份:2022
- 资助金额:
$ 2.53万 - 项目类别:
The role of transcription factor Ying-Yang 1 in the cardiac bioenergetics regulation
转录因子Ying-Yang 1在心脏生物能调节中的作用
- 批准号:
10504503 - 财政年份:2022
- 资助金额:
$ 2.53万 - 项目类别:
The Role of Myocardial BDNF signaling in Myocardial physiology and myocardial response to pathological stress
心肌 BDNF 信号在心肌生理和心肌对病理应激反应中的作用
- 批准号:
9620358 - 财政年份:2018
- 资助金额:
$ 2.53万 - 项目类别:
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