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
项目摘要/摘要
脑源性神经营养因子(BDNF)是一种神经营养因子,调节能量稳态,
线粒体生物能量学和介导运动诱导的大脑中的神经发生。BDNF及其ITS
原肌球蛋白相关的受体B(TrkB)存在于心肌中。然而,它的作用是
BDNF/TrkB信号转导通路在心肌生理学和心肌对病理性应激反应中的作用
未知。我最近在PNAS上发表的第一作者文章发现,构成心肌BDNF/TrkB信号是
是正常心脏收缩和松弛所必需的。在新的初步数据中,我们发现运动诱导的BDNF
在心脏中表达,而BDNF在心力衰竭心肌中的表达减少
患者和小鼠心力衰竭模型。转基因心肌BDNF过表达的小鼠显示
保护心功能,对抗经主动脉缩窄(TAC)引起的压力超负荷。相反,
心脏特异性TrkB-/-小鼠(cTrkB-/-)在压力超负荷下表现出心力衰竭加速进展。
此外,一种小分子TrkB激动剂阻止了小鼠心力衰竭的进展,这表明
BDNF/TrkB通路可能成为新的治疗靶点。重要的是,我们发现了过氧化酶体的表达
线粒体的主要调节因子--增殖物激活受体γ共激活因子1-α(Pgc1α)
在压力超负荷的情况下,小鼠的生物发生和线粒体呼吸功能降低,而过度的
脑源性神经营养因子的表达恢复了应激心脏受损的前列环素α的表达。此外,我们还发现,
TAC后心肌肌原纤维肌酸激酶(CK)亚型表达减少,
在cBDNF-TG小鼠体内恢复。CK通过ATP的再生在能量储备中起关键作用
磷酸肌酸(PCR)和ADP的转化率。因此,我将测试BDNF/TrkB激活是
通过改善心脏生物能量学,对运动生理学和防止病理性应激至关重要,通过
PgC1ATP依赖的线粒体功能增强和CK介导的α再生。这一假设
利用我们的新型转基因小鼠模型将在三个具体目标中得到解决:1)确定
心肌BDNF/TrkB在运动能力和运动适应性反应中的重要性;2)测试
心肌BDNf/TrkB信号通路是否通过激活Pgc1α保护压力超负荷;3)检测
心肌BDNF/TrkB信号通路是否通过增加肌酸激酶来保护压力超负荷
介导的三磷酸腺苷再生
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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