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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：
Ning Feng
金额：
$ 2.53万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
https://reporter.nih.gov/project-details/9337496
关键词：
Address Agonist Biochemical Bioenergetics Biogenesis Brain Brain-Derived Neurotrophic Factor Cardiac Cardiac Myocytes Cause of Death Creatine Kinase Data Deterioration Exercise Exercise Physiology Genetic Growth Factor Healthcare Heart Heart failure Homeostasis Human Impairment Magnetic Resonance Spectroscopy Measures Mediating Mitochondria Modeling Mus Myocardial Myocardium Names Natural regeneration Neurons PPAR gamma Pathologic Pathway interactions Patients Phosphocreatine Phosphotransferases Physiological Physiology Play Production Protein Isoforms Public Health Publications Relaxation Reporting Reservations Respiration Respiratory physiology Role Signal Transduction Skeletal Muscle Stress Testing Transgenic Mice Transgenic Organisms Tropomyosin Up-Regulation Work base constriction endurance exercise enhancing factor exercise capacity image guided improved in vivo indexing knock-down mouse model neurogenesis neurotrophic factor neurotropin new therapeutic target novel novel therapeutics overexpression pressure prevent protective effect receptor response small 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