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

项目摘要/摘要脑衍生的神经营养因子（BDNF）是一种神经营养蛋白，可调节能量稳态，线粒体生物能学并介导运动诱导的大脑神经发生。 BDNF及其心肌中存在与受体肌球蛋白相关激酶受体B（TRKB）。但是，心肌生理中的BDNF/TRKB信号传导和对病理压力的心肌反应在很大程度上是未知。我最近在PNAS中的第一篇作者出版物发现构成心肌BDNF/TRKB信号是正常心脏收缩和放松所必需的。在新的初步数据中，我们发现运动诱导的BDNF 心脏的表达在心脏中的表达降低了BDNF的表达患者和小鼠心力衰竭模型。显示了带有转基因心肌BDNF过表达的小鼠防止心脏超负荷的心脏功能（TAC）引起的压力超负荷。反过来，心脏特异性TRKB - / - 小鼠（CTRKB - / - ）在压力超负荷下显示出心力衰竭进展。此外，一个小的分子TRKB激动剂阻止了小鼠心力衰竭的进展，这表明 BDNF/TRKB途径可能是一个新型的热目标。重要的是，我们发现过氧化物酶体的表达增殖者激活的受体伽马共振剂1-α（PGC1α），线粒体的主调节剂在小鼠的压力超负荷中，生物发生和线粒体呼吸功能降低，而过度 BDNF的表达恢复了应力心脏中PGC1α的受损表达。此外，我们还发现 TAC后心肌的创造激酶（CK）的肌原纤维同工型的表达得到了改善，并且在CBDNF-TG小鼠中恢复。 CK通过ATP再生在能源保留中起关键作用创造磷酸盐（PCR）和ADP的转化。我将测试BDNF/TRKB激活的假设运动生理至关重要，并通过改善心脏生物能源技术来防止病理压力 PGC1α依赖性线粒体功能增强和CK介导的ATP再生。这个假设将在三个特定目标中解决我们的新型转基因小鼠模型：1）确定心肌BDNF/TRKB对运动能力和运动引起的适应性反应的重要性； 2）测试心肌BDNF/TRKB信号是否通过激活PGC1α来防止压力超负荷； 3）测试心肌BDNF/TRKB信号是否通过增加创建激酶来防止压力超负荷介导的ATP再生