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
• 负责人: Ning Feng
• 金额: $ 9.94万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9620358
• 关键词: Role; Myocardial; BDNF; signaling; physiology

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

项目概要/摘要 脑源性神经营养因子（BDNF）是一种调节能量稳态的神经营养因子， 线粒体生物能量学和介导运动诱导的脑神经发生。BDNF及其 受体原肌球蛋白相关激酶受体B（Trk B）存在于心肌中。但是，作用 BDNF/TrkB信号在心肌生理和心肌对病理应激的反应中很大程度上是 未知我最近在PNAS上发表的第一作者文章发现，心肌组织中的BDNF/TrkB信号传导是 正常的心脏收缩和舒张所需的。在新的初步数据中，我们发现运动诱导的BDNF BDNF在心脏中的表达，而BDNF在心力衰竭的心肌中的表达减少 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， 保护心脏功能，对抗经主动脉缩窄（TAC）引起的压力超负荷。相反地， 心脏特异性TrkB-/-小鼠（cTrkB-/-）在压力超负荷下显示加速的心力衰竭进展。 此外，小分子TrkB激动剂阻止了小鼠心力衰竭的进展，表明 BDNF/TrkB通路可能成为一个新的治疗靶点。重要的是，我们发现过氧化物酶体的表达 增殖物激活受体γ辅激活因子1 α（PGC 1 α），线粒体膜电位的主要调节因子 生物合成和线粒体呼吸功能，在小鼠的压力超负荷下降，而过度， BDNF的表达恢复了应激心脏中受损的PGC 1 α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小鼠中回收。CK通过ATP再生在能量储备中起关键作用， 磷酸肌酸（pCr）和ADP的转化。因此，我将检验BDNF/TrkB激活是 对运动生理学至关重要，并通过改善心脏生物能量学， PGC 1 α依赖性线粒体功能增强和CK介导的ATP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解决：1）确定 心肌BDNF/TrkB对运动能力和运动诱导的适应性反应的重要性; 2）测试 心肌BDNF/TrkB信号传导是否通过激活PGC 1 α来防止压力超负荷; 3）测试 心肌BDNF/TrkB信号是否通过增加肌酸激酶来保护压力超负荷 ATP介导再生