Administrative supplement - Feng

行政补充-冯

• 批准号: 10393096
• 负责人: Ning Feng
• 金额: $ 6.71万
• 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 2022-03-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393096
• 关键词: Administrative Supplement; Attenuated; Award; Bioenergetics; Biogenesis; Brain-Derived Neurotrophic Factor; COVID-19 pandemic; Cardiac; Cardiac Myocytes; DNA copy number; Exercise; Exposure to; Functional disorder; Funding; Growth Factor; Heart failure; Knockout Mice; Measurement; Metabolic; Metabolism; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Modeling; Molecular; Mus; Myocardial; PPAR gamma; Pathologic; Patients; Phosphotransferases; Production; Public Health; Regulation; Respiratory physiology; Role; Signal Pathway; Signal Transduction; Stress; Swimming; Testing; Tropomyosin; Up-Regulation; Yin-Yang; constriction; endurance exercise; experimental study; heart cell; novel; novel therapeutics; receptor; response; transcription factor

ABSTRACT Brain-derived Neurotrophic Factor (BDNF) is markedly decreased in heart failure patients. Both BDNF and its receptor, Tropomyosin Related Kinase Receptor (TrkB), are expressed in cardiomyocytes, however the role of myocardial BDNF signaling in cardiac pathophysiology is poorly understood. During my K08 award tenure, we found that myocardial BDNF expression was increased in mice with swimming exercise, but decreased in a mouse heart failure model. Cardiac-specific TrkB knockout (cTrkB KO) mice displayed a blunted adaptive cardiac response to exercise, with attenuated upregulation of transcription factor networks controlling mitochondrial biogenesis/metabolism, including Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). However, due to the COVID-19 pandemic, the experiments to assess the functional consequence of suppressed PGC-1α and other metabolic transcription factors expression were delayed. In the funded extension period, we will test whether endurance exercise induced cardiac bioenergetic enhancement is attenuated in cTrkB KO mice by mitochondrial biogenesis assessment and mitochondrial respiratory function measurement using Oroboros Respirometer. We also found, in response to pathological stress (transaortic constriction, TAC), cTrkB KO mice showed an exacerbated heart failure progression. The expression of PGC-1α and other metabolic transcription factors were downregulated in cTrkB KO mice exposed to TAC. Consistent with this, mitochondrial DNA copy number and mitochondrial protein abundance was markedly decreased in cTrkB KO mice, resulting in decreased mitochondrial respiratory function. We further unraveled that BDNF induces PGC-1α upregulation and bioenergetics through a novel signaling pathway, the pleiotropic transcription factor Yin Yang 1 (YY1). However, the molecular mechanism of the activation of YY1 by BDNF/TrkB signaling is unclear. In the extension period, we will further delineate the underlying mechanisms of the BDNF induced YY1 activation.

抽象的 心力衰竭患者的脑部神经营养因子（BDNF）明显降低。 BDNF及其受体Tropomyosin相关激酶受体（TRKB）均在 心肌细胞，但是心肌BDNF信号在CardiACC病理生理学中的作用是 在我的K08奖励任期内，我们发现心肌表达不佳 通过游泳运动增加了小鼠的增加，但在小鼠心力衰竭模型中减少了。 心脏特异性TRKB敲除（CTRKB KO）小鼠表现出钝性的自适应心脏反应 进行锻炼，随着转录转录转录转录转录转录的转录转录的转录上调 线粒体生物发生/代谢，包括过氧化物酶体增殖物激活受体 伽马共激活因子1α（PGC-1α）。 经验以评估支持的PGC-1α和其他代谢的功能障碍 转录因子的表达延迟。 CTRKB中是否会衰减耐力的心脏生物能增强型 通过线粒体生物发生评估和mitchondrial呼吸功能的KO小鼠 使用Oroboros呼吸仪的测量，我们还发现了病理应力 （经跨性收缩，TAC），CTRKB KO小鼠的心力衰竭进展恶化。 PGC-1α和其他代谢转录因子的表达在 CTRKB KO小鼠暴露于TAC。 线粒体蛋白丰度在CTRKB KO小鼠中明显降低，重新占领 线粒体呼吸功能降低。 通过新颖的信号通路，上调和生物能学，多效性转录 Yin Yang 1（YY1）。 BDNF/TRKB信号在延长期内不清楚。 BDNF诱导YY1激活的机制。