Administrative supplement - Feng

摘要 脑源性神经营养因子（BDNF）在心力衰竭患者中显著降低。 BDNF及其受体原肌球蛋白相关激酶受体（TrkB）在脑胶质瘤中表达。 然而，心肌BDNF信号传导在心脏病理生理学中的作用是 不太了解。在我的K 08奖任期内，我们发现心肌BDNF表达 游泳运动可使小鼠心肌缺血再灌注损伤后心肌缺血再灌注损伤的发生率升高，而心力衰竭模型则降低。 心脏特异性TrkB敲除（cTrkB KO）小鼠表现出迟钝的适应性心脏反应 运动，随着转录因子网络控制的减弱上调， 线粒体生物发生/代谢，包括过氧化物酶体增殖物激活受体 γ辅激活因子1 α（PGC-1α）。然而，由于COVID-19疫情， 评估抑制PGC-1α和其他代谢产物的功能后果的实验 转录因子表达延迟。在受资助的延长期内，我们将测试 耐力运动诱导的心脏生物能增强是否在cTrkB中减弱 通过线粒体生物发生评估和线粒体呼吸功能的KO小鼠 使用Oroboros呼吸计测量。我们还发现，在应对病理性压力时， （经主动脉缩窄，TAC），cTrkB KO小鼠显示加重的心力衰竭进展。 PGC-1α和其他代谢转录因子的表达下调， 暴露于TAC的cTrkB KO小鼠。与此一致，线粒体DNA拷贝数和 cTrkB基因敲除小鼠的线粒体蛋白丰度显著降低， 线粒体呼吸功能下降。我们进一步揭示了BDNF诱导PGC-1α 通过一种新的信号传导途径，多效性转录， 阴阳因子1（YY 1）。然而，YY 1被激活的分子机制是不确定的。 BDNF/TrkB信号转导尚不清楚。在延长期内，我们会进一步界定 BDNF诱导YY 1激活的机制。

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.