The role of C/EBP?? and CITED4 in the heart

描述（由申请人提供）：临床研究记录了运动在普通人群和心力衰竭（HF）患者中的益处。毫无疑问，运动的全身效应在这些益处中起着重要作用。然而，我们假设运动在心脏本身内启动有益的信号传导机制，这也有助于并可用于减轻HF。 为了识别运动差异调节的心脏转录成分，我们使用最近开发的平台来评估小鼠基因组中所有~2000个转录成分在早期生理性（运动诱导）和病理性（压力超负荷诱导）心脏肥大模型中的表达。最初的候选人确定C/EBP 2和CITED 4，为我们的整体假设提供支持，是本申请的重点。我们的初步数据表明，转录因子C/EBP 2特异性下调运动，而CITED 4的表达增加。与此相反，在由横向主动脉缩窄（TAC）引起的早期病理性肥大中，两者都没有改变。体外研究表明，C/EBP 2的减少足以驱动心肌细胞大小和增殖的增加，以及CITED 4表达的增加。在杂合子生殖系基因敲除小鼠中，体内C/EBP 2表达减少导致与耐力训练相似的表型，包括运动能力提高以及心肌细胞大小和增殖增加。杂合子C/EBP 2基因敲除小鼠也显示出与运动相当的CITED 4表达增加，并且在TAC后对心功能障碍具有抗性。 本提案的总体目标是了解C/EBP 2和CITED 4在心脏中的交叉作用。我们现在建议开发独特的体内模型，使我们能够确定观察到的表型是否反映了这些转录因子在心肌细胞中的细胞自主作用，以及这些途径在完全成年心脏中介导保护和/或心肌细胞增殖的潜力。我们还将研究负责观察到的表型的下游机制。 了解运动对心脏有益的途径可以为控制心肌细胞生长和增殖的生理机制提供新的见解，并为心力衰竭和其他心脏疾病的新治疗方法奠定基础。

DESCRIPTION (provided by applicant): Clinical studies document the benefits of exercise both in the general population and in heart failure (HF) patients. Undoubtedly systemic effects of exercise play an important role in these benefits. However, we hypothesize that exercise initiates salutary signaling mechanisms within the heart itself that also contribute and could be exploited to mitigate HF. To identify cardiac transcriptional components differentially regulated by exercise, we used a recently developed platform to assess expression of all ~2000 transcriptional components in the mouse genome in models of early physiological (exercise-induced) and pathological (pressure overload-induced) cardiac hypertrophy. The initial candidates identified C/EBP2 and CITED4, provide support for our overall hypothesis and are the focus of this application. Our preliminary data demonstrate that the transcription factor C/EBP2 is specifically downregulated with exercise, while expression of CITED4 is increased. In contrast, neither changes in early pathological hypertrophy induced by transverse aortic constriction (TAC). In vitro studies demonstrate that a reduction in C/EBP2 is sufficient to drive an increase in both cardiomyocyte size and proliferation, as well as increased CITED4 expression. Reduced C/EBP2 expression in vivo in heterozygous germline knockout mice resulted in phenotypes similar to those seen with endurance training, including improved exercise capacity as well as increased cardiomyocyte size and proliferation. Heterozygous C/EBP2 knockout mice also showed increased CITED4 expression comparable to that seen with exercise, and were resistant to cardiac dysfunction after TAC. The overall goal of this proposal is to understand the intersecting roles of C/EBP2 and CITED4 in the heart. We now propose to develop unique in vivo models that will enable us to determine whether the phenotypes observed reflect cell autonomous effects of these transcription factors in cardiomyocytes as well as the potential of these pathways to mediate protection and/or cardiomyocyte proliferation in fully adult hearts. We will also investigate the downstream mechanisms responsible for the phenotypes observed. Understanding the pathways that confer the cardiac benefits of exercise may provide new insights into physiological mechanisms controlling cardiomyocyte growth and proliferation as well as a foundation for novel therapeutic approaches in heart failure and other cardiac diseases.