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

描述(由申请人提供)：临床研究记录了锻炼对普通人群和心力衰竭(HF)患者的益处。毫无疑问，运动的系统效应在这些益处中扮演着重要的角色。然而，我们假设运动在心脏内部启动了有益的信号机制，这也有助于并可以被利用来缓解心衰。为了确定运动对心脏转录调控的差异，我们利用最近开发的一个平台，评估了早期生理性(运动诱导)和病理性(压力超负荷诱导)心肌肥厚模型中All~2000转录成分在小鼠基因组中的表达。最初的候选者确定为C/EBP2和CITED4，为我们的总体假设提供支持，也是本申请的重点。我们的初步数据表明，转录因子C/EBP2在运动中特异性下调，而CITED4的表达增加。相反，在横动脉缩窄(TAC)引起的早期病理性肥厚中，这两种变化都不明显。体外研究表明，C/EBP2的降低足以推动心肌细胞大小和增殖的增加，以及CITED4表达的增加。杂合生殖系基因敲除小鼠体内C/EBP2表达减少导致表型与耐力训练相似，包括提高运动能力以及增加心肌细胞大小和增殖。杂合子C/EBP2基因敲除小鼠也表现出CITED4表达增加，与运动组相似，并对TAC后的心功能不全具有抵抗力。这项建议的总体目标是了解C/EBP2和CITED4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效应，以及这些途径在成年心脏中介导心肌细胞保护和/或增殖的潜力。我们还将调查导致观察到的表型的下游机制。了解运动对心脏有益的途径可能会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.