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

C/EBP的作用？

• 批准号: 8459344
• 负责人: ANTHONY ROSENZWEIG
• 金额: $ 41.41万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459344
• 关键词: Adult; CCAAT-Enhancer-Binding Proteins; Cardiac; Cardiac Myocytes; Cells; Characteristics; Clinical; Clinical Research; Data; Development; Exercise; Foundations; Functional disorder; General Population; Genes; Genetic; Goals; Growth; Health; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hypertrophy; In Vitro; Knockout Mice; Lead; Maps; Measurement; Mediating; Modeling; Molecular; Mus; Neonatal; Pathway interactions; Patients; Phenocopy; Phenotype; Physiological; Play; Process; Resistance; Role; Sampling; Serum Response Factor; Signal Transduction; Source; Staging; Stimulus; Testing; Tetracyclines; Time; Training; Transgenic Mice; Transgenic Organisms; constriction; factor C; gain of function; genome-wide; improved; in vivo; in vivo Model; insight; mouse genome; novel therapeutic intervention; pressure; research study; response; transcription factor

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.

描述（由申请人提供）：临床研究证明了运动对普通人群和心力衰竭（HF）患者的益处。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内部启动了有益的信号机制，这也有助于并可能被用来减轻心衰。为了确定运动对心脏转录成分的差异调节，我们使用了一个最近开发的平台来评估小鼠基因组中所有约2000个转录成分在早期生理性（运动诱导）和病理性（压力过载诱导）心脏肥厚模型中的表达。最初确定的候选基因是C/EBP2和CITED4，它们为我们的总体假设提供了支持，也是本应用程序的重点。我们的初步数据表明，随着运动，转录因子C/EBP2特异性下调，而CITED4的表达增加。相比之下，这两种情况在主动脉横缩（TAC）引起的早期病理性肥厚中都没有改变。体外研究表明，C/EBP2的减少足以驱动心肌细胞大小和增殖的增加，以及CITED4表达的增加。杂合子种系基因敲除小鼠体内C/EBP2表达的降低导致了与耐力训练相似的表型，包括运动能力的提高以及心肌细胞大小和增殖的增加。杂合子C/EBP2基因敲除小鼠也显示出与运动小鼠相当的CITED4表达增加，并且TAC后对心功能障碍具有抗性。本提案的总体目标是了解C/EBP2和CITED4在核心中的交叉作用。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人心脏中介导保护和/或心肌细胞增殖的潜力。我们还将研究下游机制负责观察到的表型。了解运动对心脏有益的途径可能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。