COBRE: W & I HOSP OF RI: SIGNALING PATHWAYS IN CARDIOMYOCYTE PROLIFERATION

铜芯：W

• 批准号: 7381991
• 负责人: YI-TANG TSENG
• 金额: $ 20.83万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381991
• 关键词: COBRE; HOSP; RI; SIGNALING; PATHWAYS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The growth mode of cardiomyocytes switches from hyperplasia to hypertrophy shortly after birth. The molecular mechanisms responsible for the switch are not well understood. A number of intracellular signal transduction pathways have been suggested to be important in regulation of cardiac growth including the phosphoinositide 3-kinase (PI3K)/p70 S6 kinase (p70S6K) pathway and extracellular signal-regulated kinase 1 & 2 (ERK1,2). We demonstrated a profound reduction in neonatal cardiomyocyte proliferation following b-adrenergic receptor (bAR) blockade. This effect is associated with reduction in p70S6K activity but not in ERK1,2 activity. These suggest that bAR have an important role in mitogenic signaling and regulation of cardiac growth during fetal and early newborn development. We further demonstrated the ontogeny of p70S6K and PI3K in the heart appears to be synchronized and highly regulated throughout development in the heart. There are high basal levels of cardiac p70S6K and PI3K activity in the late gestation fetus and newborn but not in the adult. The high activities of both kinases occur when cardiomyocytes are undergoing hyperplastic growth. Hence, there is a correlation between p70S6K/PI3K activities and cardiomyocyte growth. Recent advances in genetic techniques have provided valuable experimental tools to answer fundamental biological questions. Conditional expression systems can be developed which allows cardiac-specific overexpression of PI3K at selected time points during development. We will us this approach to examine the role of these pathways at different developmental stages and to determine if post-proliferative cardiomyocytes can be "re-initiated" to undergo cell division under the control of the PI3K. The specific aims in this proposal will 1) characterize the role of b1AR regulation of p70S6K/PI3K activity in mouse models with genetically altered bAR and PI3K signaling and 2) create a mouse line with conditional overexpression of cardiac PI3K in the heart and characterize its effects on cardiomyocyte proliferation at different stages of development. These studies will contribute to our understanding of the regulation of cardiac growth during the perinatal transition and in pathological conditions during adult life.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。心肌细胞的生长模式在出生后不久从增生转变为肥大。负责开关的分子机制还没有很好地理解。许多细胞内信号转导途径被认为在心脏生长的调节中是重要的，包括磷酸肌醇3-激酶（PI 3 K）/p70 S6激酶（p70 S6 K）途径和细胞外信号调节激酶1和2（ERK 1，2）。我们证明了β-肾上腺素能受体（bAR）阻断后新生心肌细胞增殖的显著减少。这种作用与p70 S6 K活性的降低有关，但与ERK 1，2活性无关。这表明bAR在胎儿和早期新生儿发育过程中在促有丝分裂信号传导和心脏生长调节中具有重要作用。我们进一步证明了心脏中p70 S6 K和PI 3 K的个体发生似乎是同步的，并且在心脏的整个发育过程中受到高度调节。有高基础水平的 妊娠晚期胎儿和新生儿心脏p70 S6 K和PI 3 K活性升高，而成人则无。这两种激酶的高活性发生在心肌细胞经历增生性生长时。因此，p70 S6 K/PI 3 K活性与心肌细胞生长之间存在相关性。遗传技术的最新进展为回答基本的生物学问题提供了宝贵的实验工具。可以开发条件表达系统，其允许PI 3 K在发育期间的选定时间点的心脏特异性过表达。我们将使用这种方法来检查这些通路在不同发育阶段的作用，并确定增殖后心肌细胞是否可以在PI 3 K的控制下“重新启动”进行细胞分裂。本提案的具体目标是：1）在具有基因改变的bAR和PI 3 K信号传导的小鼠模型中表征b1 AR对p70 S6 K/PI 3 K活性的调节作用; 2）在心脏中创建心脏PI 3 K条件性过表达的小鼠品系，并表征其对不同发育阶段心肌细胞增殖的影响。这些研究将有助于我们了解在围产期过渡期和成年期的病理条件下心脏生长的调节。