THE ROLE OF P13 KINASE IN CARDIAC REPAIR AND REMODELING

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 已证实AR信号在胎儿和出生后早期的心肌细胞增殖调节中起重要作用。我们还证实了在心脏生长的增殖期，PI3激酶/P70核糖体蛋白S6激酶活性(P70 S6K)通路的信号水平呈结构性升高。成年期心肌细胞终末分化和缺失分裂的教义最近受到了挑战。我们最近的研究表明，采用独特和成熟的干细胞武装策略，静脉输注武装LIN-c-KIT干细胞可以显著恢复心肌室功能，防止心脏重构，这与增加梗死心肌血管生成和减少心肌细胞凋亡有关。干细胞Akt-1的缺失是已知的1AR/PI3Kinase信号的下游靶点，完全消除了干细胞注入梗死心肌的有利作用，表明Akt-1在介导干细胞产生再生能力方面发挥了关键作用。目前尚不清楚这种独特信号的这些成分是如何介导心肌再生的。我们将结合过表达PI3激酶p110α的转基因动物、针对受损心肌表达的抗原的干细胞、心功能评估以及再生心肌细胞的生化和遗传学研究来研究这些问题。我们的具体目标是：1)利用成熟的干细胞武装策略和心肌梗死模型，比较接受Lin-c-kit/PI3K-p110/干细胞和接受野生型干细胞的受损心脏的心功能恢复；2)检测高表达PI3K-p110α的Lin-c-kit干细胞对新生心肌细胞和血管生成的影响；3)通过利用独特的TTA系统，结合体内条件，我们将尝试确定细胞融合对心肌再生和功能恢复的贡献，并评估PI3K-Akt-1工作模型是否将协调干细胞移植后的心肌再生。PI3K/-Akt 1-/-lin-c-kit将通过与PI3K/和Akt 1-/-小鼠品系杂交，从双转基因小鼠中获得干细胞。

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. It has been demonstrated an important role of ¿1AR signaling in regulation of cardiac myocytes proliferation during the fetal and early postnatal period. We have also demonstrated a constitutively elevated level of signaling of PI3 kinase/P70 ribosomal protein S6 kinase activity (p70 S6K) pathway during the proliferative period of cardiac growth. The dogma of terminal differentiation and absence of cardiomyocytes division in adulthood has been recently challenged. Using unique and well-established stem cell arming strategy, our recent study revealed that intravenously infusion of armed lin-c-kit+ stem cells markedly restored myocardial ventricular function and prevention of cardiac remodeling, which was associated with increase of angiogenesis as well as reduction myocardial apoptosis in infarcted myocardium. Deletion of Akt-1 of stem cells, the known downstream target of ¿1AR /PI3 Kinase signaling, completely eliminated the beneficial effect of stem cells infused in infarcted myocardium, demonstrating a crucial role of Akt-1 in mediating stem cells to produce regenerative capacity. It remains known how these components of this unique signaling mediate the myocardial regeneration. We will examine these questions using a combination of genetically modified animals with overexpression of PI3 kinase p110 alpha, stem cells targeted to antigens expressed by injured myocardium, the assessment of cardiac function and biochemical and genetic studies of regenerated cardiomyocytes. Our specific aims are: 1) Using well-established stem cell arming strategy and myocardial infarction models, we will compare cardiac functional restoration in the damaged heart receiving Lin-c-kit /PI3K-p110 +/+ stem cells with hearts receiving the wild type stem cells; 2) we will examine the impact of Lin-c-kit stem cells over-expressing PI3K-p110 alpha on newly regenerated myocyte and angiogenesis; 3) By taking advantage of unique tTA system in combination with the in vivo condition, we will attempt to define the contribution of the cell fusion to myocardial regeneration and functional restoration and, We will assess whether the PI3K-Akt-1 working model will orchestrate myocardial regeneration following stem cells administration. PI3K+/+-Akt 1-/- Lin-c-kit+stem cells will be generated from double transgenic mice by crossing PI3K+/+ and Akt 1-/- mouse lines.