THE ROLE OF P13 KINASE IN CARDIAC REPAIR AND REMODELING

P13 激酶在心脏修复和重塑中的作用

• 批准号: 8360540
• 负责人: YI-TANG TSENG
• 金额: $ 22.1万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360540
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adult; Antigens; Apoptosis; Biochemical Genetics; Biology; Cardiac; Cardiac Myocytes; Cell fusion; Centers of Research Excellence; Funding; Genetically Modified Animals; Grant; Growth; Heart; Infarction; Infusion procedures; Mediating; Modeling; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardium; National Center for Research Resources; Natural regeneration; Pathway interactions; Perinatal; Phosphotransferases; Prevention; Principal Investigator; Proto-Oncogene Protein c-kit; Regulation; Research; Research Infrastructure; Resources; Ribosomal Protein S6 Kinase; Role; ST5 gene; Signal Transduction; Source; Stem cells; System; Transgenic Mice; United States National Institutes of Health; Ventricular Function; Work; angiogenesis; arm; cost; defined contribution; fetal; functional restoration; human PIK3CA protein; in vivo; injured; overexpression; postnatal; regenerative; repaired

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 研究表明，1 AR信号在胎儿和产后早期心肌细胞增殖的调节中发挥着重要作用。我们还证明了在心脏生长的增殖期，PI 3激酶/P70核糖体蛋白S6激酶活性（p70 S6 K）通路的信号传导水平组成性升高。最近，终末分化和成年期心肌细胞分裂缺失的教条受到了挑战。我们最近的研究显示，使用独特且完善的干细胞武装策略，静脉输注武装的lin-c-kit+干细胞显著恢复心肌心室功能并预防心脏重构，这与增加血管生成以及减少梗死心肌中的心肌细胞凋亡有关。干细胞Akt-1的缺失，即已知的AR/PI 3激酶信号传导的下游靶点，完全消除了注入梗死心肌的干细胞的有益作用，证明Akt-1在介导干细胞产生再生能力中的关键作用。这一独特信号的这些成分如何介导心肌再生仍然是已知的。我们将研究这些问题，使用基因修饰的动物与过度表达的PI 3激酶p110 α，干细胞靶向受损心肌表达的抗原，心脏功能的评估和再生心肌细胞的生化和遗传研究的组合。我们的具体目标是：1）使用完善的干细胞武装策略和心肌梗死模型，我们将比较接受Lin-c-kit /PI 3 K-p110 +/+干细胞的受损心脏与接受野生型干细胞的心脏中的心脏功能恢复; 2）我们将检查过表达PI 3 K-p110 α的Lin-c-kit干细胞对新再生的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，并且我们将评估PI 3 K-Akt-1工作模型是否会在干细胞施用后协调心肌再生。通过使PI 3 K +/+和Akt 1-/-小鼠系杂交，从双转基因小鼠中产生PI 3 K +/+-Akt 1-/- Lin-c-kit+干细胞。