Antagonism of myocardial aging and senescence with Pim-1 kinase

项目摘要 认识到心脏是一个再生器官，激发了人们对心脏再生的可能性的新兴趣。 通过增强修复对抗心肌老化。然而，心肌恶化 在我们的生命周期中的功能源于再生能力减弱的组合效应， 增加具有边缘功能性能的衰老细胞的积累。因此， 对抗心脏衰老的干预策略需要促进年轻的维持， 干细胞具有以强健的干细胞群体和最小的衰老细胞积累为代表的特征。这项建议 将通过涉及Pim-1的分子策略拮抗衰老表型，Pim-1是一种存活和增殖的细胞因子， 最近在心肌中发现的激酶。明智地增强Pim-1活性将拮抗 干细胞和心肌细胞群的衰老，赋予心脏更年轻的表型 能够更好的血流动力学功能和抵抗心肌病性损伤，包括退行性 老化的后果。实现该提案的既定目标将提供一个全面的 对心肌Pim-1活性介导的改善机制的理解。的创新之处 一项提议在于Pim-1激酶作为对抗衰老的靶向策略的独特性质， 表型和延长心肌细胞以及心脏祖细胞的功能寿命 负责修复和再生。短期目标是描绘与衰老相关的目标 受Pim-1的影响，并证明Pim-1干预方法延缓衰老的有效性 过程具体目标是：1）心肌衰老被Pim-1介导的信号传导拮抗，2）心肌细胞衰老的丧失， Pim-1活性导致心肌过早老化和相关的血流动力学下降 性能，和3）心脏祖细胞和年轻心肌细胞扩增的增殖期是 Pim-1激酶的延伸。这些研究的意义在于抑制心肌老化， 在较长的生命周期内保持年轻的特征。总的来说，这些研究将确定 干预性方法调节Pim-1激酶活性以对抗衰老阶段 和促进干细胞介导的再生。

PROJECT SUMMARY The realization that the heart is a regenerative organ has spurred renewed interest in the possibilities for antagonizing the aging of the myocardium through enhanced repair. However, deterioration of myocardial function over our lifespan stems from combinatorial effects of diminished regenerative capabilities together with increasing accumulation of senescent cells with marginal functional performance. Thus, the optimal interventional strategy to antagonize aging of the heart would need to promote maintenance of youthful characteristics typified by a robust stem cell population and minimal accrual of senescent cells. This proposal will antagonize the aging phenotype through a molecular strategy involving Pim-1, a survival and proliferative kinase recently identified in the myocardium. Judicious enhancement of Pim-1 activity will antagonize senescence of stem cell and cardiomyocyte populations, conferring upon the heart a more youthful phenotype capable of greater hemodynamic function and resistance to cardiomyopathic injury including the degenerative consequences of aging. Accomplishing the stated aims of the proposal will provide a comprehensive mechanistic understanding of improvements mediated by myocardial Pim-1 activity. The innovation of this proposal rests with the unique nature of Pim-1 kinase as a targeted strategy to antagonize the aging phenotype and prolong the functional lifespan of cardiomyocytes as well as cardiac progenitor cells responsible for repair and regeneration. The short term goal is to delineate the aging-associated targets influenced by Pim-1 and demonstrate the efficacy of Pim-1 interventional approaches to retard the aging process. Specific aims are: 1) Myocardial senescence is antagonized by Pim-1 mediated signaling, 2) Loss of Pim-1 activity leads to premature aging of the myocardium and associated decline in hemodynamic performance, and 3) the proliferative phase of cardiac progenitor cell and young cardiomyocyte expansion is extended by Pim-1 kinase. The significance of these studies is the inhibition of myocardial aging and maintenance of youthful characteristics for a longer period of lifespan. Collectively, these studies will set the stage for interventional approaches to regulate Pim-1 kinase activity in service of antagonizing senescence and promoting stem cell-mediated regeneration.