Antagonism of myocardial aging and senescence with Pim-1 kinase

项目总结 人们意识到心脏是一个再生器官，这激起了人们对 通过加强修复来对抗心肌的衰老。然而，心肌的恶化 我们一生中的功能源于再生能力减弱和 衰老细胞的积累增加，具有边缘功能表现。因此，最优的 对抗心脏老化的介入策略需要促进保持年轻 以强大的干细胞群体和最低限度的衰老细胞为特征。这项建议 将通过一种涉及存活和增殖因子Pim-1的分子策略来对抗衰老表型 最近在心肌中发现了一种激酶。明智地增强Pim-1的活性将对抗 干细胞和心肌细胞群体的衰老，赋予心脏更年轻的表型 具有更强的血流动力学功能，能抵抗包括退行性心肌损伤在内的心肌病变 老龄化的后果。实现提案的既定目标将提供一个全面的 从机制上理解心肌Pim-1活性介导的改善。它的创新之处在于 该提议基于Pim-1激酶的独特性质，作为一种靶向策略来对抗衰老 心肌细胞和心脏祖细胞的表型和延长功能寿命 负责维修和再生。短期目标是勾勒出与老龄化相关的目标 受Pim-1的影响并证明Pim-1干预方法延缓衰老的有效性 进程。具体目标是：1)Pim-1介导的信号转导拮抗心肌衰老；2)心肌细胞缺失 PIM-1活性导致心肌过早衰老和相关的血流动力学下降 表现，3)心脏前体细胞和年轻心肌细胞的增殖期是 由Pim-1激酶延伸。这些研究的意义在于抑制心肌衰老和 在更长的寿命内保持年轻的特征。总体而言，这些研究将设定 介入性方法调节Pim-1激酶活性用于抗衰老的阶段 并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.