Antagonism of myocardial aging and senescence with Pim-1 kinase

描述（由申请人提供）：意识到心脏是一个再生器官，激发了人们对通过增强修复来对抗心肌衰老的可能性的新兴趣。然而，心肌功能在我们一生中的恶化是由于再生能力下降和衰老细胞积累增加的综合影响，衰老细胞的功能表现不佳。因此，对抗心脏衰老的最佳干预策略需要促进年轻特征的维持，其典型特征是强大的干细胞群和最小的衰老细胞积累。该建议将通过涉及Pim-1的分子策略对抗衰老表型，Pim-1是最近在心肌中发现的一种存活和增殖激酶。明智地增强皮姆-1活性将对抗干细胞和心肌细胞群的衰老，赋予心脏更年轻的表型，具有更大的血流动力学功能和对心肌病损伤（包括衰老的退行性后果）的抵抗力。完成该提议的既定目标将提供一个全面的机制理解改善介导心肌皮姆-1活性。这一建议的创新之处在于Pim-1激酶作为一种靶向策略来对抗衰老表型，延长心肌细胞以及负责修复和再生的心脏祖细胞的功能寿命。短期目标是描述受皮姆-1影响的衰老相关靶点，并证明皮姆-1干预方法延缓衰老过程的有效性。具体目的是：1)通过Pim-1介导的信号传导拮抗心肌衰老；2)Pim-1活性的丧失导致心肌早衰和相关的血流动力学性能下降；3)Pim-1激酶延长了心脏祖细胞和年轻心肌细胞的增殖期。这些研究的意义在于抑制心肌老化和维持较长寿命的年轻特征。总的来说，这些研究将为通过干预方法调节Pim-1激酶活性，以对抗衰老和促进干细胞介导的再生奠定基础。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Heart disease remains a major cause or morbidity and mortality in the United States, with long term care and hospitalization of patients a significant burden on the national health care system. Despite advances over the last several decades we are still not truly capable of addressing the fundamental issue in heart failure: the progressive loss of contractile function and viable tissue. This proposal focuses upon a novel fundamental molecular mechanism involving antagonizing the aging phenotype to maintain cardiac structure and function resulting in extended quality of life and decreased medical cost.