Antagonism of myocardial aging and senescence with Pim-1 kinase

描述(由申请人提供)：认识到心脏是一个再生器官，重新激发了人们对通过加强修复来对抗心肌老化的可能性的兴趣。然而，在我们的寿命中，心肌功能的恶化源于再生能力减弱和具有边缘功能的衰老细胞的增加的综合影响。因此，对抗心脏衰老的最佳干预策略需要促进保持年轻的特征，其典型特征是强大的干细胞群体和最低限度的衰老细胞积累。这项建议将通过涉及Pim-1的分子策略来对抗衰老表型，Pim-1是最近在心肌中发现的一种生存和增殖激酶。Pim-1活性的适当增强将拮抗干细胞和心肌细胞群体的衰老，赋予心脏更年轻的表型，能够更好地发挥血流动力学功能，并对心肌损伤包括衰老的退化后果具有抵抗力。实现该提案规定的目标将提供对心肌Pim-1活性介导的改善的全面机制理解。这一方案的创新之处在于Pim-1激酶的独特性质，它是一种靶向策略，可以对抗衰老表型，延长心肌细胞以及负责修复和再生的心脏前体细胞的功能寿命。短期目标是描述受Pim-1影响的衰老相关靶点，并证明Pim-1干预方法延缓衰老过程的有效性。其具体目的是：1)Pim-1介导的信号转导可拮抗心肌衰老；2)Pim-1活性丧失导致心肌过早衰老并伴随血流动力学性能下降；3)Pim-1激酶延长心肌祖细胞增殖期和年轻心肌细胞扩张期。这些研究的意义在于抑制心肌衰老，并在更长的寿命内保持年轻的特征。总而言之，这些研究将为干预方法调节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。 公共卫生相关性：心脏病仍然是美国的一个主要原因或发病率和死亡率，患者的长期护理和住院是国家医疗保健系统的重大负担。尽管在过去的几十年里取得了进展，但我们仍然不能真正解决心力衰竭的根本问题：收缩功能和活性组织的进行性丧失。这项建议侧重于一种新的基本分子机制，涉及对抗衰老表型以维持心脏结构和功能，从而延长生活质量和降低医疗成本。

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.