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，激发了人们对通过增强修复对抗心肌老化的可能性的新兴趣。然而，心肌功能在我们的生命周期中的恶化源于再生能力降低以及功能性能边缘的衰老细胞积累增加的组合效应。因此，对抗心脏衰老的最佳干预策略需要促进维持以健壮的干细胞群和最小的衰老细胞积累为代表的年轻特征。该建议将通过涉及Pim-1的分子策略拮抗衰老表型，Pim-1是最近在心肌中鉴定的存活和增殖激酶。Pim-1活性的明智增强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，其能够具有更大的血液动力学功能和对心肌病损伤（包括衰老的退行性后果）的抗性。实现该提案的既定目标将提供对心肌Pim-1活性介导的改善的全面机制理解。该提案的创新在于Pim-1激酶作为靶向策略的独特性质，以拮抗衰老表型并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。短期目标是描绘受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。具体目标是：1）心肌衰老被Pim-1介导的信号传导拮抗，2）Pim-1活性的丧失导致心肌过早老化和相关的血液动力学性能下降，和3）心脏祖细胞的增殖期和年轻心肌细胞扩增被Pim-1激酶延长。这些研究的意义在于抑制心肌老化并在更长的寿命期内保持年轻特征。总的来说，这些研究将为干预性方法调节Pim-1激酶活性以拮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：心脏病仍然是美国发病率和死亡率的主要原因，患者的长期护理和住院治疗是国家卫生保健系统的重大负担。尽管在过去的几十年里取得了进展，但我们仍然没有真正能够解决心力衰竭的基本问题：收缩功能和存活组织的逐渐丧失。该建议的重点是一种新的基本分子机制，涉及拮抗衰老表型，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.