Beta-adrenergic signaling: double edged sword of myocardial repair

描述(申请人提供)：心肌具有固有的细胞替代能力，但这种修复过程不足以应对急性损伤或慢性应激。心脏祖细胞的发现奠定了心脏作为一个动态器官的地位，使其成为心肌整形修复的有效选择。再生性介入治疗可显著改善心肌结构和功能，但心肌修复的功能恢复必然需要破译 破坏细胞替换和修复的分子信号。这一建议的主要前提是，心肌修复机制受到病理刺激的影响，导致与细胞替代不足有关的心功能不全的螺旋式下降。具体地说，这一建议描述了β-肾上腺素能受体(β-AR)信号和CpC介导的修复过程之间的关系。β-AR信号调节心脏的收缩能力和对生理和病理应激的适应，但在急性损伤和慢性应激反应中对维持CPC功能的影响从未被研究过。初步结果表明，β1-AR和β2-AR在未承诺和早期心源性CPC中的差异表达，这种受体谱的变化对存活和增殖产生了截然不同的影响。因此，短期目标是了解β-AR信号对心肌CpC功能的影响，并扩展这些发现以开发治疗干预策略，通过操纵肾上腺素能驱动来增强CpC介导的再生。这些发现的翻译潜力将使用临床相关的药理学药物以及慢病毒载体进行探索，以表达β方舟-ct，以改善衰竭心脏中CPC的存活、增殖、植入和承诺。其具体目的是：1)β2-肾上腺素能系统调节心脏前体细胞功能；2)β存活被心脏承诺期间获得的β1-肾上腺素能受体拮抗；3)心衰心脏通过阻断β介导的心肌修复；4)CPC过表达ARK-CT增强其再生潜能。这项研究的意义在于了解影响内源性心肌修复能力的潜在分子信号。创新在于在心肌中肾上腺素能驱动和伤口愈合的新颖交集，通过细胞、分子和动物模型的尖端组合进行检查，以涵盖基础研究的光谱，其中包括来自心力衰竭患者的人类CPC：正是将从拟议研究的成功完成中受益最大的目标人群。长期目标是将β-肾上腺素能驱动力的概念重新定义为“病理性”，并揭示利用肾上腺素能驱动力促进心肌再生的潜力，同时保留成熟心肌。

DESCRIPTION (provided by applicant): The myocardium possesses an inherent capacity for cellular replacement, yet this reparative process is inadequate to cope with acute injury or chronic stress. Discovery of cardiac progenitor cells (CPCs) has established the heart as a dynamic organ with CPCs emerging as an efficacious choice for cardiomyoplastic repair. Myocardial structure and function is significantly improved by regenerative interventional approaches, but functional restoration of myocardial repair will inevitably require deciphering the molecular signaling that impairs cellular replacement and healing. The overarching premises of this proposal is that myocardial reparative mechanisms become compromised by pathologic stimuli leading to a downward spiral of cardiac insufficiency linked to inadequate cellular replacement. Specifically, this proposal delineates the relationship between β-adrenergic receptor (β-AR) signaling and CPC-mediated reparative processes. β-AR signaling regulates cardiac contractility and adaptation to physiological and pathological stress, but the impact upon maintenance of CPC function in response to acute injury and chronic stress has never been studied. Preliminary results indicate differential expression of β1- versus β2-ARs in uncommitted versus early cardiogenic CPCs, and this shift in receptor profile exerts profoundly divergent effects upon survival and proliferation. Therefore, short-term goals are to understand the consequences of β-AR signaling for CPC function in the myocardium and extend these findings to develop therapeutic interventional strategies to empower CPC-mediated regeneration through manipulation of adrenergic drive. Translational potential of these findings will be explored using clinically relevant pharmacologic agents as well as a lentiviral vector engineered to express βARK-ct to improve survival, proliferation engraftment and commitment of CPCs in failing hearts. Specific aims are: 1) β2-adrenergic system regulates cardiac progenitor cell function, 2) CPC survival is antagonized by β1-adrenergic receptor acquired during cardiac commitment, 3) CPC mediated myocardial repair is restored by β-blockade in failing hearts, and 4) Regenerative potential of human CPCs is augmented by βARK-ct overexpression. The significance of the study is to understand the underlying molecular signaling affecting endogenous myocardial repair capability. Innovation rests with the novel intersection of adrenergic drive and wound healing in the myocardium, examined with a cutting edge combination of cellular, molecular, and animal models to cover the spectrum of basic studies that include human CPCs derived from heart failure patients: the exact target population that would benefit most from the successful completion of the proposed studies. The long term goal is to redefine perceptions of β-adrenergic drive as "pathologic" and reveal the potential of leveraging adrenergic drive to enhance myocardial regeneration while concurrently preserving mature myocardium.