Beta-adrenergic signaling: double edged sword of myocardial repair

β-肾上腺素能信号传导：心肌修复的双刃剑

• 批准号: 8996702
• 负责人: MARK ALAN SUSSMAN
• 金额: $ 37.38万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996702
• 关键词: ADRBK1 gene; Acute; Adrenergic Agents; Adrenergic Receptor; Affect; Aging; Animal Model; Apoptotic; Biological Preservation; Cardiac; Cardiac Myocytes; Cardiotoxicity; Catecholamines; Cell Cycle; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cell Survival; Cell model; Cell physiology; Chronic; Chronic stress; Engineering; Engraftment; Environment; Face; Functional disorder; Future; G-Protein-Coupled Receptors; Goals; Healed; Health; Healthcare Systems; Heart; Heart Diseases; Heart Rate; Heart failure; Human; Injury; Intervention; Lead; Learning; Lentivirus Vector; Link; Long-Term Effects; Maintenance; Malignant Neoplasms; Mediating; Molecular; Molecular Models; Muscle Cells; Myocardial; Myocardium; Natural regeneration; Organ; Pathologic; Patients; Peptides; Perception; Performance; Phosphotransferases; Physiological; Process; Proto-Oncogene Protein c-kit; Proto-Oncogene Proteins c-akt; Public Health; Receptor Signaling; Research; Rest; Signal Transduction; Stem cells; Stimulus; Stress; Structure; Structure of thyroid parafollicular cell; System; Target Populations; Therapeutic; United States; Wound Healing; base; beta-2 Adrenergic Receptors; beta-adrenergic receptor; clinically relevant; conventional therapy; coping; desensitization; differential expression; empowered; functional restoration; healing; improved; innovation; insight; molecular modeling; mortality; novel; novel strategies; overexpression; receptor; receptor expression; regenerative; repaired; response; stem cell biology

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.

描述（由申请人提供）：心肌具有细胞替代的固有能力，但这种修复过程不足以科普急性损伤或慢性应激。心脏祖细胞（CPC）的发现已经确立了心脏作为一个动态的器官，CPC成为心肌成形修复的有效选择。再生性介入方法显著改善了心肌结构和功能，但心肌修复的功能恢复将不可避免地需要破译心肌损伤机制。 损害细胞替换和愈合的分子信号。这一建议的首要前提是，心肌修复机制受到病理刺激的损害，导致与细胞替代不足相关的心功能不全的螺旋式下降。具体来说，该提案描绘了β-肾上腺素能受体（β-AR）信号传导与CPC介导的修复过程之间的关系。β-AR信号调节心脏收缩力和对生理和病理应激的适应，但尚未研究过在急性损伤和慢性应激反应中对CPC功能维持的影响。初步结果表明，β1-和β2-AR在未定型和早期心源性CPC中的差异表达，这种受体谱的变化对存活和增殖产生了深刻的不同影响。因此，短期目标是了解β-AR信号传导对心肌CPC功能的影响，并将这些发现扩展到开发治疗性干预策略，以通过操纵肾上腺素能驱动来增强CPC介导的再生。将使用临床相关药理学药物以及经工程改造以表达βARK-ct的慢病毒载体来探索这些发现的转化潜力，以改善衰竭心脏中CPC的存活、增殖植入和定型。具体目标是：1）β2-肾上腺素能系统调节心脏祖细胞功能，2）CPC存活被心脏定型过程中获得的β1-肾上腺素能受体拮抗，3）CPC介导的心肌修复在衰竭心脏中通过β-阻断恢复，以及4）人CPC的再生潜力通过βARK-ct过表达增强。该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。创新在于肾上腺素能驱动和心肌伤口愈合的新交叉点，采用细胞，分子和动物模型的尖端组合进行检查，以涵盖基础研究的范围，包括来自心力衰竭患者的人类CPC：将从成功完成拟议研究中受益最多的确切目标人群。长期目标是重新定义β-肾上腺素能驱动为“病理性”，并揭示利用肾上腺素能驱动增强心肌再生同时保留成熟心肌的潜力。