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: 8790766
• 负责人: MARK ALAN SUSSMAN
• 金额: $ 36.81万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8790766
• 关键词: ADRBK1 gene; Acute; Adrenergic Agents; Adrenergic Receptor; Affect; Aging; Animal Model; Apoptotic; Biological Preservation; Cardiac; Cardiac Myocytes; 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 Receptor Genes; 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; adrenergic; base; 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应对急性损伤或慢性应激。心脏祖细胞（cardiac progenitor cells, CPCs）的发现确立了心脏作为一个动态器官的地位，并使其成为心肌成形性修复的有效选择。心肌结构和功能通过再生介入途径得到显著改善，但心肌修复的功能恢复不可避免地需要对其进行解码