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

基本信息

批准号：
8431986
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
项目类别：
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/8431986
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 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 empowered functional restoration healing improved innovation insight molecular modeling mortality novel novel strategies overexpression public health relevance receptor receptor expression regenerative repaired response stem cell biology

项目摘要

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 ?-adrenergic receptor (?-AR) signaling and CPC-mediated reparative processes. ?-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 ?1- versus ?2-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 ?-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 ?ARK-ct to improve survival, proliferation engraftment and commitment of CPCs in failing hearts. Specific aims are: 1) ?2-adrenergic system regulates cardiac progenitor cell function, 2) CPC survival is antagonized by ?1-adrenergic receptor acquired during cardiac commitment, 3) CPC mediated myocardial repair is restored by ?-blockade in failing hearts, and 4) Regenerative potential of human CPCs is augmented by ?ARK-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 ?-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）：心肌具有固有的细胞置换能力，但是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（CPC）的发现已确立了心脏作为动态器官，CPC出现了，作为心肌塑性修复的有效选择。心肌结构和功能通过再生介入方法可显着改善，但是心肌修复的功能恢复将不可避免地需要破译损害细胞置换和愈合的分子信号传导。该提案的总体前提是，心肌修复机制受到病理刺激的损害，导致与细胞替代不足有关的心脏不足螺旋式下降。具体而言，该提案描述了肾上腺素能受体（？-AR）信号传导与CPC介导的修复过程之间的关系。？ - AR信号传导调节心脏收缩性并适应生理和病理压力，但是从未研究过对CPC功能维持对CPC功能维持的影响。初步结果表明，在不合同的和早期心源性CPC中，1- 1-ARS的差异表达，受体谱的这种转移对生存和增殖产生了明显不同的影响。因此，短期目标是了解心肌中CPC功能的影响的后果，并将这些发现扩展到制定治疗性介入策略，以通过操纵肾上腺素驱动来增强CPC介导的再生能力。这些发现的转化潜力将使用临床上相关的药理学剂以及设计用于表达ARK-CT的慢病毒载体，以提高生存率，增殖植入和CPC的承诺。 Specific aims are: 1) ?2-adrenergic system regulates cardiac progenitor cell function, 2) CPC survival is antagonized by ?1-adrenergic receptor acquired during cardiac commitment, 3) CPC mediated myocardial repair is restored by ?-blockade in failing hearts, and 4) Regenerative potential of human CPCs is augmented by ?ARK-ct overexpression.该研究的重要性是了解影响内源性心肌修复能力的潜在分子信号。创新取决于肾上腺素能驱动和心肌中伤口愈合的新型交集，并通过细胞，分子和动物模型的尖端组合进行了检查，以涵盖包括心力衰竭患者的人类CPC的频谱：从心力衰竭患者中得出的基本研究：确切的目标人群将从提出的研究成功完成中受益最大的目标人群。长期的目标是重新定义对肾上腺素能驱动为“病理学”的看法，并揭示利用肾上腺素能驱动以增强心肌再生的潜力，同时同时保留成熟的心肌。