Ephrin A1/EphA2 Signaling and Myocardial Aging

Ephrin A1/EphA2 信号传导与心肌衰老

• 批准号: 8631722
• 负责人: Polina Goihberg
• 金额: $ 35.12万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631722
• 关键词: Affect; Age; Age of Onset; Aging; Animal Model; Animals; Area; Autologous; Binding Proteins; Biological Markers; Cardiac; Cardiac Myocytes; Cell Aging; Cell Transplants; Cell physiology; Cells; Chemotactic Factors; Cicatrix; Coronary Vessels; Data; Defect; Differentiation and Growth; Elderly; Eph Family Receptors; EphA2 Receptor; Ephrin-A1; Ephrins; Family; Growth; Harvest; Health; Heart; Hepatocyte Growth Factor; Homeostasis; Human; Infarction; Injection of therapeutic agent; Injury; Life; Ligands; Longevity; Membrane; Mus; Muscle Cells; Myocardial; Myocardium; Myopathy; Natural regeneration; Organ; Pathway interactions; Performance; Phenotype; Physiological; Process; Property; Proto-Oncogene Protein c-kit; Rattus; Recovery; Sarcolemma; Signal Pathway; Signal Transduction; Site; Stem cells; Structure; Supporting Cell; Surface; System; Testing; Time; Tissues; Treatment Efficacy; Ventricular; Work; aged; base; cell motility; functional loss; hemodynamics; improved; migration; novel therapeutics; prevent; regenerative; repaired; response; restoration; senescence; stem cell niche; trafficking

DESCRIPTION (provided by applicant): The central hypothesis of this application is that myocardial aging is dictated by time-dependent changes in the motility of c-kit-positive cardiac stem cells (CSCs). Defective migration of CSCs may oppose their egress from the niches and translocation to the sites of damage in the old heart. A guidance system that regulates stem cell migration involves the family of Eph receptor tyrosine kinases, which interact with the neighboring cells expressing the ephrin ligands. EphA2 receptors are preferentially located on the surface of CSCs, while the corresponding ligand, ephrin A1, is distributed on the membrane of cardiomyocytes, which act as supporting cells within the niches. Activation of EphA2 by ephrin A1 results in directional migration of CSCs, promoting their recruitment to the site of injury, while blockade of the EphA2 pathway abrogates the motile response of CSCs. Abnormalities in ephrin A1/EphA2 signaling may interfere with the translocation of old CSCs in the aging heart. The impaired migration of CSCs in old myocardium may be dictated by: a) reduced synthesis of ephrin A1 by senescent cardiomyocytes; b) decreased expression of EphA2 in CSCs; and/or c) alterations at the translational or post-translational level of EphA2 and its downstream effectors. These possibilities will be tested to identify targets aiming at the recovery of the therapeutic efficacy of old CSCs in the senescent myocardium. Restoration of EphA2 signaling in old CSCs may delay, prevent, or reverse the manifestations of the aging cardiac phenotype. Additionally, we have developed a strategy for the recognition and selective isolation of CSCs with intact regenerative potential from the old heart. With aging, senescent CSCs accumulate in the myocardium; however, a pool of "young" cells with high growth reserve persists throughout life. These cells are expected to retain ephrin A1/EphA2 signaling capacity and migratory properties. Based on the differential ability of young and old CSCs to activate the ephrin A1 pathway, the pool of functionally-competent CSCs may be harvested and implemented to repopulate the senescent heart with mechanically efficient cardiomyocytes. Ultimately, the profound restructuring of the old heart may prolong the health span and lifespan in humans.

描述（由申请人提供）：本申请的中心假设是，心肌老化是由c-kit阳性心脏干细胞（CSC）运动的时间依赖性变化决定的。 CSC 的迁移缺陷可能会阻碍它们从生态位中流出并转移到旧心脏的损伤部位。调节干细胞迁移的引导系统涉及 Eph 受体酪氨酸激酶家族，该家族与表达肝配蛋白配体的邻近细胞相互作用。 EphA2受体优先位于CSC表面，而相应的配体肝配蛋白A1分布在心肌细胞膜上，心肌细胞充当微环境内的支持细胞。肝配蛋白 A1 激活 EphA2 会导致 CSC 定向迁移，促进其募集到损伤部位，而阻断 EphA2 途径会消除 CSC 的运动反应。肝配蛋白 A1/EphA2 信号传导异常可能会干扰衰老心脏中旧 CSC 的易位。衰老心肌中 CSC 的迁移受损可能是由于： a) 衰老心肌细胞合成肝配蛋白 A1 的减少； b) EphA2在CSC中的表达降低；和/或c) EphA2及其下游效应子的翻译或翻译后水平的改变。将测试这些可能性，以确定旨在恢复衰老心肌中旧 CSC 治疗功效的目标。旧 CSC 中 EphA2 信号的恢复可能会延迟、预防或逆转衰老心脏表型的表现。此外，我们还制定了一种策略，用于从旧心脏中识别和选择性分离具有完整再生潜力的 CSC。随着年龄的增长，衰老的 CSCs 在心肌中积累；然而，具有高生长储备的“年轻”细胞库在整个生命过程中持续存在。这些细胞预计将保留肝配蛋白 A1/EphA2 信号传导能力和迁移特性。基于年轻和年老 CSC 激活肝配蛋白 A1 途径的差异能力，可以收获功能健全的 CSC 池并用于用机械高效的心肌细胞重新填充衰老心脏。最终，对旧心脏的深刻重组可能会延长人类的健康寿命和寿命。