Stem Cells and Myocardial Aging in Dogs

狗的干细胞和心肌老化

• 批准号: 8464870
• 负责人: Marcello Rota
• 金额: $ 38.11万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8464870
• 关键词: Adult; Affect; Age; Age-Years; Aging; Aging-Related Process; Animal Model; Animals; Canis familiaris; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cells; Characteristics; Chronic; Clinical; Collagen; Complex; Data; Defect; Development; Diagnosis; Diastolic blood pressure; Diastolic heart failure; Disease; EFRAC; Environment; Environmental Risk Factor; Epidemic; Equilibrium; Etiology; Event; Evolution; Female; Fibroblasts; Functional disorder; Genetic; Growth; Heart; Heart failure; Human; Incidence; Individual; Instruction; Knowledge; Lead; Life; Life Style; Longevity; Mediating; Methodology; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardium; Myopathy; Organ; Organism; Pathology; Patients; Performance; Phenotype; Physiological; Process; Recording of previous events; Relaxation; Research; Research Institute; Sex Characteristics; Stem cells; Stretching; Supporting Cell; Symptoms; Testing; Text; Time; Ventricular; Woman; Work; aged; base; health record; hemodynamics; male; men; novel; novel strategies; novel therapeutics; older men; older women; response; senescence; telomere

PROJECT SUMMARY (See instructions): Studies of myocardial aging in humans are complex, dictated by the difficulty to separate the effects of time on the heart from concomitant morbidities, and a variety of ethnic, lifestyle, and environmental factors, which affect physiological aging. Because of the mystery of aging, the need to acquire information on a large animal model, maintained under controlled conditions during the organism lifespan, is of critical importance to define the etiology of the aging heart, and recognize novel targets for the management of the aging myopathy. Project 3 will characterize the mechanisms that determine the transition from adulthood to cardiac aging and senescence in male and female Beagle dogs raised and kept in a highly regulated environment at the Lovelace Biomedical and Environmental Research Institute (LBERI) in which a detailed record of the health history of the animals is maintained. The major hypothesis to be tested is that stem cells in the dog heart change their phenotypic characteristics with age so that the balance between myocytes and fibroblasts being formed is lost, resulting in an increase in collagen content and alterations in ventricular compliance. This hemodynamic abnormality, together with a smaller myocyte progeny, increases diastolic load per cell. Myocytes function as supporting cells in the myocardial niches, and myocyte stretch may activate a large pool of CSCs, and replicating CSCs undergo telomere attrition with loss of growth reserve. Aged CSCs generate myocytes that rapidly acquire the senescent phenotype and old myocytes typically show prolonged relengthening and decreased shortening, further impairing diastolic relaxation and, eventually, overall cardiac performance. Diastolic heart failure with normal or near normal ejection fraction comprises -50% of pafients affected by chronic heart failure, and the information to be obtained in this Project is fundamental for understanding whether myocardial aging is dictated by stem cell defects and whether preserved CSCs may be implemented as a novel strategy for the treatment of this devastating, obscure disease.

项目摘要(参见说明)：人类心肌老化的研究是复杂的，这是由于很难区分时间对心脏的影响和伴随的疾病，以及影响生理性衰老的各种种族、生活方式和环境因素。由于衰老的奥秘，需要在一个大型动物模型上获得信息，并在生物体的生命周期内保持在可控的条件下，这对于确定衰老心脏的病因和识别衰老肌病的新靶点至关重要。项目3将描述在Lovelace生物医学和环境研究所(LBERI)高度规范的环境中饲养和保存的雄性和雌性Beagle犬从成年到心脏衰老和衰老的机制，其中保存了动物健康历史的详细记录。需要检验的主要假设是，狗心脏中的干细胞随着年龄的增长而改变其表型特征，从而失去了肌细胞和成纤维细胞之间的平衡，导致胶原含量增加和心室顺应性的改变。这种血流动力学异常，加上较小的心肌细胞后代，增加了每个细胞的舒张期负荷。心肌细胞在心肌微环境中起支持细胞的作用，心肌细胞拉伸可以激活大量的CSCs，复制的CSCs经历端粒磨损并失去生长储备。衰老的CSCs产生的心肌细胞迅速获得衰老表型，而老年心肌细胞通常表现出延长的再延长和缩短的减少，进一步损害舒张期松弛，最终影响整体心脏功能。射血分数正常或接近正常的舒张性心力衰竭患者占慢性心力衰竭患者的-50%，本项目中获得的信息是了解心肌老化是否由干细胞缺陷决定的基础，以及保存的CSCs是否可以作为治疗这种毁灭性的、不知名的疾病的新策略。