Stem Cells and Myocardial Aging in Dogs

狗的干细胞和心肌老化

• 批准号: 8822192
• 负责人: Marcello Rota
• 金额: $ 32.63万
• 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 2015-02-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822192
• 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; Clinical; Collagen; Complex; Congestive Heart Failure; 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）：人类心肌衰老的研究很复杂，因为很难将时间对心脏的影响与伴随的发病率分开，以及影响生理衰老的各种种族、生活方式和环境因素。由于衰老的奥秘，需要获取大型动物模型的信息，并在生物体生命周期内将其维持在受控条件下，这对于确定衰老心脏的病因和识别治疗衰老肌病的新目标至关重要。项目 3 将描述决定雄性和雌性比格犬从成年期向心脏老化和衰老转变的机制，这些犬是在洛夫莱斯生物医学和环境研究所 (LBERI) 高度监管的环境中饲养和饲养的，该研究所保存了动物健康史的详细记录。要测试的主要假设是，狗心脏中的干细胞随着年龄的增长而改变其表型特征，从而导致形成的肌细胞和成纤维细胞之间的平衡丧失，导致胶原含量增加和心室顺应性改变。这种血流动力学异常与较小的子代肌细胞一起增加了每个细胞的舒张负荷。肌细胞在心肌微环境中充当支持细胞，肌细胞拉伸可能会激活大量 CSC，并且复制的 CSC 会经历端粒磨损并丧失生长储备。老化的 CSC 产生的肌细胞会迅速获得衰老表型，而老化的肌细胞通常会表现出延长的再延长和缩短的减少，进一步损害舒张期舒张，最终损害整体心脏功能。射血分数正常或接近正常的舒张性心力衰竭占慢性心力衰竭患者的-50%，本项目获得的信息对于了解心肌衰老是否由干细胞缺陷决定以及保存的CSC是否可以作为治疗这种毁灭性的、晦涩的疾病的新策略至关重要。