Stem Cells and Myocardial Aging in Dogs

项目总结（见说明）：人类心肌老化的研究是复杂的，这是由于难以将时间对心脏的影响与伴随疾病分开，以及影响生理老化的各种种族、生活方式和环境因素。由于衰老的神秘性，需要获得在生物体寿命期间保持在受控条件下的大型动物模型的信息，对于定义衰老心脏的病因学和识别用于管理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）高度监管的环境中饲养和饲养的雄性和雌性比格犬从成年期向心脏衰老和衰老过渡的机制，该研究所保留了动物健康史的详细记录。待检验的主要假设是，狗心脏中的干细胞随着年龄的增长而改变其表型特征，从而失去了正在形成的肌细胞和成纤维细胞之间的平衡，导致胶原蛋白含量增加和心室顺应性改变。这种血流动力学异常，加上较小的心肌细胞后代，增加舒张负荷每细胞。肌细胞在心肌小生境中起支持细胞的作用，并且肌细胞拉伸可以激活大量CSC，并且复制的CSC经历端粒磨损并丧失生长储备。老化的CSC产生快速获得衰老表型的肌细胞，并且老化的肌细胞通常表现出延长的再充盈和减少的缩短，进一步损害舒张期舒张，并最终损害总体心脏性能。射血分数正常或接近正常的舒张性心力衰竭包括约50%的受慢性心力衰竭影响的患者，并且在该项目中获得的信息对于理解心肌老化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、模糊的疾病的新策略来实施是基本的。

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.