Stem Cells and Myocardial Aging in Dogs

项目概述（见说明）：人类心肌衰老的研究是复杂的，因为很难将时间对心脏的影响与伴随的疾病分开，以及各种影响生理衰老的种族、生活方式和环境因素。由于衰老的神秘性，需要获取大型动物模型的信息，并在生物体生命周期内保持在受控条件下，这对于确定衰老心脏的病因和识别衰老肌病管理的新靶点至关重要。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到心脏老化和衰老的过渡机制，该研究所保存了动物健康史的详细记录。要验证的主要假设是，狗心脏中的干细胞会随着年龄的增长而改变其表型特征，从而导致肌细胞和成纤维细胞之间的平衡丧失，从而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，加上较小的肌细胞子代，增加了每个细胞的舒张负荷。肌细胞在心肌壁龛中起支持细胞的作用，肌细胞拉伸可能激活大量的CSCs，而复制的CSCs会发生端粒磨损，失去生长储备。衰老的CSCs产生的肌细胞迅速获得衰老表型，衰老的肌细胞通常表现出延长的再延长和缩短的减少，进一步损害舒张舒张，最终损害心脏的整体表现。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%，该项目获得的信息对于理解心肌衰老是否由干细胞缺陷决定以及保存的CSCs是否可以作为治疗这种破坏性的、模糊疾病的新策略至关重要。

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.