Stem Cells and Myocardial Aging in Dogs

狗的干细胞和心肌老化

基本信息

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
项目类别：
财政年份：
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

项目摘要

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.

项目摘要（请参阅说明）：人类心肌衰老的研究很复杂，这取决于将时间对心脏的影响与伴随性病的影响以及影响生理衰老的各种种族，生活方式和环境因素的困难。由于衰老的奥秘，需要在有机体寿命期间保持在受控条件下的大型动物模型上的信息，对于定义衰老心脏的病因并认识到管理衰老肌病的新目标至关重要。项目3将表征确定在Lovelace生物医学和环境研究所（LBERI）的男性和雌性小猎犬犬（lovelace狗）中从成年到心脏衰老和衰老过渡的机制，在高度调节的环境中，该研究所（LBERI）详细记录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，因此丢失了肌细胞和成纤维细胞之间的平衡，从而导致胶原蛋白含量的增加和心室顺应性的改变。这种血液动力学异常以及较小的肌细胞后代会增加每个细胞的舒张压负荷。心肌细胞在心肌壁ches中充当支撑细胞，而心肌细胞可能会激活大量的CSC，并且复制CSC经历了端粒损耗，而生长储备的损失。老化的CSC会产生肌细胞，从而快速获得衰老表型和旧的肌细胞通常会显示长时间的缩短并减少缩短，进一步损害了舒张期松弛，并最终损害了整体心脏表现。舒张性心力衰竭（正常或接近正常的射血分数）占受慢性心力衰竭影响的-50％的PAFIENT，并且该项目中要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是否可以将保留的CSC实现为对这种令人沮丧的，遮罩的疾病的新策略的实施至关重要。