Mechanisms of Skeletal Stem Cell Aging

 描述（由申请人提供）： 在与年龄增长相关的疾病和障碍中，最使人衰弱的一种是骨骼正常稳态功能的丧失。骨质疏松症尤其如此，其中髋部骨折总是与慢性疼痛、活动能力降低、残疾和依赖程度增加相关。此外，高达20%的患者在髋部骨折后的第一年内死亡。不到一半的髋部骨折幸存者恢复了以前的功能水平。随着世界人口继续快速老龄化，骨骼疾病的发病率预计将大幅上升。目前针对年龄相关性骨疾病的内科和外科治疗是次优的，大多数依赖于植入异物，这些异物容易发生大量并发症，包括感染和进一步骨折。出于这个原因，我们专注于骨骼内的干细胞群，作为理解和利用身体内在潜力来治愈骨骼疾病的潜在目标。干细胞是负责维持器官正常稳态和损伤后再生的细胞。我们已经确定了一个骨骼干细胞群，它能够形成骨骼的所有组成部分-骨，软骨和骨髓基质。有人提出，随着衰老而发生的再生能力降低是一个多方面的问题，可能是由于干细胞本身的内在变化或细胞所在环境的变化-干细胞“生态位”，或者是这些的组合。我们的第一个目标是描述衰老对年轻和老年小鼠正常骨稳态的影响，探索骨转换和骨密度等参数。我们设计了一种新的损伤模型来识别与年龄相关的损伤反应差异。有了这些数据，我们将研究全身环境对骨骼系统的作用，特别是探索骨骼系统的作用。 利用异时共生模型，将年轻和年老的小鼠通过手术配对，在维持有效的骨骼干细胞库方面发挥作用。这项研究将允许识别负责骨骼衰老的新机制，并将允许识别 利用干细胞内在的再生潜力， 骨骼系统，以减少目前与年龄相关的骨骼疾病的生物医学负担。

 DESCRIPTION (provided by applicant): Among the diseases and disorders associated with advancing age, one of the most debilitating is the loss of normal homeostatic function of the skeleton. This is particularly true with osteoporosis, wherein hip fractures are invariably associated with chronic pain, reduced mobility, disability, and an increased degree of dependence. In addition, up to 20% of patients die within the first year following hip fractures. Less than half of those who survive the hip fracture regain their previous level of function. As th world's population is continuing to age at a rapid rate, the incidence of skeletal disease is expected to rise substantially. Current medical and surgical therapies for age-related bone disease are suboptimal, the majority relying on the implantation of foreign materials that are subject to a host of complications including infection and further fractures. For this reason, we are focusing on the stem cell population within bone as a potential target to understand and harness the body's intrinsic potential to heal disorders of the skeleton. Stem cells are the cells that are responsible for maintaining normal homeostasis in an organ, and for regeneration following injury. We have identified a skeletal stem cell population which is capable of forming all of the components of the skeleton - bone, cartilage and the marrow stroma. It is proposed that the reduced regenerative capacity that occurs with aging is a multifaceted problem, perhaps due to intrinsic changes in the stem cells themselves or changes in the environment in which the cells reside - the stem cell "niche", or perhaps a combination of these. Our first aim is to characterize the effects of aging on normal bone homeostasis in young and old mice, exploring parameters such as bone turnover and bone mineral density. We have devised a novel injury model to identify age-related differences in response to injury. With this data we will then look a the role of the systemic environment on the skeletal system, specifically exploring the role of the niche in maintaining an efficient pool of skeletal stem cells using a heterochronic parabiosis model where a young and an old mouse will be surgically paired. This study will allow for identification of novel mechanisms responsible for skeletal aging and will allow for identification of clinically-translatable ways of harnessing the intrinsic regenerative potential of stem cells in the skeleton system to reduce the biomedical burden currently associated with age-related skeletal disease.