Mechanisms of Skeletal Stem Cell Aging

 描述(申请人提供)：在与年龄增长相关的疾病和障碍中，最令人衰弱的是骨骼正常的体内平衡功能的丧失。这在骨质疏松症中尤其如此，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有关。此外，多达20%的患者在髋部骨折后的第一年内死亡。在髋部骨折中幸存下来的人中，只有不到一半的人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。目前治疗年龄相关性骨骼疾病的内科和外科治疗方法并不理想，大多数依赖于异体材料的植入，这些异体材料容易出现包括感染和进一步骨折在内的一系列并发症。出于这个原因，我们将重点放在骨骼中的干细胞群体上，作为一个潜在的目标，以了解和利用身体的内在潜力来治疗骨骼疾病。干细胞是负责维持器官内正常内环境平衡和损伤后再生的细胞。我们已经确定了一个骨骼干细胞群体，它能够形成骨骼的所有成分-骨、软骨和骨髓基质。有人提出，随着衰老而出现的再生能力下降是一个多方面的问题，可能是由于干细胞本身的内在变化，或者是细胞所在环境的变化--干细胞“利基”，或者这些因素的组合。我们的第一个目标是表征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 利基在维持有效的骨骼干细胞池中使用异慢性异种异生模型，在这种模型中，一只幼鼠和一只老年鼠将通过手术配对。这项研究将有助于确定导致骨骼老化的新机制，并将有助于确定 临床上可翻译的利用干细胞内在再生潜力的方法 骨骼系统，以减少目前与年龄相关的骨骼疾病相关的生物医学负担。

 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.