Mechanisms of Skeletal Stem Cell Aging

骨骼干细胞衰老的机制

• 批准号: 9789789
• 负责人: Charles KF Chan
• 金额: $ 24.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789789
• 关键词: Affect; Age; Aging; Area; Atherosclerosis; Atrophic condition of skin; Award; Biological Assay; Biology of Aging; Bone Density; Bone Diseases; Bone Resorption; Cartilage; Cause of Death; Cell Aging; Cell Lineage; Cells; Data; Defect; Degenerative polyarthritis; Dependence; Deterioration; Disease; Dysmyelopoietic Syndromes; Elderly; Endocrine system; Environment; Fracture; Frequencies; Generations; Genes; Genetic; Hematopoietic; Hematopoietic stem cells; Hip Fractures; Homeostasis; Impairment; In Vitro; Incidence; Individual; Infection; Infertility; Injury; Ions; Kyphosis deformity of spine; Lead; Lentivirus Vector; Light; Limb structure; Link; Longevity; Marrow; Measures; Medical; Metabolism; Minerals; Modeling; Morbidity - disease rate; Mus; Muscular Atrophy; Myelogenous; Neonatal; Operative Surgical Procedures; Osteoclasts; Osteopenia; Osteoporosis; Parabiosis; Patients; Phase; Phenotype; Play; Population; Positioning Attribute; Process; Production; Pulmonary Emphysema; Regulation; Resolution; Role; Serum; Skeletal system; Skeleton; Stem cells; Stromal Cells; Surface; System; T-Lymphocyte; Testing; Therapeutic; Tissues; Transplantation; Vitamin D; age effect; age group; age related; aged; bone; bone turnover; calcification; chronic pain; clinically translatable; computational platform; disability; editorial; experimental study; falls; healing; implantation; in vivo; novel; organ regeneration; progenitor; prospective; public health relevance; regenerative; response to injury; skeletal; skeletal disorder; soft tissue; stem cell niche; stem cell population; transcriptome

 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.

 描述（由适用提供）：在与年龄相关的疾病和疾病中，最令人沮丧的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，迁移率降低，残疾和依赖程度增加有关。此外，髋部骨折后的第一年，多达20％的患者死亡。在髋部骨折中幸存下来的人中，只有一半仍然是他们以前的功能水平。随着世界人口持续以快速衰老，骨骼疾病的事件预计将大幅增长。当前针对年龄相关的骨病的医学和外科手术疗法是最佳的，大多数依赖于植入异物的植入，这些外国材料受到了许多并发症，包括感染和进一步的骨折。因此，我们将重点放在骨骼内的干细胞种群上，这是理解和利用人体治愈骨骼疾病的内在潜力的潜在目标。干细胞是负责在器官中维持正常稳态的细胞，并在受伤后再生。我们已经确定了一个骨骼干细胞种群，该干细胞群体能够形成骨骼的所有成分 - 骨骼，软骨和骨髓基质。有人提出，随着老化而发生的降低的再生能力是一个多方面的问题，这可能是由于干细胞本身的内在变化或细胞所在的环境中的变化所致 - 干细胞“小裂”，或者可能是这些组合的组合。我们的第一个目的是表征衰老对年轻小鼠正常骨稳态的影响，探索参数，例如骨骼更新和骨矿物质密度。我们设计了一种新型的伤害模型，以识别与年龄相关的差异，以应对伤害。然后，使用这些数据，我们将在骨骼系统上查看系统环境的作用，专门探索 利基在使用异性抛物线模型中维持有效的骨骼干细胞池，其中将通过手术配对年轻小鼠和旧小鼠。这项研究将允许识别负责骨骼衰老的新机制，并允许识别 利用干细胞固有再生潜力的临床转换方式 减少与年龄有关的骨骼疾病相关的生物医学伯嫩的骨骼系统。