Mechanisms of Skeletal Stem Cell Aging

骨骼干细胞衰老的机制

• 批准号: 9780833
• 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/9780833
• 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; 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.