Inflamm-aging of osteoprogenitor cells: A therapeutic target for improved bone healing - Resubmission - 1 - Revision - 3

骨祖细胞的炎症老化：改善骨愈合的治疗靶点 - 重新提交 - 1 - 修订 - 3

• 批准号: 10365117
• 负责人: Philipp Leucht
• 金额: $ 7.22万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10365117
• 关键词: 1 year old; Affect; Age; Aging; Animals; Anti-Inflammatory Agents; Back; Behavior; Biological Assay; Biomechanics; Bone Marrow; Bone Regeneration; Bone Transplantation; Cell Aging; Cell Count; Cell Separation; Cell physiology; Cells; Chronic; Chronology; Data; Defect; Degenerative Disorder; Disease; Elderly; Elements; Environment; Exhibits; Fibrous capsule of kidney; Fluorescence-Activated Cell Sorting; Fracture; Frequencies; Functional disorder; Future; Goals; Health; Impaired healing; Impairment; In Vitro; Individual; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Investigation; Knock-in; Knock-out; Lead; Learning; Life; Link; Mediating; Modeling; Mus; NF-kappa B; Natural regeneration; Nervous system structure; Osteoblasts; Osteogenesis; PTGS2 gene; Parabiosis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Process; Proliferating; Property; Quality of life; Regenerative capacity; Rejuvenation; Reporter; Role; Skeletal Muscle; Skeleton; Skin Aging; Stimulus; TNFRSF5 gene; Testing; Therapeutic; Time; Tissues; Translations; Trauma; Treatment Protocols; adult stem cell; age effect; age related; aged; bone; bone aging; bone healing; cytokine; design; experimental study; functional decline; improved; in vivo; in vivo Model; inflammatory milieu; medical complication; middle age; mouse model; muscular system; negative affect; new therapeutic target; novel; older patient; osteogenic; osteoprogenitor cell; parent grant; regeneration function; regeneration potential; regenerative; response; restoration; senescence; skeletal; skeletal disorder; skeletal stem cell; stem cell biology; stem cell biomarkers; stem cell function; stem cells; telomere; therapeutic target; young adult

PARENT GRANT ABSTRACT Aging has a dramatic effect on regeneration of all tissues, bone included. When a young adult fractures a bone, stem cells residing within the bone marrow cavity proliferate and differentiate into osteoblasts. This process results in regeneration of the skeletal element with complete restoration of its biomechanical properties. In the elderly, however, this process is often inadequate, which will result in a delayed healing response and subsequent medical complications. Chronic inflammation mediated by activation of the NF-κB pathway has recently been linked to a decline in regenerative potential in aged skin, skeletal muscle and nervous system, although the direct effects of NF-κB activation on stem cell function in these tissues is still under investigation. Accumulation of senescent cells in aging tissues has been suggested as the driver of chronic inflammation, as these cells secrete inflammatory factors, which affect the entire surrounding cellular milieu, further stimulating inflammation. The mechanisms underlying this age-related decline in stem cell function are the focus of this proposal. We hypothesize that the accumulated effects of chronic inflammation lead to osteoprogenitor cell dysfunction. Within this proposal, we will quantify and qualify age-dependent alterations in progenitor cell frequency, proliferative and osteogenic differentiation potential, and determine if these changes are caused by chronological aging or age-associated inflammation. While previous studies have demonstrated a reduced regenerative potential of heterogeneous bone grafts from aged animals, this study will for the first time assess the affect of aging on a homogeneous progenitor cell population in an in vivo environment. In the second part of this proposal, we will investigate the underlying mechanism of action that is responsible for increased osteoprogenitor cell senescence and resulting regenerative dysfunction. Here, we will identify the machinery that activates telomere dysfunction and cell senescence. From this experiment, we will learn, whether chronic inflammation is the culprit for reduced regenerative function of the aged bone progenitor cell, and whether this process is reversible. Finally, we will study the effect of chronic inflammation on the regenerative decline of the aging osteoprogenitor cell in a regenerative context and will utilize the information gained in the previous aims to design a therapeutic approach that will lead to the rejuvenation of skeletal progenitor cells. The goal of this highly translational project is to identify the basis of the age-related decline in osteogenic progenitor cell function and thus to define a new therapeutic target for improved bone healing in the elderly patient.

父级赠款摘要 衰老对包括骨骼在内的所有组织的再生都有显著的影响。当一个年轻人骨折时 骨，存在于骨髓腔内的干细胞增殖并分化为成骨细胞。这 过程导致骨骼元素的再生和其生物力学的完全恢复 属性。然而，在老年人中，这一过程往往不充分，这将导致延迟愈合。 反应和随后的医疗并发症。 由NF-κB途径激活所介导的慢性炎症最近被认为与 老年皮肤、骨骼肌和神经系统的再生潜力，尽管NF-κB的直接作用 对这些组织中干细胞功能的激活仍在调查中。衰老细胞在体内的积累 老化的组织被认为是慢性炎症的驱动力，因为这些细胞分泌炎症。 影响整个周围细胞环境的因素，进一步刺激炎症。 干细胞功能与年龄相关的下降背后的机制是这项提议的重点。我们 假设慢性炎症的累积效应会导致骨祖细胞功能障碍。 在这项建议中，我们将量化和鉴定祖细胞频率随年龄变化的情况， 增殖和成骨分化潜能，并确定这些变化是否由 年龄老化或年龄相关性炎症。虽然之前的研究表明， 老年动物异种骨移植的再生潜力，这项研究将首次评估 在活体环境中老化对同种祖细胞群体的影响。 在这项建议的第二部分，我们将调查潜在的行动机制，即 导致骨祖细胞衰老增加，并导致再生功能障碍。 在这里，我们将确定激活端粒功能障碍和细胞衰老的机制。由此 实验，我们将了解，慢性炎症是否是再生功能降低的罪魁祸首 衰老的骨祖细胞，以及这一过程是否可逆。最后，我们将研究慢性精神分裂症的影响。 在再生环境中对老化的骨祖细胞再生衰退的炎症 并将利用在先前目标中获得的信息来设计一种治疗方法，该方法将导致 骨骼祖细胞的再生。 这个高度翻译的项目的目标是确定与年龄相关的成骨能力下降的基础。 祖细胞功能，从而为改善老年人的骨愈合确定新的治疗靶点 有耐心的。