Project 2 - Role of bone-derived exosomes in musculoskeletal aging

项目 2 - 骨源性外泌体在肌肉骨骼衰老中的作用

• 批准号: 9902286
• 负责人: MARK W HAMRICK
• 金额: $ 32.91万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9902286
• 关键词: Address; Affect; Age; Age-Related Bone Loss; Aging; Animals; Aromatic Amino Acids; Biodistribution; Biological Assay; Bone Density; Bone Marrow; Bone Marrow Stem Cell; Bone Resorption; Caloric Restriction; Cell Differentiation process; Cell physiology; Cells; Characteristics; Data; Development; Diagnosis; Disease; Disease Outcome; Elderly; Event; Financial Hardship; Fracture; Functional disorder; Future; Genes; Goals; Hematopoietic; Human; Impairment; In Vitro; Inflammatory; Intervention; Knowledge; Kynurenine; Mesenchymal; MicroRNAs; Molecular; Molecular Target; Mus; Muscle; Muscle Fibers; Muscular Atrophy; Musculoskeletal; Myoblasts; Nutrient; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Outcome; Pathology; Pathway interactions; Process; Public Health; Quality of life; Reporter; Role; Signal Transduction; Source; Stimulus; Stromal Cells; Testing; Tissues; Transplantation; age related; aged; base; bone; bone loss; bone mass; clinical practice; cost; cytokine; exosome; experimental study; extracellular vesicles; falls; improved; in vivo; microvesicles; muscle form; organ injury; osteoclastogenesis; osteogenic; patient population; prevent; progenitor; sarcopenia; small molecule; stem cells; uptake

Aging is associated with a loss of muscle mass in the form of sarcopenia and a loss of bone mass and density in the form of osteoporosis. Loss of muscle and bone mass with age are in turn underlying factors contributing to falls and fractures in the elderly, and these fractures are very costly both in terms of financial burden and quality of life. A critical barrier to progress in correcting the problem of muscle and bone loss with aging is a poor understanding of the molecular and cellular mechanisms underlying age-related musculoskeletal dysfunction. Our goal is to address this problem by providing critical, new information on the molecular and cellular mechanisms that control these processes, and thereby improve scientific knowledge, technical capability, and eventually clinical practice. Our central hypothesis is that extracellular vesicles (EVs), including exosomes and microvesicles, secreted by stem cells in bone marrow are significantly altered with aging, and that altered EVs contribute to muscle and bone loss by transporting specific microRNAs (miRNAs). This hypothesis is based on our preliminary data indicating that the miRNAs carried by EVs in bone marrow are significantly altered with age. Moreover, treatment of young bone marrow stromal cells (BMSCs) with EVs from bone marrow of aged animals suppresses the osteogenic differentiation of these cells, and treatment of young myoblasts with these EVs suppresses the expression of myogenic genes. Our preliminary results also suggest that these age-related changes in EV-derived miRNAs can be reversed with long-term caloric restriction. Our objectives are to 1) define how aging alters the secretion and cargo of EVs from bone-derived stem cells, and 2) determine how these EVs regulate key cellular events in bone loss and muscle atrophy. Our expected outcomes include 1) identification of EV-derived miRNAs that are actively secreted by bone marrow stem cells and are altered with age, and 2) determination of how these small molecules affect key cellular processes directly related to bone and muscle loss with aging. The impact of this project will be new findings on the role of EVs and miRNAs in the development of age-related diseases and end-organ injuries. In the future this knowledge may be critical in the diagnosis, treatment and management of vulnerable patient populations debilitated by the vast array of age-induced pathologies. Aim 1 will test the hypothesis that bone- derived EVs, and their miRNAs, are induced by specific age-related stimuli. Aim 2 will test the hypothesis that EVs, and their miRNAs, altered with aging directly impact key cellular events in muscle atrophy and bone formation in vitro. Aim 3 will test the hypothesis that EVs, and their miRNAs, altered with aging directly impact key cellular events in muscle atrophy and bone formation in vivo.

衰老与肌肉质量的损失有关，肌肉减少症和骨质和密度的损失 以骨质疏松症的形式。随着年龄的增长，肌肉和骨量的损失反过来又是导致 老年人的福尔斯和骨折，这些骨折在经济负担和 生活质量一个关键的障碍，以进步，纠正问题的肌肉和骨骼损失与老化是一个 对与年龄相关的肌肉骨骼系统的分子和细胞机制了解不足 功能障碍我们的目标是通过提供关键的，新的信息，分子和 控制这些过程的细胞机制，从而提高科学知识， 能力，最终临床实践。我们的中心假设是细胞外囊泡（EV），包括 由骨髓中的干细胞分泌的外泌体和微泡随着年龄的增长而显著改变， 改变的EV通过运输特定的microRNA（miRNAs）导致肌肉和骨骼损失。这 这一假设是基于我们的初步数据，表明骨髓中EV携带的miRNAs是 随着年龄的增长而显著改变。此外，用EV处理年轻的骨髓基质细胞（BMSC）， 从老年动物骨髓中提取的细胞抑制了这些细胞的成骨分化， 具有这些EV的年轻成肌细胞抑制肌原基因的表达。我们的初步结果也 这表明EV来源的miRNA中这些与年龄相关的变化可以通过长期热量逆转 限制.我们的目标是：1）确定衰老如何改变骨源性肠上皮细胞的分泌和货物， 干细胞，2）确定这些EV如何调节骨丢失和肌肉萎缩中的关键细胞事件。 预期的结果包括1）鉴定由骨髓主动分泌的EV衍生的miRNA 干细胞，并随着年龄的变化，和2）确定这些小分子如何影响关键细胞 与骨骼和肌肉随着衰老而流失直接相关的过程。这个项目的影响将是新的发现 关于EV和miRNA在年龄相关疾病和终末器官损伤发展中的作用。在 未来，这些知识可能对脆弱患者的诊断、治疗和管理至关重要。 人口因大量年龄引起的疾病而衰弱。目标1将检验骨- 衍生的EV及其miRNA是由特定的年龄相关刺激诱导的。目的2将检验以下假设： 随着年龄的增长，EV及其miRNA的改变直接影响肌肉萎缩和骨骼中的关键细胞事件 体外形成。目的3将检验EV及其miRNA随衰老而改变直接影响 体内肌肉萎缩和骨形成的关键细胞事件。