Mechanism of Mitochondrial Dysfunction in Mesenchymal Stem Cells During Aging

衰老过程中间充质干细胞线粒体功能障碍的机制

• 批准号: 8486853
• 负责人: Roman Eliseev
• 金额: $ 10.28万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8486853
• 关键词: Aging; Apoptosis; Area; Bioenergetics; Biology of Aging; Bone Diseases; Bone Regeneration; Bone Resorption; Bone remodeling; Cardiovascular system; Cell Aging; Cell Survival; Cell physiology; Cells; Data; Development; Diabetes Mellitus; Disease; Equilibrium; Event; Failure; Femoral Fractures; Fracture; Fracture Healing; Genetic Models; Glycolysis; Goals; Histology; Human; Knock-out; Knockout Mice; Knowledge; Lead; Link; Literature; Mechanics; Mentored Research Scientist Development Award; Mesenchymal Stem Cells; Metabolism; Methods; Mission; Mitochondria; Molecular; Mus; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Outcome Study; Oxidative Phosphorylation; Oxidative Stress; Pathogenesis; Permeability; Prevention therapy; Production; Property; Public Health; Recruitment Activity; Research; Role; Site; Stem cells; System; Testing; Tissues; Undifferentiated; United States National Institutes of Health; Wild Type Mouse; age related; aged; base; bone; bone quality; career; career development; cell age; cyclophilin D; design; disability; improved; inhibitor/antagonist; innovation; loss of function; mitochondrial dysfunction; mouse model; novel; novel strategies; osteogenic; prevent; programs; public health relevance; repaired; sanglifehrin A; stem cell biology

DESCRIPTION (provided by applicant): The goal of this K01 Award application is to enhance career development of the Candidate, Dr. Eliseev. Under the guidance of Drs. Regis O'Keefe, Matthew Hilton and Paul Brookes, the Candidate will elucidate the link between bioenergetics and osteogenicity of mesenchymal stem cells (MSC) and aging-related changes in this link. These studies will serve as a vehicle for introducing Dr. Eliseev into research areas that are new to him, such as stem cells, bone remodeling and repair, aging, osteoporosis, and mouse genetic models. MSCs use glycolysis for energy production and switch to mitochondrial oxidative phosphorylation during osteogenic differentiation. This bioenergetic switch is disrupted in aging, diabetes and other disorders leading to decreased MSC osteogenicity and osteoporosis. Our long-term research goal is to understand how cell metabolism determines cell fate and how it can be manipulated for the purposes of prevention and therapies. The objective of this proposal is to determine the mechanism underlying changes in MSC bioenergetics during aging and its effect on MSC osteogenicity and bone quality. Activation of the mitochondrial permeability transition (MPT) is a well documented event in cardiovascular and other systems during aging. The role of the MPT in aged bone has not been elucidated. Based on our data and the literature, our central hypothesis is that bioenergetic failure and decreased viability due to the MPT disrupt osteogenic potential of aged MSCs, leading to osteoporosis and delayed fracture healing that can be reversed by inhibition of the MPT. Our specific aims are: (1) determine the mechanism of mitochondrial dysfunction in aged MSCs and its effect on MSC viability and osteogenicity. We hypothesize that the MPT is such a mechanism; (2) elucidate the effect of inhibition of the MPT on osteoporosis during aging. We hypothesize that this will improve bone quality in aged mice; and (3) determine the effect of inhibition of the MPT on fracture healing in aged mice. We hypothesize that this will accelerate fracture healing. To attain our aims we will use MSC biology methods; mouse genetic models of global or MSC-specific loss-of-function of the MPT; and novel pharmacological inhibitors. Our contribution here is expected to be a detailed understanding of how MSC bioenergetics is disrupted in aging and how it can be improved for the purposes of prevention and therapies. This is very significant because it will lead to new strategies for osteoporosis and fracture repair and provide significant benefits for public health. Our research will also advance the field of bone biology and aging by elucidating yet unknown mechanisms connecting MSC bioenergetics and osteogenicity. Our research is innovative because it departs from the status quo and puts impaired bioenergetics in MSCs in the center of pathogenesis of osteoporosis; and tests a novel approach, MPT inhibition, to treat osteoporosis and delayed fracture healing during aging.

描述（由申请人提供）：此K 01奖申请的目标是提高候选人的职业发展，博士。在Regis O 'Keefe，Matthew希尔顿和Paul Brookes博士的指导下，候选人将阐明生物能量学和间充质干细胞（MSC）的成骨性之间的联系以及该联系中与衰老相关的变化。这些研究将作为将Eliseev博士引入他新的研究领域的工具，如干细胞，骨重建和修复，衰老，骨质疏松症和小鼠遗传模型。 MSCs利用糖酵解产生能量，并在成骨分化过程中转变为线粒体氧化磷酸化。这种生物能量转换在衰老、糖尿病和其他疾病中被破坏，导致MSC成骨性降低和骨质疏松症。我们的长期研究目标是了解细胞代谢如何决定细胞命运，以及如何操纵它以达到预防和治疗的目的。本提案的目的是确定衰老过程中MSC生物能量学变化的机制及其对MSC成骨性和骨质量的影响。线粒体通透性转换（MPT）的激活是一个有据可查的事件，在心血管和其他系统在老化过程中。MPT在老化骨中的作用尚未阐明。根据我们的数据和文献，我们的中心假设是，由于MPT破坏了老化MSC的成骨潜力，导致骨质疏松症和延迟骨折愈合，这可以通过抑制MPT来逆转。我们的具体目标是：（1）确定衰老MSC中线粒体功能障碍的机制及其对MSC活力和成骨性的影响。我们推测MPT是这样一种机制：（2）阐明MPT抑制对衰老过程中骨质疏松的影响。我们假设这将改善老年小鼠的骨质量;（3）确定抑制MPT对老年小鼠骨折愈合的影响。我们假设这将加速骨折愈合。为了实现我们的目标，我们将使用MSC生物学方法; MPT的整体或MSC特异性功能丧失的小鼠遗传模型;和新的药理学抑制剂。 我们在这里的贡献预计是详细了解MSC生物能量学如何在衰老中被破坏，以及如何为了预防和治疗的目的而改善。这是非常重要的，因为它将导致骨质疏松症和骨折修复的新策略，并为公共卫生提供显着的好处。我们的研究还将通过阐明连接MSC生物能量学和成骨性的未知机制来推进骨生物学和衰老领域。我们的研究是创新的，因为它从现状出发，将骨髓间充质干细胞中受损的生物能量学置于骨质疏松症发病机制的中心;并测试了一种新的方法，MPT抑制，以治疗骨质疏松症和衰老过程中骨折愈合延迟。