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: 8827247
• 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/8827247
• 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; Health; 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; microCT; mitochondrial dysfunction; mouse model; novel; novel strategies; osteogenic; prevent; programs; 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）：本次 K01 奖申请的目标是促进候选人 Eliseev 博士的职业发展。在博士的指导下。候选人 Regis O'Keefe、Matthew Hilton 和 Paul Brookes 将阐明间充质干细胞 (MSC) 的生物能学和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 博士引入他不熟悉的研究领域的工具，例如干细胞、骨重塑和修复、衰老、骨质疏松症和小鼠遗传模型。 间充质干细胞利用糖酵解来产生能量，并在成骨分化过程中转换为线粒体氧化磷酸化。这种生物能开关在衰老、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。该提案的目的是确定衰老过程中 MSC 生物能变化的机制及其对 MSC 成骨性和骨质量的影响。线粒体通透性转变（MPT）的激活是衰老过程中心血管和其他系统中一个有据可查的事件。 MPT 在老化骨骼中的作用尚未阐明。根据我们的数据和文献，我们的中心假设是，由于 MPT 导致的生物能衰竭和活力下降破坏了老化 MSC 的成骨潜力，导致骨质疏松和骨折愈合延迟，这些可以通过抑制 MPT 来逆转。我们的具体目标是：（1）确定衰老间充质干细胞线粒体功能障碍的机制及其对间充质干细胞活力和成骨性的影响。我们假设MPT就是这样一种机制； (2)阐明抑制MPT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MPT抑制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 整体或 MSC 特异性功能丧失的小鼠遗传模型；和新型药理抑制剂。 我们在这里的贡献预计是详细了解 MSC 生物能量学在衰老过程中如何受到破坏，以及如何改进它以达到预防和治疗的目的。这是非常重要的，因为它将带来骨质疏松症和骨折修复的新策略，并为公众健康带来重大益处。我们的研究还将通过阐明间充质干细胞生物能学和成骨性之间的未知机制，推动骨生物学和衰老领域的发展。我们的研究具有创新性，因为它脱离了现状，将 MSC 中受损的生物能学置于骨质疏松症发病机制的中心；并测试了一种新方法——MPT抑制，以治疗衰老过程中的骨质疏松症和骨折愈合延迟。