Mitochondrial genetics as a determinant of bone health

线粒体遗传学是骨骼健康的决定因素

• 批准号: 10349639
• 负责人: Roman Eliseev
• 金额: $ 20.33万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349639
• 关键词: ATAC-seq; Affect; African ancestry; Aging; Alabama; Bioenergetics; Bone Marrow; Bone Tissue; Brain; Cells; Chromatin; Climate; Cold Climate; Communication; Data; Energy Metabolism; Epigenetic Process; Female; Foundations; Gene Expression; Genes; Genetic; Genetic Models; Genetic study; Genome; Goals; Haplogroup; Haplotypes; Histology; Homeostasis; Human; In Vitro; Inherited; Knowledge; Label; Literature; Maintenance; Measures; Mesenchymal Stem Cells; Mission; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Modeling; Mus; Myocardium; Nuclear; Nude Mice; Organelles; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Oxidative Phosphorylation; Pathology; Patients; Pattern; Persons; Phenotype; Physiology; Play; Population Study; Predisposition; Public Health; Reporting; Research; Role; Signal Transduction; Testing; Tissues; United States National Institutes of Health; Universities; biomechanical test; bone; bone aging; bone fragility; bone health; disability; high risk; metabolomics; microCT; mitochondrial dysfunction; novel; osteogenic; osteoprogenitor cell; premature; subcutaneous; targeted treatment; tool; trait; transcriptome sequencing; zygote

Abstract The role of mitochondria in bone tissue physiology and pathology remains understudied. Our long-term goal is to fill this gap of knowledge and this high risk proposal is a step towards this goal. It will test if mitochondrial genetics (mtDNA haplotype) influences bone phenotype and function of osteoblasts (OB) and their precursors, bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSCs). The scientific premise here is that: 1) mitochondrial oxidative phosphorylation (OxPhos) is required for osteogenic differentiation; 2) mitochondrial dysfunction plays a significant role in bone aging; 3) patients with mitochondrial diseases have fragile bones; 4) Eurasians with ‘less efficient’ mtDNA haplogroups developed as an adaptation to cold climate, also have weaker bones when compared to people of African descent with ‘more efficient’ mtDNA haplogroup L; and 5) C3H/HeN (C3H) mice with more efficient mtDNA haplotype, also have stronger bones then C57BL/6J (C57) mice with less efficient mtDNA haplotype. To study contributions of nuclear vs mtDNA genome to a phenotype, we will use a delicate new genetic model, mitochondrial/nuclear exchange (MNX) mice. These MNX mice have C57 or C3H nuclear background but C3H and C57 mtDNA, respectively (C57n;C3Hmt and C3Hn;C57mt). Cells in these mice show OxPhos activity according to their mtDNA haplotype rather than their nuclear background. Our pilot data show that C57n;C3Hmt BMSCs have higher, while C3Hn;C57mt BMSCs have lower osteogenic potential than their corresponding controls, C57 and C3H, respectively. We also observed that bone accrual in 3 mo old F mice reflected their mtDNA haplogroup (C57n;C3Hmt > C57 while C3Hn;C57mt < C3H). Our central hypothesis that mitochondrial genetics is a strong determinant of BMSC osteogenic potential, OB bone-forming function, and bone phenotype. To test it, we will determine if MNX mice have altered bone phenotype (Aim 1) and altered BMSC osteogenic and OB bone-forming function and mitochondrio-nuclear communication (Aim 2) when compared to their wild type controls. If successful, this project will lay strong foundation for a new direction in our research and bone field in general, mitochondrial genetics of bone.

抽象的 线粒体在骨骼组织生理和病理学中的作用仍然被了解。我们的长期目标 是填补这一知识的空白，而这一高风险建议是朝着这一目标迈出的一步。它将测试线粒体是否 遗传学（mtDNA单倍型）影响成骨细胞（OB）及其前体的骨表型和功能， 骨髓基质（又称间充质干）细胞（BMSC）。这里的科学前提是：1） 线粒体氧化磷酸化（OXPHOS）是成骨分化所必需的。 2）线粒体 功能障碍在骨老化中起重要作用。 3）线粒体疾病患者的骨骼脆弱； 4） 欧亚人的“效率较低” mtDNA单倍群以适应寒冷的气候，也较弱 与非洲血统的人相比，骨骼具有“更有效”的麦克动物单倍群体； 5）C3H/HEN （C3H）具有更有效mtDNA单倍型的小鼠的骨骼也比C57BL/6J（C57）小鼠更强 有效的mtDNA单倍型。为了研究核与mtDNA基因组对表型的贡献，我们将使用 精致的新遗传模型，线粒体/核交换（MNX）小鼠。这些MNX小鼠有C57或C3H 核背景分别但C3H和C57 mtDNA（C57N； C3HMT和C3HN； C57MT）。这些小鼠的细胞 根据其mtDNA单倍型而不是其核背景显示出Oxphos活性。我们的飞行员数据 表明C57N; C3HMT BMSC具有较高 相应的控件分别为C57和C3H。我们还观察到3个月旧F小鼠中的骨骼骨骼 反映了他们的mtDNA HaplogGroup（C57N； C3HMT> C57，而C3HN； C57MT <C3H）。我们的中心假设是 线粒体遗传学是BMSC成骨潜力，OB骨形成功能和 骨表型。要测试它，我们将确定MNX小鼠是否改变了骨表型（AIM 1）并改变 BMSC成骨和OB骨形成函数以及线粒体 - 核交流（AIM 2） 与它们的野生型控件相比。如果成功，这个项目将为我们的新方向奠定坚实的基础 总体而言，研究和骨场是骨的线粒体遗传学。