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 线粒体在骨组织生理学和病理学中的作用仍有待研究。我们的长期目标 是为了填补这一知识空白，而这个高风险提案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（又名间充质干）细胞（BMSC）。这里的科学前提是：1） 成骨分化需要线粒体氧化磷酸化（OxPhos）； 2）线粒体 功能障碍在骨老化中起着重要作用； 3）线粒体疾病患者骨骼脆弱； 4） 为适应寒冷气候而开发的线粒体DNA单倍群“效率较低”的欧亚人，其线粒体DNA单倍群的效率也较弱 与具有“更高效”mtDNA 单倍群 L 的非洲人后裔相比，骨骼更优； 5) C3H/HeN 具有更有效 mtDNA 单倍型的 (C3H) 小鼠，也比具有较少 mtDNA 单倍型的 C57BL/6J (C57) 小鼠具有更强的骨骼 有效的线粒体DNA单倍型。为了研究核基因组与线粒体 DNA 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 小鼠具有 C57 或 C3H 核背景，但分别为 C3H 和 C57 mtDNA（C57n;C3Hmt 和 C3Hn;C57mt）。这些小鼠体内的细胞 根据其 mtDNA 单倍型而非核背景显示 OxPhos 活性。我们的试点数据 结果表明，C57n;C3Hmt BMSCs 具有较高的成骨潜力，而 C3Hn;C57mt BMSCs 的成骨潜力低于其 相应的对照分别为 C57 和 C3H。我们还观察到 3 个月大的 F 小鼠的骨增长 反映了他们的线粒体DNA单倍群（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 成骨功能和 骨表型。为了测试它，我们将确定 MNX 小鼠是否改变了骨表型（目标 1）并改变了 BMSC 成骨和 OB 成骨功能以及线粒体-核通讯（目标 2） 与野生型对照相比。如果成功，该项目将为我们的新方向奠定坚实的基础 研究和骨领域一般，骨的线粒体遗传学。