Bone Cell Growth Regulation by Runx2/Cbfa1

Runx2/Cbfa1 调节骨细胞生长

• 批准号: 8530154
• 负责人: Andre J. Van Wijnen
• 金额: $ 33.99万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8530154
• 关键词: 3' Untranslated Regions; Age-Related Bone Loss; Attenuated; Biological; Biological Process; Bone Regeneration; Cell Count; Cell Cycle; Cell Cycle Regulation; Cell Line; Cell Lineage; Cell Proliferation; Cell Survival; Cell division; Cells; Chromosomes; Commit; Complement; Cues; Data; Dimensions; Ensure; Epigenetic Process; Fracture Healing; Future; Gene Expression; Generations; Genetic; Genetic Transcription; Growth; Histone Code; Homeodomain Proteins; Mediating; Memory; Mesenchymal Stem Cells; Messenger RNA; Methylation; MicroRNAs; Microscopy; Mitosis; Mitotic; Mitotic Cell Cycle; Molecular; Osteoblasts; Osteogenesis; Phenotype; Physiological; Proliferating; Property; Proteins; Proteomics; RNA; Regenerative Medicine; Regulation; Role; Runx2 protein; Skeletal Development; Stem cells; Therapeutic; Tissues; Transgenic Mice; Translations; Validation; base; bone; bone cell; cell growth; cell growth regulation; daughter cell; epigenomics; in vivo; mouse model; non-genomic; novel; osteogenic; osteoprogenitor cell; programs; protein profiling; response; skeletal; time use; transcription factor; transmission process

DESCRIPTION (provided by applicant): Skeletal regenerative medicine promises to mitigate age-related bone loss and support fracture healing but requires manipulation of biological properties of osteogenic progenitor cells. Osteogenic cells must sustain their phenotype during lineage-expansion yet undergo a number of mitotic cell cycles to generate the requisite number of cells for proper tissue-organization. The proposed study will examine fundamental mechanisms that ensure cells retain a post-mitotic molecular memory of the bone phenotype. The central hypothesis of our study is that key mRNAs for osteogenic factors are passed on to daughter cells during mitosis as a component of a non-genomic epigenetic mechanism and that selected microRNAs (miRs) attenuate the translation of these transmitted mRNAs. Our hypothesis is based on a robust set of preliminary data showing that the osteogenic master regulator Runx2 is controlled by mitotic miRs in osteoblastic cell lines. Based on these and other preliminary data, we will (i) characterize the full complement of miRs that suppress expression of Runx2 in proliferating osteogenic cells, as well as begin characterization of mRNAs and cognate miRs during mitosis; (ii) examine miR dependent changes in fidelity of cell growth, survival and lineage-direction in proliferating osteoblasts, and (iii) characterize the physiological role of selected mitosis-related miRs during skeletal development in vivo. Validation of this concept would (i) establish a major new dimension in cell cycle regulation, (ii) reveal a previously unrecognized function for miRs during mitosis, (iii) define a novel molecular mechanism for biological control of gene expression in lineage-committed cells, and (iv) identify specific miRs that are transmitted to osteogenic progeny cells upon mitosis ('mito-miRs'). From a molecular therapeutic perspective, these miRs permit generation of epigenomic agents that control cellular inheritance by targeting cell fate determining factors which mediate mesenchymal stem cell expansion and differentiation.

描述（由申请人提供）：骨骼再生医学有望减轻与年龄相关的骨质流失和支持骨折愈合，但需要对成骨祖细胞的生物学特性进行操作。成骨细胞必须在谱系扩增过程中维持其表型，并经历许多有丝分裂细胞周期，以产生适当组织组织所需的细胞数量。提出的研究将检查基本机制，确保细胞保留有丝分裂后骨表型的分子记忆。本研究的中心假设是，成骨因子的关键mrna在有丝分裂过程中作为非基因组表观遗传机制的组成部分传递给子细胞，而选择的microRNAs （miRs）减弱了这些传递mrna的翻译。我们的假设是基于一组强有力的初步数据，这些数据表明成骨主调控因子Runx2是由成骨细胞系中的有丝分裂miRs控制的。基于这些和其他初步数据，我们将(i)表征增殖成骨细胞中抑制Runx2表达的miRs的完整补体，并开始表征有丝分裂期间的mrna和同源miRs；（ii）研究miR对增殖成骨细胞生长、存活和谱系方向保真度的依赖性变化，以及（iii）表征有丝分裂相关的miR在体内骨骼发育过程中的生理作用。这一概念的验证将(i)建立细胞周期调控的主要新维度，（ii）揭示有丝分裂过程中miRs先前未被认识的功能，（iii）定义谱系承诺细胞中基因表达的生物控制的新分子机制，以及（iv）确定有丝分裂时传递给成骨后代细胞的特定miRs（“mito-miRs”）。从分子治疗的角度来看，这些miRs允许产生表观基因组药物，通过靶向介导间充质干细胞扩增和分化的细胞命运决定因素来控制细胞遗传。