Roles of miRNAs in dermal bone development

miRNA 在真皮骨发育中的作用

• 批准号: 7570596
• 负责人: Arkhat Abzhanov
• 金额: $ 8.38万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7570596
• 关键词: Alleles; Bioinformatics; Biological; Biology; Bone Development; Brain; Breathing; Calvaria; Cartilage; Cells; Cephalic; Child; Congenital Abnormality; Craniofacial Abnormalities; Data; Databases; Dermal; Development; Developmental Disabilities; Diagnosis; Dicer Enzyme; Disease; Dorsal; Eating; Face; Foundations; Functional Hearing Loss; Future; Genomics; Human; Image; Injury; Knock-out; Learning; MicroRNAs; Morphogenesis; Mutation; Nature; Neural Crest Cell; Neural tube; Osteoblasts; Osteogenesis; Pathogenesis; Phenotype; Phosphotransferases; Population; Prevention; Principal Investigator; Process; Proteomics; Regulator Genes; Role; Skeletal Development; Speech; Structure; Syndrome; bone; craniofacial; face bone structure; human DICER1 protein; human disease; interest; intramembranous bone; osteoblast differentiation; prevent; programs; skeletal; skeletal tissue; tool

DESCRIPTION (provided by applicant): Craniofacial abnormalities are some of the most common structural birth defects that are often associated with developmental disabilities, abnormalities to brain maturation, hearing loss, functional problems related to breathing, eating, and speech. Impaired cranial bone formation and remodeling can contribute to many of these craniofacial abnormalities and pathogenesis of the developing cranial skeletal structures still remains poorly understood. Our preliminary data suggests that, microRNAs (miRNAs) are a new class of abundant gene regulatory molecules, have an important role in cranial intramembranous bone development. This was revealed with a conditional allele of Dicer, an enzyme required for processing of precursors into functional miRNAs, and a Wnt1::Cre construct that is specific to cells originating from the dorsal neural tube, including cranial neural crest cells, which give rise to most of the facial, calvarial and jawbones. The resulting phenotype includes reduced cranial cartilages, completely absent facial bones and extensive ectopic calvarial cartilage suggesting an altered differentiation phenotype. As many of the craniofacial human diseases mentioned above range from mild to very severe, better understanding of both normal and abnormal intramembranous bone development will be will be paramount to the advancement of future diagnoses, treatments and prevention of many craniofacial disorders, diseases and injuries in the human population, including young children. The long-term objective of this project is to understand mechanisms of the cranial bone development and morphogenesis in normal and abnormal conditions. In this proposal, we aim to investigate the biological roles for several previously identified cranial dermal bone-specific candidate miRNAs. The results of this analysis will be used to start a more comprehensive bioinformatics examination to establish how miRNAs control intramembranous osteoblast differentiation. Project Narrative: Each year thousands of children are born with mild to severe craniofacial diseases related to abnormal cranial bone biology. We found that microRNAs, an interesting class of regulatory molecules, are required for normal cranial bone formation. We believe that that learning about functions of these molecules using sophisticated bioinformatics tools will help us understand the mechanism governing normal cranial bone biology and allow us to develop ways to diagnose, prevent and treat various bone-related craniofacial syndromes in the future.

描述(申请人提供)：头面部异常是一些最常见的结构性出生缺陷，通常与发育障碍、大脑成熟异常、听力损失、与呼吸、饮食和语言有关的功能问题有关。颅骨形成和重塑受损可导致许多颅面畸形，而发育中的颅骨结构的发病机制仍不清楚。我们的初步数据表明，microRNAs(MiRNAs)是一类新的丰富的基因调控分子，在颅膜内骨发育中具有重要作用。这一点在DICER的条件等位基因和Wnt1：：Cre结构中得到了揭示，DICER是一种将前体加工成功能性miRNAs所需的酶，Wnt1：：Cre结构专用于起源于背侧神经管的细胞，包括形成大部分面部、头盖骨和颌骨的颅神经脊细胞。由此产生的表型包括颅骨软骨减少，面骨完全缺失，以及广泛的异位颅骨软骨，表明分化表型发生了变化。由于上面提到的许多颅面人类疾病从轻微到非常严重，更好地了解膜内骨骼的正常和异常发育将是推动未来诊断、治疗和预防包括幼儿在内的许多人类头面部疾病、疾病和损伤的关键。本项目的长期目标是了解正常和异常条件下颅骨发育和形态发生的机制。在这项提案中，我们的目标是研究几个先前发现的颅真皮骨骼特异的候选miRNAs的生物学作用。这项分析的结果将被用于启动更全面的生物信息学检查，以确定miRNAs如何控制成骨细胞膜内分化。 项目简介：每年有数以千计的儿童出生时就患有与颅骨生物学异常有关的轻微到严重的头面部疾病。我们发现，microRNAs是一类有趣的调节分子，是正常颅骨形成所必需的。我们相信，使用先进的生物信息学工具了解这些分子的功能将有助于我们了解正常颅骨生物学的机制，并使我们能够开发出未来诊断、预防和治疗各种骨相关颅面综合征的方法。