Roles of miRNAs in dermal bone development

miRNA 在真皮骨发育中的作用

• 批准号: 7473517
• 负责人: Arkhat Abzhanov
• 金额: $ 8.35万
• 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 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7473517
• 关键词: Alleles; Bioinformatics; Biological; Biology; Bone Development; Brain; Breathing; Calvaria; Cartilage; Cells; Cephalic; Child; Class; Condition; 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; Range; Regulator Genes; Role; Skeletal Development; Skeletal system; Speech; Structure; Syndrome; Tissues; bone; craniofacial; face bone structure; human DICER1 protein; human disease; interest; intramembranous bone; prevent; programs; 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（由申请人提供）：颅面畸形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、呼吸、饮食和语言相关的功能问题有关。受损的颅骨形成和重塑可以导致许多这些颅面异常和发病机制的发展颅骨骨骼结构仍然知之甚少。我们的初步研究结果表明，microRNAs（miRNAs）是一类新的基因调控分子，在颅骨膜内骨发育中具有重要作用。这是用Dicer的条件等位基因和Wnt1：：Cre构建体揭示的，Dicer是将前体加工成功能性miRNA所需的酶，Wnt1：：Cre构建体对源自背神经管的细胞具有特异性，包括颅神经嵴细胞，其产生大部分面部，颅骨和颌骨。由此产生的表型包括减少颅软骨，完全没有面骨和广泛的异位颅骨软骨表明一个改变的分化表型。由于上述许多颅面人类疾病的范围从轻度到非常严重，因此更好地理解正常和异常的膜内骨发育对于人类群体（包括幼儿）中许多颅面病症、疾病和损伤的未来诊断、治疗和预防的进步将是至关重要的。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。在这个提议中，我们的目标是研究几个先前确定的颅真皮骨特异性候选miRNAs的生物学作用。该分析的结果将用于启动更全面的生物信息学检查，以确定miRNAs如何控制膜内成骨细胞分化。 项目叙述：每年有数千名儿童出生时患有与颅骨生物学异常有关的轻度至重度颅面疾病。我们发现microRNA是一类有趣的调控分子，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，并使我们能够在未来开发诊断，预防和治疗各种骨相关颅面综合征的方法。