Characterization of cranial dermal bone-specific miRNAs

描述（由申请人提供）：人类头部和颈部区域的形成是一个极其复杂的过程，需要精确协调许多不同类型的组织和细胞（骨骼、肌肉、大脑等）。这个过程是如此复杂和敏感，遗传错误往往会导致各种类型的颅骨畸形。事实上，至少超过三分之一的人类遗传问题与头部结构的畸形有关，通常是硬组织，如骨骼和软骨。这些异常情况的范围可以从相对轻微到非常严重，并且通常以存在各种类型的癌症以及表明细胞增殖/分裂和细胞分化的基本过程的破坏为特征。最近的研究表明，一组相对较新的基因（称为microRNA）在胚胎发育中发挥着重要作用。我们发现了microRNAs（miRNAs）在颅膜内骨发育中的重要作用的证据，我们假设这些分子对于理解颅面硬组织异常和癌症将是重要的。在这里，我们希望揭示颅面组织特异性miRNA在分离的颅骨骼细胞（体外）和发育胚胎的颅骨骼结构（体内）中的确切功能。颅面畸形和综合征是一些最常见的出生缺陷，通常与严重残疾，癌症，听力损失，呼吸，饮食和语言相关的问题有关。我们的目的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，我们希望研究几个已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检查，以确定miRNA如何控制正常和患病组织中的膜内成骨细胞分化。 公共卫生相关性：每年有数千名儿童出生时患有与颅骨生物学异常有关的颅面疾病。我们最近发现，microRNA，一类重要的调控分子，是颅骨形成所必需的。我们相信，使用复杂的遗传和分子工具来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，预防和治疗各种颅面综合征的方法。

DESCRIPTION (provided by applicant): Formation of a head and neck region in humans is an extremely complex process, which requires precise orchestration of many different types of tissues and cells (skeleton, muscles, brain, etc). This process is so complicated and sensitive that genetic mistakes often lead to various types of cranial malformations. In fact, at least over a third of genetic problems in humans have associated malformations of head structures, often hard tissues, such as bones and cartilages. These abnormal situations can range from relatively mild to very severe and are often characterized by presence of various types of cancers as well suggesting disruption of basic process of cell proliferation/division and cell differentiation. Recent studies suggest an important role for a relatively novel group of genes, called microRNAs, in embryonic development. We found evidence for an important role of microRNAs (miRNAs) in cranial intramembranous bone development and we hypothesize that these molecules will be important to understand craniofacial hard tissue abnormalities and cancers. Here we wish to reveal the exact functions of craniofacial tissues-specific miRNAs in isolated cranial skeletal cells (in vitro) and in cranial skeletal structures of the developing embryos (in vivo). RELEVANCE Craniofacial abnormalities and syndromes are some of the most common birth defects that are often associated with severe disabilities, cancers, hearing loss, problems related to breathing, eating, and speech. We aim to understand mechanisms of the cranial bone development and morphogenesis in normal and abnormal conditions. In this proposal, we want to investigate the biological roles for several identified cranial dermal bone-specific candidate miRNAs. The results of this analysis will be used to start a more comprehensive examination to establish how miRNAs control intramembranous osteoblast differentiation in normal and diseased tissue. PUBLIC HEALTH RELEVANCE: Each year thousands of children are born with craniofacial diseases related to abnormal cranial bone biology. We recently found that microRNAs, an important class of regulatory molecules, are required for cranial bone formation. We believe that that learning about functions of these molecules using sophisticated genetic and molecular tools will help us understand the mechanisms governing normal cranial bone biology and allow us to develop ways to diagnose, prevent and treat various craniofacial syndromes in the future.