Characterization of cranial dermal bone-specific miRNAs

描述(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，需要对许多不同类型的组织和细胞(骨骼、肌肉、大脑等)进行精确的协调。这一过程非常复杂和敏感，以至于遗传错误往往会导致各种类型的颅骨畸形。事实上，人类至少有三分之一以上的遗传问题与头部结构的畸形有关，这些结构通常是硬组织，如骨骼和软骨。这些异常情况从相对轻微到非常严重不等，通常以存在各种类型的癌症为特征，这表明细胞增殖/分裂和细胞分化的基本过程被破坏。最近的研究表明，一组相对较新的基因，称为microRNAs，在胚胎发育中发挥着重要作用。我们发现了microRNAs(MiRNAs)在颅膜内骨发育中发挥重要作用的证据，并假设这些分子将对了解颅面部硬组织异常和癌症具有重要意义。在这里，我们希望揭示颅面组织特异的miRNAs在分离的颅骨细胞(体外)和发育中的胚胎的颅骨结构(体内)中的确切功能。头面部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、饮食和语言有关的问题有关。我们的目的是了解正常和异常情况下颅骨发育和形态发生的机制。在这项提案中，我们想要研究几个已确定的颅真皮骨骼特异性候选miRNAs的生物学作用。这项分析的结果将被用来开始一项更全面的检查，以确定miRNAs如何控制正常和疾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就患有与颅骨生物学异常有关的头面部疾病。我们最近发现，MicroRNAs是一类重要的调节分子，是颅骨形成所必需的。我们相信，使用先进的遗传和分子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.