MicroRNAs as Mediators of Birth Defects

项目概要/摘要： 口面裂是最常见的出生缺陷之一，在全世界约1/800的活产婴儿中发生。 尽管在识别口面裂的遗传和环境风险因素方面取得了进展，但大多数 孤立的腭裂病例--特别是腭裂--仍然无法完全理解。一 因此，深入了解口面发育的分子基础是至关重要的 用于诊断、预防和治疗策略的发展。 在人类基因组中发现了大量保守的非编码调节RNA， 作为微小RNA（miRNAs），揭示了一个以前未被认识的重要基因组信息层， 对人类健康和疾病的影响。本申请中提出的研究进入了这一新的具有挑战性的领域。 科学竞技场，以检查miRNAs在协调复杂的形态发生机制中的功能 以及哺乳动物次级腭形成的基因表达程序。 这些研究是我们发表的miRNAs综合图谱的逻辑延伸， 表达在发展中的面部过程和腭，将调查精心挑选的功能， miRNAs在哺乳动物腭发育中的作用功能丧失/获得策略和原位杂交将是 用于系统地确定生物学功能和时空表达模式， 第二腭的发育。这些研究的结果将阐明miRNA在特定细胞中的功能。 哺乳动物腭部形态发生、生长和细胞分化的方面。的直接影响 拟议的研究将描绘出可用于人类变异的miRNA候选基因 与人类孤立性腭裂的风险增加有关。

Project Summary/Abstract: Orofacial clefts are amongst the most prevalent birth defects occurring in ~1/800 live births worldwide. Despite progress identifying genetic and environmental risk factors for orofacial clefting, causes of the majority of isolated cleft cases — particularly clefts of the palate — continue to elude our complete comprehension. A greater depth of understanding of the molecular underpinnings of orofacial development is therefore essential for the development of diagnostic, preventative, and therapeutic strategies. The discovery of vast conserved stretches in the human genome of non-coding regulatory RNAs, such as microRNAs (miRNAs), has revealed a previously unrecognized layer of genomic information of significance to human health and disease. Studies proposed in the current application enter this new and challenging scientific arena to examine the function of miRNAs in orchestrating the complex morphogenetic mechanisms and gene expression programs underlying formation of the mammalian secondary palate. These studies, which are a logical extensions of our published comprehensive profile of miRNAs expressed in the developing facial processes and palate, will investigate the functions of carefully selected miRNAs in mammalian palatal ontogenesis. Loss/gain of function strategies and in situ hybridization will be employed to systematically determine the biological functions and spatio-temporal expression patterns during development of the secondary palate. Results from these studies will elucidate miRNA functionality in specific aspects of mammalian palatal morphogenesis, growth, and cellular differentiation. The immediate impact of the proposed research will be delineation of miRNA candidate genes that can be interrogated for human variants associated with an increased risk of human isolated cleft palate.