MicroRNAs as Mediators of Birth Defects

项目摘要/摘要： 口腔裂是世界上最常见的出生缺陷之一，发生在全世界约1/800的活产儿中。 尽管在确定口腔裂隙的遗传和环境风险因素方面取得了进展，但大多数 孤立的唇裂病例--尤其是腭裂--仍然是我们无法完全理解的。一个 因此，更深入地了解口腔面部发育的分子基础是至关重要的。 用于制定诊断、预防和治疗策略。 在人类基因组中发现大量保守的非编码调控RNA片段，如 作为microRNAs(MiRNAs)，揭示了一层以前未被识别的有意义的基因组信息 为人类健康和疾病干杯。当前申请中提出的研究进入了这一新的和具有挑战性的领域 科学领域研究miRNAs在协调复杂的形态发生机制中的功能 和哺乳动物次级腭部形成的潜在基因表达程序。 这些研究是我们已发表的miRNAs综合概况的逻辑扩展 表现在面部的发育过程中，会仔细挑选突起和上颚的功能 哺乳动物腭部个体发育中的miRNAs。功能策略和原位杂交的损失/获得将是 用来系统地确定生物功能和时空表达模式 次级上颚的发育。这些研究的结果将阐明特定的miRNA功能 哺乳动物腭部形态发生、生长和细胞分化的各个方面。经济衰退的直接影响 拟议的研究将描绘可以询问人类变异的miRNA候选基因 与人类孤立性腭裂风险增加有关。

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.