MicroRNAs as Mediators of Birth Defects

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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.