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NIH Awards Grants to Study miRNAs in Melanoma, Cleft Palate

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The National Institutes of Health this month awarded more than $800,000 in grant funding to support efforts investigating the role of microRNAs in skin cancer and in craniofacial malformation.

The first grant was awarded to Case Western Reserve University's Nikki Harter to support her research into the effects of ultraviolet radiation on miRNA expression in both healthy individuals and those with melanoma.

According to her grant's abstract, she and her colleagues hypothesize that the dysregulation of miRNAs in melanoma-prone melanocytes differs than in healthy ones when exposed to solar UV rays, and that this “leads to the perturbation of molecular pathways that contribute in part to the development of melanoma.”

To test this, the investigators will evaluate the expression of miRNAs in melanocytes of healthy individuals and melanoma patients after exposure to solar UV in situ. Specifically, biologically relevant doses of simulated solar UV light will be used to irradiate a statistical number of melanocytes by laser capture microdissection.

The relative changes in miRNA expression between irradiated and non-irradiated cells from each volunteer will be quantified, and the miRNAs that are most commonly dysregulated between the two groups will be identified, the abstract states.

Harter and her team then aim to confirm the miRNA expression patterns observed and use available software databases to predict miRNA target genes. Next, they plan to profile mRNAs between the same set of irradiated and un-irradiated melanocytes to identify candidate UV-responsive miRNA-mRNA relationships. 

The researchers plan to follow up on this work with a proteomic analysis of the pathways potentially affected by aberrantly expressed UV-responsive miRNAs in melanoma patient melanocytes.

Using reverse-phase protein microarrays, they will measure the quantity of individual proteins targeted by the miRNAs in both irradiated and un-irradiated melanocytes. They will then use RPMA to analyze the “potentially altered state of molecular pathways relevant to the early development of melanoma,” the abstract states.

Overall, the data generated from this work is expected to help discover biomarkers for melanoma risk and assist in the development of new treatments for the disease, it adds.

The grant began on Dec. 1 and runs until the end of November 2014. It is worth $241,515 in its first year.

The second NIH grant went to James Martin from Baylor College of Medicine to fund his examination of a novel miRNA, miR-17-92, in the development of cleft lip and palate.

Last year, Martin and his colleagues reported that this miRNA cluster is a direct target for bone morphogenetic protein signaling in cardiac progenitor cells.

“Our preliminary data indicate that miR-17-92 mutant embryos have severe craniofacial phenotypes, including cleft lip and palate and mandibular hypoplasia, consistent with the hypothesis that miR17-92 is a Bmp-target in craniofacial morphogenesis,” he wrote in his grant's abstract.

Further, the abstract notes that the published findings indicate that miR-17-92 plays an important role in cell differentiation by down-regulating progenitor genes such as the DiGeorge/velo-cardio-facial syndrome gene Tbx1, adding that preliminary data suggest that the miRNA also represses the ulnar mammary syndrome gene Tbx3.

To further investigate the role of miR-17-92 in craniofacial structures, Martin and his lab will use the NIH funding to examine whether the miRNA inhibits Tbx3 to regulate lip and palate development, then test the hypothesis that it is a genetic modifier of Tbx1.

Lastly, they plan to investigate the hypothesis that miR-17-92 seed sites in Tbx1 and Tbx3 directly inhibit Tbx1 and Tbx3 spatiotemporal expression during in vivo midface development, according to the grant's abstract.

The grant runs from Dec. 4 until Nov. 30, 2017, and is worth $577,179 in its first year.

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