The National Institute of Mental Health last month announced three related funding opportunities for research projects investigating the role of microRNAs and other non-coding RNAs in the origin of mental disorders.
“The data generated by [these efforts] will contribute to the disaggregation of the molecular machinery underlying mental disorders by integrating sequence-specific modulators of post-transcriptional gene expression into a theoretical framework of disease pathophysiology,” the NIMH said.
Among the research projects the NIMH is looking to fund are ones designed to determine the expression of computationally predicted miRNAs by high-throughput miRNA microarray analysis, then to validate the sequences of those predicted miRNAs that give high signals using sequence-directed cloning and sequencing methods.
Data resulting from the research are expected to be widely disseminated within the scientific community in order to “accelerate genetic analysis of human diseases,” the institute noted.
The first funding opportunity runs under the National Institutes of Health’s exploratory/developmental award mechanism and is designed to solicit research proposals of up to two years with direct costs of up to $275,000.
The funding available under the other two opportunities, which use the NIH’s research project grant award mechanism, are not limited but “need to reflect the actual needs of the proposed project,” according to the NIH. These grants typically run between one and five years.
“According to their origin or function, three types of naturally occurring small RNAs have been described: short interfering RNAs, repeat-associated short interfering RNAs, and microRNAs,” the NIMH said in its funding announcement.
“Large-scale cDNA analysis and genome annotations predict thousands of non-coding RNAs, and computational analyses suggest that over 20 percent of human genes are regulated by miRNAs,” it noted.
In early 2005, researchers from the Massachusetts Institute of Technology and the Whitehead Institute reported in Cell that a computational analysis indicated that up to one-third of all human genes may be regulated by miRNAs (see RNAi News, 1/21/2005).
Almost a year later, the same researchers published data in Science suggesting that a majority of mammalian genes are influenced by miRNAs, if not directly regulated by the small non-coding RNAs (see RNAi News, 12/2/2005).
“The potential importance of non-coding RNAs is suggested by the observation that the complexity of an organism is poorly correlated with its number of protein-coding genes, yet highly correlated with its number of non-coding RNA genes, and that in the human genome only a small fraction of genetic transcripts are actually translated into proteins,” the NIMH added. “A systematic analysis of transcription observed about 10 times more transcriptional activity than can be accounted for by predicted protein-coding genes. Much of this activity was subsequently shown to be regulated.”
Such findings, the institute said, support the theory that miRNAs play “a central role in the regulation of protein translation throughout the human genome,” and understanding the mechanisms by which these and other non-coding RNAs work may offer insights into human disease.
“The potential importance of non-coding RNAs is suggested by the observation that the complexity of an organism is poorly correlated with its number of protein-coding genes, yet highly correlated with its number of non-coding RNA genes, and that in the human genome only a small fraction of genetic transcripts are actually translated into proteins.”
“While the biological functions of most miRNAs are unknown, some have already been found to be of relevance to understanding the genetics of mental disorders and cancer,” the NIMH said. “For example, in Fragile X syndrome the dFmr1 protein regulates the translation of its mRNA via miRNA interaction, [while] other studies have linked diseases to the loss of miRNA expression that may result from the deletion or the translocation of a chromosomal region.”
“A particular focus of this initiative will be the characterization of inadequate, spatially aberrant, or mis-timed expression of a functional protein as modulated by non-coding RNAs,” the NIMH added.
“Alterations in protein expression attributable to these novel mechanisms are expected to play a significant role in the etiology of mental disorders,” the institute said. “One or more susceptibility genes for mental disorders may turn out to include abnormal transcriptional units that code for RNA regulators of protein coding genes or to be proximal to such units, rather than to be abnormalities in the protein coding gene itself. Understanding the genetics of mental disorders might very well include consideration of RNA regulation of protein expression.”
The NIMH said that it is seeking proposals for projects that include the identification and analysis of genes, pathways, and circuits regulated by miRNAs in mental disorders; the characterization of aberrant and normal expression patterns, as modulated by non-coding RNAs, in genes and brain regions that are expected to play a role in the etiology of mental disorders; and genome-wide miRNA expression mapping of the brain in humans and model systems.
The institute is also looking to fund projects that examine the effects of miRNA antagonists in the brains of model systems; that map brain-specific non-coding RNA transcripts; that validate miRNA targets in brain tissue; that identify novel non-coding regulatory elements using computational and other methods; that investigate miRNA signatures and their association with clinical and endophenotypes in mental disorders; and that analyze conservation and clustering patterns of miRNAs in human and animal model brains.