The National Institutes of Health last week announced that it has earmarked $3 million to fund a handful of research projects investigating the role of microRNAs and other non-coding RNAs in mental disorders.
According to the NIH, the data generated from the research efforts will contribute to the dissection of "the molecular machinery underlying mental disorders by integrating sequence-specific modulators of post-transcriptional gene expression into a theoretical framework of disease pathophysiology."
Funding under this program, which is being overseen by the National Institute of Mental Health, will be used to support between five and seven grants during 2007. Projects may run up to 5 years and receive up to $800,000 a year in direct costs.
"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 NIH said. "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."
"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."
These and other findings suggest that miRNAs may play an important role in the regulation of protein translation throughout the human genome, the NIH noted. And while the functions of most miRNAs are still unknown, some have already been found to impact the genetics of mental disorders and cancer.
In January 2004, researchers from Emory University published data in Nature Neuroscience showing a link between fragile X mental retardation and the microRNA pathway. Earlier this year, a team from the National Cancer Institute published a paper in Cancer Cell describing a link between the survival of patients with lung cancer and the expression profiles of two microRNAs (see RNAi News, 3/16/2006).
"This initiative will focus on genome-wide approaches to characterize the role that miRNAs and other non-coding RNAs play in the etiology of mental disorders," the NIH said. "Projects to be funded … include [ones determining] the expression of computationally predicted [miRNAs] by high-throughput miRNA microarray analysis; and [ones validating] the sequence of predicted miRNAs that give high signals on the microarray using state-of-the-art sequence-directed cloning and sequencing methods."
Of particular interest to the NIH are projects focused on "the characterization of inadequate, spatially aberrant, or mistimed expression of a functional protein as modulated by non-coding RNAs," the NIH noted. "Alterations in protein expression attributable to these novel mechanisms are expected to play a significant role in the etiology of mental disorders. 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," the NIH said. "Understanding the genetics of mental disorders might very well include consideration of RNA regulation of protein expression."
The NIH cited several research projects as critical to this miRNA initiative including the identification and analysis of genes, pathways, and circuits regulated by miRNA in mental disorders in humans and animal models; the characterization of normal and aberrant expression patterns, as modulated by non-coding RNAs, in genes that are expected to play a role in the etiology of mental disorders in humans and model systems; and the genome-wide mapping of miRNA expression in the brain in humans and model systems.
Also key to the initiative are projects studying miRNA antagonists in the brains of model systems; efforts to map brain-specific non-coding RNA transcripts; target-validation studies of miRNAs in animal model brain tissue; behavioral, biochemical, and neurophysiological studies of miRNA targets and expression; the identification of novel non-coding regulatory elements using computational methods using cDNA and other experimental data in humans and animal models; studies of miRNA signatures and their association with clinical and endophenotypes in mental disorders; and analyses of conservation and clustering patterns of miRNAs in the human and animal brain.
Letters of intent are due from research funding applications by June 21, with formal applications due a month later. Applications will be reviewed around the end of the year, and grant projects are expected to begin no earlier than April 2007. The NIH noted that applications for funding under this initiative must include a plan for how data generated from the research projects will be disseminated or an explanation of why data-sharing is not possible.
— Doug Macron ([email protected])