By Doug Macron
The National Institutes of Health this month handed out nearly $700,000 in research funding to support three projects studying the role of microRNAs in brain disease and health, and gastrointestinal disorders.
The first grant was awarded to University of Cincinnati researcher James Herman to fund his investigations into the role of non-coding RNAs, including miRNAs, in regulating stress in the prefrontal cortex, which is the “primary brain mediator of stress and mood,” according to the grant's abstract.
“In humans and in animal models, medial prefrontal cortical dysfunction is associated with emotional disturbances, impaired fear extinction, and inefficient termination of physiological stress responses,” it states.
Dysfunction in this region of the brain has been linked to a variety of mental illnesses, most notably depression and post-traumatic stress disorder, both of which are triggered by stress and cause “long-term inappropriate stress responding,” the abstract notes.
Studies have shown that stress can trigger significant changes in prefrontal cortex gene expression, including a pronounced down-regulation in the “vast majority” of regulated mRNAs, and “convincingly demonstrated that non-coding RNAs, including microRNAs and alternatively expressed 3'-untranslated mRNA sequences, play a major role in mRNA down-regulation in numerous tissues, including brain.”
As such, Herman and his colleagues aim to use deep-sequencing techniques to analyze prefrontal cortex ncRNAs to study their regulation by using “chronic unpredictable stress” in rats, which “reliably models physiological and behavioral symptoms of depression, allowing for extrapolation of preclinical findings to putative mechanisms of functional dysregulation in human cortex," the abstract states.
Follow-up work will be done to verify the specific regulation of targeted miRNAs and 3'-UTR sequences in the prefrontal cortex, and to “localize expression to distinct cortical subregions and cell types.”
Herman hopes his efforts will help develop a database of stress-regulated ncRNA regulation that can help identify novel processes endangering cortical integrity in response to stress.
His grant, which is worth $248,159 in its first year, runs from June 1 until May 31, 2013.
Drexel University's Sonia Navas-Martin was awarded the second grant to support her work into the role of miRNAs in coronvavirus-induced lethal encephalitis.
“Coronaviruses are enveloped, positive-sense, single-stranded polyadenylated RNA viruses,” she notes in her grant's abstract.
In previous studies conducted in her lab, miRNA microarray analysis has indicated that select cellular miRNAs are expressed differently in macrophages in vitro depending on the strain of coronavirus with which they are infected: MHV-JHM, a highly neurovirulent strain that produces lethal encephalitis, or MHV-A59, a mildly neurovirulent strain that induces acute meningoencephalitis.
“Changes in the macrophage miRNA profiles after murine … infection were overlapping but distinct, and were observed early after infection in the absence of type I [interferons], [IFN-beta], and pro-inflammatory cytokine secretion,” the abstract states. “Our data suggest that MHV infection can modify the pattern of cellular miRNA expression.”
Two miRNAs in particular where up-regulatd by MHV-JHM but not MHV-A59 and were found to “potentially target" IFN-beta and the 3' UTR of IL-1 receptor antagonist, "a cytokine involved in both neuroprotection and neuropathogenesis
Navas-Martin wrote that she and her team hypothesize that coronvaviruses that induce different disease outcomes promote distinct miRNA profiles in macrophages and microglia, and that virus-specific changes in miRNA expression contribute to the pathologies by modulating inflammatory responses.
To test this, they will “systematically identify” miRNA and mRNA regulatory networks that correlate with the progression of lethal encephalitis in the infected brain, the abstract states. They also aim to further investigate the impact of the miRNAs up-regulated in JHM infection on interferon induction in macrophages and glial cells ex vivo and in vivo with the help of miRNA antagonists.
“Overall, there is significant translational potential in the proposed investigations since they will facilitate the development of therapeutic approaches to prevent and/or treat neuro-inflammatory diseases of viral etiology,” Martin-Navas states in the abstract.
Her grant runs from June 1 until May 31, 2013, and is worth $231,688 in the first year.
Looking beyond the CNS is University of Nevada, Reno, investigator Seungil Ro, who received an NIH grant to explore how miRNAs affect the development and maintenance of interstitial cells of Cajal, or ICC, which serve as electrical pacemakers affecting gastrointestinal motility.
“Recent studies have demonstrated that ICC [play] an important role in the development of diabetic gastroenteropathy,” a condition characterized by a loss or defects in ICC networks that, in turn, may lead to gastrointestinal motility disorders, according to the grant's abstract.
ICC express the Kit receptor tyrosine kinase, which is required for their normal development and maintenance in the gut, the abstract states. As such, the loss of ICC in diabetic gastroenteropathy may be linked to reduced expression of Kit, which has been found to be a target of miRNA regulation.
“Thus, our central hypothesis is that miRNAs targeting Kit inhibit the development and maintenance of ICC” in the disease, Ro wrote in the abstract.
To test this, he and his team will characterize the miRNAome in ICC, identify changes to these cells during diabetic gastroenteropathy development, and suppress the cells using miRNAs targeting Kit in animal models with the goal of understanding how Kit expression in ICC is regulated and how ICC are lost during the development of diabetic gastroenteropathy.
“Identification of the miRNAs inhibiting KIT expression may aid in the development of a therapeutic antisense miRNA drug that might be useful in blocking or reversing damaged ICC networks” in diabetic gastroenteropathy and other disorders characterized by a loss of ICC.
Ro's grant runs from June 20 until March 31, 2013. It is worth $211,500 in its first year.
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