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NIH Awards $1.1M in Grants to Support Projects Studying Cardiac miRNAs

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By Doug Macron

The National Institutes of Health this month awarded more than $1.1 million in research grants related to the role of microRNAs in cardiac function and disease.

The first grant was awarded to University of Texas Southwestern Medical Center investigator Eric Olson to support his work investigating miRNAs and myocardial metabolism and energy homeostasis.

“The heart requires highly efficient metabolism to maintain the levels of ATP needed for contractility and pump function,” Olson wrote in the grant's abstract. Meanwhile, nuclear hormone receptors and their co-activators and co-repressors play “critical roles in the control of energy metabolism by regulating the expression of genes involved in energy homeostasis and mitochondrial function.”

Research shows that transcriptional control by nuclear hormone receptors is mediated by a large multiprotein complex that control gene expression through association with transcriptional activators and repressors, the abstract notes. Experiments in mice have revealed that a component of the complex called MED13/Thrap1 helps regulate cardiac metabolism and thereby influences cardiac function and metabolic homeostasis.

“Thus, elevated cardiac expression of MED13 enhances cardiac function and metabolic rate and confers resistance to obesity, whereas MED13 deficiency in the heart causes diminished cardiac metabolism and susceptibility to obesity,” the abstract states.

MED13 has been found to be negatively regulated by two microRNAs: miR-208 and miR-378, both of which play a role in stress-dependent cardiac remodeling and metabolism.

With funding from the NIH, Olson and his colleagues aim to identify the exact mechanisms by which MED13 and the miRNAs control metabolism, energy homeostasis, mitochondrial biogenesis, cardiac stress-responsiveness, and phenotypic switching of cardiac and skeletal muscles.

“These studies will provide important new insights into a previously unrecognized regulatory network for the control of striated muscle metabolism and function, and will open opportunities for therapeutic modulation of metabolic syndromes and muscle diseases,” the abstract concludes.

Olson's grant runs from Dec. 1 until Nov. 30, 2015. It is worth $555,188 in its first year.

The second grant was awarded to Richard Goodman of the Oregon Health and Science University to fund research into miRNA regulation of cardiac transcription factors.

“The fact that individual cardiac cells can express hundreds of microRNAs, each with potentially hundreds of targets, raises the question of how such a complex mode of regulation can possibly achieve specificity,” he wrote in his grant's abstract.

He and his colleagues speculate that this specificity results from the ability of individual 3' UTRs to interact with multiple miRNAs simultaneously — a coordination required for “biologically meaningful regulation.”

Previously, he and his team demonstrated that miR-1 and miR-133a associate simultaneously with the 3' UTR of the cardiac transcription factor, Hand2.

“We hypothesize that binding of miR-1 and miR-133a to the Hand2 3' UTR is mutually interdependent, such that both microRNAs must associate with their recognition elements to achieve efficient repression,” Goodman wrote in the grant's abstract. “Such a mechanism would increase signaling complexity, generating specificity of targeting and constraining the number of effective mRNA targets for an individual microRNA.”

Hypothesizing that this might be common to other miRNA targets, he and his colleagues plan to use a newly developed assay to identify additional cardiac mRNAs that are subject to a similar mode of regulation, and to identify other cardiac miRNAs that associate with both miR-1 and miR-133a in order to see whether miRNA binding and function are similarly interdependent.

“Understanding how combinations of microRNAs affect expression of targets is essential for developing effective microRNA-based therapies,” he concluded.

Goodman's grant began on Dec. 1 and runs until the end of November 2013. It is worth $231,000 in its first year.

The last grant was awarded to Washington University's Gerald Dorn for his work examining miRNA targeting in heart failure.

Research has shown the miRNA expression is regulated in cardiac hypertrophy and heart failure, helping to fine-tune cardiomyocyte function in response to immediate physiological stresses, he wrote in his grant's abstract.

Though miRNAs represent “attractive therapeutic targets,” given their tendency to regulate different genes within the same functional pathway, “targeting of dozens or hundreds of different mRNAs by one [miRNA], together with regulated expression of [miRNAs] and mRNAs in cardiac disease, complicates delineation of specific [miRNA] functions relevant to heart disease.”

He and his team have overcome this problem by developing techniques that combine RNA sequencing with in vivo miRNA programming of cardiac RISCs, according to the abstract. They have also identified common sequence variants and rare mutations for 30 mature human miRNAs, demonstrating that both seed sequence and non-seed sequence miRNA variants can alter mRNA targeting.

As such, Dorn and his colleagues hypothesize that the effects of miRNA on normal and diseased hearts are determined by the levels of miRNA and mRNA expression, and the efficiency of miRNA-mRNA pairing as determined by sequence complementarity. Additionally, they suspect that miRNA sequence variations further alter the effects of the non-coding RNAs independently of miRNA and mRNA expression levels.

To test these hypotheses, the investigators aim to “systematically and comprehensively define” key miRNA-mRNA pairing events and “determine their functional consequences in genetically programmed mouse hearts under different pathophysiological conditions,” the abstract states.

They will then identify the effects of human miRNA sequence variants and mutations on cardiac miRNA-mRNA targeting, target protein expression, and cardiac structure and function.

His grant began on Dec. 15 and runs until Nov. 30, 2015. It is worth $380,000 in its first year.


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