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NIH Awards More than $1.25M in microRNA Grants in March

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The National Institutes of Health this month awarded more than $1.25 million in grant funding to support four separate research project related to the role of microRNAs in central nervous system development and functioning, the use of these small, non-coding RNAs as ocular biomarkers, and the effect on the inflammatory disease lupus.

The first award was given to Drexel University’s Seena Ajit to help advance her work on hsa-miR-939 and complex regional pain syndrome, a poorly understood chronic pain condition.

Given the dysregulation of miRNAs in a variety of disorders, in 2011 Ajit and her colleagues examined miRNA expression changes in whole blood samples from 41 CRPS patients and 20 controls, and reported differential expression of 18 miRNAs.

With the help of the NIH grant, she now aims to see whether the top candidate from that previous research — hsa-miR-939 — is involved in the neurogenic inflammation common to CRPS by affecting genes known to influence inflammation and pain.

Specifically, Ajit will test whether down-regulation of the miRNA increases expression of vascular endothelial growth factor A, inducible nitric oxide synthase, and tumor necrosis factor-alpha — all of which have pro-inflammatory properties.

She also plans to look at exosomes secreted by THP-1 leukemia cells stimulated with lipopolysaccharides, as well as exosomes purified from patient blood samples, to measure the alterations in hsa-miR-939 and other miRNAs that occur alongside inflammation.

“In addition to providing insight into the molecular underpinnings of the multifactorial pathophysiological mechanisms in CRPS, these studies can help determine if miRNAs or the genes they modulate can be direct targets for future therapeutic interventions,” she wrote in her grant’s abstract.

Ajit’s grant began on March 1 and runs until Jan. 31, 2015. It is worth $231,750 in its first year.

Also receiving NIH support is Emory University’s Gary Bassell, who is studying the possibility that miRNAs influence the activity of axon growth cones, the extension of growing axons that seek out the correct synaptic partners during embryonic development.

To do so, Bassell and his colleagues plan to profile miRNAs from axonal fractions of cortical neuron balls and visualize their localization using fluorescent in situ hybridization, according to his grant’s abstract. The researchers will then test the effects of manipulating axonal miRNAs on axon growth, cone growth, and steering responses.

The top miRNAs identified from these experiments will be studied for their effect on axonal protein expression and local protein synthesis in growth cones using immunofluorescence and live cell imaging of fluorescent reporters.

“The proposed research will advance our limited understanding of growth cone localized miRNAs and elucidate their mechanistic role in local protein synthesis underlying growth cone guidance,” Bassell wrote in the grant’s abstract.

The research project began on March 1 and runs for two years. The grant is worth $234,000 in its first year.

At Vanderbilt University, investigator Ashwath Jayagopal was awarded a five-year grant from the NIH to develop a molecular imaging platform to study miRNAs in the retina.

According to the grant abstract, Jayagopal’s approach is based on hairpin DNA-functionalized gold nanoparticles, or hAuNPs, which are biocompatible gold colloids engineered to enter living tissues and fluoresce upon hybridization with targeted mRNA or miRNA sequences.

In 2010, Jayagopal and colleagues published data showing that hAuNPs could specifically target “multiple distinct RNA sequences in mammalian cells and the retinal vasculature, without adverse effects on cell function,” he wrote in the abstract.

Looking to take those findings further, he plans to use the approach to validate mRNAs and miRNAs as biomarkers of choroidal neovascularization in a mouse model with the help of the NIH funding.

The nanoparticles will be used to image disease-relevant biomarkers in both primary choroidal endothelial cells and retinal pigment epithelial cells “in order to establish the utility of longitudinal, multiplexed RNA imaging,” he noted.

“These studies will set the framework for molecular imaging of RNA and other molecular biomarkers in animal models, and will facilitate clinical translation of these technologies for early detection and staging of disease in patients,” he wrote.

The grant began on March 1 and is worth $390,000 in its first year.

The last grant was awarded to Christopher Reilly of Virginia Polytechnic Institute and State University to study the influence of miRNAs on lupus.

According to Reilly’s grant abstract, he and his colleagues have previously demonstrated the selective regulation of miRNA expression in immune cells by estrogen.

“Given the role of miRNAs in the regulation of inflammation, we hypothesize that plasmacytoid dendritic cells and mesangial cells from NZB/W female mice … [which develop autoimmune disease] will show an altered miRNA profile in the initiation and progression of glomerulonephritis,” he wrote in the abstract. Additionally, he and his team speculate that immunosuppressive agents used to treat lupus do so in part by altering miRNA profiled.

With the assistance of the NIH grant, Reilly and collaborators aim to see if miRNA expression from freshly purified mesangial cells and plasmacytoid dendritic cells from a lupus mouse model can be used to predict disease progression.

They plan to then correlate the changes in miRNA expression to pathological changes in the kidney and spleen in order to define how miRNA expression parallels disease activity, and to modify the expression of specific miRNAs to alter inflammatory mediators implicated in lupus.

Finally, the project will examine the effect of three lupus drugs on miRNA expression in the mouse models to “show if altering disease by immune modulators induces changes in miRNA expression patterns,” the abstract states.

Data from this effort could potentially yield novel targets for lupus treatment, Reilly wrote.

The grant runs from March 1 until the end of February 2016. It is worth $397,974 in its first year.

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