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NIH Awards $440K in RNAi, microRNA Grant Funding in June

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The National Institutes of Health this month awarded nearly $450,000 in funding to support two RNAi- and microRNA-related research projects, including one for the development of a low-cost oligonucleotide synthesizer and one studying the small, non-coding RNAs in cardiovascular health.

The first grant was awarded to Keith Anderson, the president of California-based startup Synthomics, to assist in the company’s development of an oligonucleotide synthesis technology designed to significantly lower production costs.

According to the grant’s abstract, Synthomics is aiming to synthesize DNA and RNA in sample plates that can hold up to 1,536 unique oligos, versus industry-standard 96-well plates.

“By miniaturizing the well geometry, we will be able to synthesize oligonucleotides at a cost that scales linearly with the reduced volume of each well,” Anderson, who is also a researcher at the Stanford Genome Technology Center, wrote in the abstract. “In this case, the well geometry is a 16-fold reduction compared to current technologies and thus a 16-fold reduction in cost is anticipated.”

To do so, the company is developing a synthesizer that incorporates ultra high-speed motion control and reagent delivery valves that permit rapid dispensing of chemicals to reaction sites, and is taking advantage of advances in the solid support used in the production process, the abstract states.

The synthesizer will also include a monitoring system, based on retroreflective laser sensors, designed to allow users to visualize the instrument’s progress and detect errors in reagent dispensing in order to eliminate the need for downstream quality-control tests.

The grant, which began on June 1, runs for six months and is worth $135,100.

The second grant was given to Chunming Dong, a researcher at the University of Miami School of Medicine who is studying the role of miRNAs as determinants of senescence in endothelial progenitor cells, or EPCs.

The small, non-coding RNAs are known to play key roles in regulating the plasticity and functions of stem cells and progenitor cells, he wrote in his grant’s abstract. And the expression patterns of these miRNAs have been shown to undergo “dynamic changes” during aging in both a tissue- and gene-specific manner.

As such, it is believed that specific miRNAs and their targets mediate senescent changes and functional impairment of both EPCs and lineage-negative bone marrow cells, also known as linBMCs, which can give rise to EPCs.

As part of his focus on cardiology, Dong and other researchers have shown that EPCs are actively involved in vascular repair — an ability that is impaired in aging EPCs, which contributes to atherosclerosis development.

“Therefore, EPC senescence may partially mediate the strong predisposing effects of aging and other cardiovascular risk factors on atherosclerosis,” he wrote in the abstract.

Last year, he and his colleagues reported on the discovery that miRNA-10a* and miRNA-21 modulate EPC senescence through the suppression of high-mobility group A2.

The team performed miRNA profiling and microarray experiments in linBMCs from young and aged mice that were either wild-type or deficient in apolipoprotein E, pinpointing the two miRNAs, as well as their common target Hmga2, as critical regulators of EPC senescence.

Specifically, overexpression of the miRNAs in young EPCs suppressed Hmga2, which caused senescence in the cells, decreased self-renewal potential, increased p16(Ink4a)/p19(Arf) expression, and resulted in impaired EPC angiogenesis in vitro and in vivo.

Suppression of the miRNAs in old EPCs, meanwhile, boosted Hmga2 expression and rejuvenated EPCs, which increased their self-renewal potential, decreased p16(Ink4a)/p19(Arf) expression, and improved EPC angiogenesis in cell culture and in live animals.

In other work, the investigators have implicated miR-29c and miR-126, and their effect on Spred-1 and vascular endothelial growth factor-stimulated angiogenesis, finding that this pathway governs linBMCs’ differentiation capacity.

With the NIH funding, he and his colleagues aim to characterize the combined effects of these two pathways in regulating linBMC senescence in vitro, as well as study the effects of other miRNAs reported in the literature. They also plan to determine how the miRNAs and their targets impact the effectiveness of linBMC in vascular repair and atherosclerosis development in mice.

“This integrated and innovative approach will allow us to thoroughly characterize the molecular mechanisms underlying linBMC senescence and functional impairment, which will facilitate the design of novel strategies to slow down/reverse the senescent process of EPC/linBMC and to enhance the therapeutic efficacy of bone marrow based cellular treatments for atherosclerosis using genetic modifications,” he stated in the abstract.

The grant began on June 1 and runs until May 31, 2018. It is worth $314,675 in its first year.

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