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NIH Awards Nearly $1.2M in February for microRNA Research

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By Doug Macron

The National Institutes of Health last month earmarked nearly $1.2 million in 2012 grant funding for five research projects examining the role of microRNAs in various diseases, such as Huntington's disease, and biological processes including vascular endothelial growth factor signaling.

Huntington's Disease

The first grant was awarded to the University of Pittsburgh's Robert Friedlander to support his work in Huntington's disease, a condition caused by an autosomal dominant mutation in the huntingtin gene and which is characterized by atrophy in the striatum.

“To better understand the biologic affects of mutant [huntingtin] expression and the early involvement of the dorsal striatum, we determined the changes in microRNA expression in normal human dorsal striatum versus normal ventral striatum using a [miRNA]-expression array,” he wrote in the grant's abstract. “Similarly, we compared the [miRNA] expression levels in dorsal striatal tissues of [Huntington's disease] patients compared to controls.”

This work revealed miRNA signatures that could be used to distinguish between normal dorsal versus normal ventral striatum, and between normal and Huntington's disaese dorsal striatum, according to the abstract. Additional in vitro work has shown that over-expression of three particular miRNAs protects mutant huntingtin-expressing neurons, while over-expression of an additional miRNA is toxic.

In light of these data, Friedlander and his colleagues hypothesize that differential expression of miRNAs may “sensitize dorsal striatum to early neuronal death and that mutant [huntingtin] expression may lead to additional disregulation of [miRNA] expression and exacerbate the [Huntington's disease] cell death phenotype,” he wrote.

To test this, as well as to determine whether these miRNAs may be targets for therapeutic intervention, the researchers aim to use the NIH funding to determine if manipulation of miRNA levels in the brain of mouse models can alter Huntington's disease onset and/or progression.

They also plan to knockout one miRNA, miR-155, which is increased in dorsal striatum as compared to ventral striatum, to see if it will alter the onset and progression of the disease in the mouse model. The investigators will also determine the downstream targets of differentially expressed miRNAs to identify potential therapeutic targets.

The grant runs from Feb. 15 until the end of January 2016, and is worth $417,559 in its first year.

Chronic Myeloid Leukemia

The second grant went to Ohio State University's Danilo Perroti to help him examine the role of miRNAs in the regulation of chronic myeloid leukemia stem cell survival and self-renewal.

The disease, the grant's abstract notes, is the first "clinically cured stem cell-derived hematopoietic neoplasm. However, tyrosine kinase inhibitor therapy leaves behind a pool of [CML stem] cells showing innate resistance to these drugs,” which represent an active cancer reservoir.

“Thus, it becomes clear that only drugs that can safely and efficiently target these [stem cells] without harming the normal ones have the potential to lead to disease eradication,” the abstract adds.

Work from Perroti and colleagues suggests that CML stem cell survival and renewal may be associated with an “aberrant balance between kinases, [such as] BCR-ABL1 and Jak2, and phosphatases, [such as] PP2A, and this may depend on altered expression of specific microRNAs.”

According to Perroti's grant abstract, he and his team have discovered altered expression of certain miRNAs that may target the Jak2-hnRNP A1-SET/PP2A-2-catenin HSC pathway, which is essential for quiescent CML stem cells, yet operates in a BCR-ABL1 expression-dependent manner, though not a kinase-dependent one.

Perroti hypothesizes that quiescent Ph+ stem cells display a dysregulated miRNA expression that depends on BCR-ABL1 expression, but not kinase activity, according to the abstract, and this contributes to enhanced survival and self-renewal of leukemic stem cells.

With the support of the NIH award, Perotti aims to “understand the requirement of altered [miRNA] expression for the maintenance of the quiescent reservoir of CML [stem cells] and determine the therapeutic relevance of pharmacologic restoration of [miRNA] expression through the identification and integrated in vitro and in vivo analysis” of the miRNAs affecting CML stem cell survival and self-renewal through direct interference with the BCR-ABL1-Jak2-hnRNP A1-SET-2-catenin pathway.

His grant runs from Feb. 16 until Jan. 31, 2017, and is worth $305,000 in the first year.

VEGF Signaling

The third grant went to Yale University's Jym Ocbina, who is investigating the role of miRNAs in VEGF signaling.

Studies indicate that a muscle-specific miRNA, miR-1/206, contributes to the regulation of a majority of mRNAs during muscle development in zebrafish, according to his grant's abstract. However, loss of the miRNA's function in somites also triggers increased growth and proliferation of surrounding segmental arteries.

“Sequence analysis of muscle-expressed genes involved in angiogenesis revealed that VEGF-A is a potential miR-1/206 target and that this regulation is conserved among vertebrates,” Ocbina wrote in the abstract.

With the NIH funding, he plans to establish a role for miR-1/206 in vascular development in vivo, study the miRNA's regulation of VEGF-A genes, and test the “physiological relevance of individual miRNA/target interactions in the context of miR-1/206 and VEGF-A signaling during vascular development.”

The grant began on Feb. 1 and runs until Jan. 31, 2015. It is worth $47,114 in its first year.

Nicotine Addiction

The fourth grant was awarded to Paul Gardner of the University of Massachusetts Medical School to fund research into the role of miRNAs on nicotine-mediated behavior.

“Nicotine is the addictive component of tobacco that binds to and activates a family of ligand-gated ion channels, nicotinic acetylcholine receptors,” or nAChRs, he wrote in the grant's abstract. “Activation of the receptors in the dopaminergic mesocorticolimbic reward pathway is thought to underlie the initiation of addiction, whereas signaling through nAChRs in the habenulo-interpeduncular pathway that feeds into the reward pathway is thought to play a key role in eliciting nicotine withdrawal symptoms.”

Nicotine's effect on nAChRs is poorly understood, in large part due to the existence of multiple nAChR subtypes, each with its own electrophysiological properties, the abstract notes.

“Chronic nicotine exposure alters the expression of nAChR subtypes, which likely contributes to nicotine dependence; however, the underlying mechanisms regulating these changes remain unclear,” it adds.

In light of increasing evidence that nicotine and cigarette smoke alter miRNA expression, preliminary work from Gardner and his colleagues has shown that mice exposed to nicotine experience decreased expression of two miRNAs, miR-71 and miR-9, in the ventral segmental area of the brain, but increased expression of the same miRNAs in the medial habenula.

“Interestingly, potential targets of miR-7a and miR-9 include members of the nAChR family as well as other components important in the reward pathway,” Gardner noted.

With the NIH funding, he and his colleagues will examine whether miR-7a and/or miR-9 modulates nicotine reward-associated behaviors, as well as nAChR expression and function, and test if miR-7a and/or miR-9 modulates nicotine withdrawal-associated behaviors.

His grant began on Feb. 1 and runs until the end of Jan. 2014. It is worth $205,625 in the first year.

Tumor Suppression

The last grant was awarded to Lizhong Wang at the University of Michigan, Ann Arbor, to fund his research into the association between miR-146 and the X-linked gene FOXP3.

“FOXP3 appears to function as the master regulator in the development and function of regulatory T cells … [and] directly targets critical oncogenes HER2/ErbB2 and SKP2 and a tumor suppressor gene p21,” according to the grant's abstract.

Wang and his team have previously demonstrated that FOXP3 suppresses breast cancer tumors and, more recently, have shown that it suppresses prostate cancer by repression transcription of c-Myc, the abstract states. Still, its potential effect on non-coding RNAs has not been studied.

An miRNA array analysis conducted by Wang revealed that FOXP3 “drastically” induced expression of two related miRNAs, miR-146a and miR-146b in human breast cancer cells, while “accumulating data from others demonstrate that miR- 146a/b inhibit cancer cell proliferation, invasion, and metastasis in human cancers, including breast, prostate, pancreatic cancers, and glioma.

“Since our preliminary data reveal a strong induction of miR-146a/b by FOXP3 in the cancer cells in vitro and in vivo, it is of great interest to identify the impact of FOXP3-miR146-NFkB axis on tumor suppression,” the abstract states.

Wang and his team hypothesize that the “FOXP3-miR146-NF-kB axis plays a critical role in tumor suppressor function of FOXP3,” and aim to demonstrate a tumor-suppressor association between the gene and miRNAs.

To do so, they will identify the functional role of miR-146a/b in FOXP3-mediated tumor suppression and elucidate the mechanism by which FOXP3 induces miR-146a/b transcriptions, according to the grant's abstract. They also plan to determine whether the function of miR-146a/b is mediated by repression of NF-kB.

“Once our in vitro studies provide evidence for the FOXP3-miR146-NFkB axis, we will take advantage of the genetic model to determine the functional role of this axis in vivo,” he wrote.

Wang's grant runs from Feb. 17 until Jan. 31, 2014. It is worth $186,600 in its first year.


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