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NIH Awards $1.6M in microRNA Research Grants in January

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The National Institutes of Health this month handed out more than $1.6 million in grant funding to support four microRNA-related research projects including ones focused on the small, non-coding RNAs' roles in women's cancers, as well as their effect on certain bone marrow and immune cells.

The first grant was awarded to University of Georgia researcher Mandi Murph who is investigating whether altered miRNA expression can be used as a biomarker of obesity-related breast and ovarian cancers.

Autotaxin is an enzyme involved in the production of the lipid-signaling molecule lysophosphatidic acid (LPA), which has been shown to enhance cellular proliferation. Murph and her colleagues hypothesize that autotaxin boosts oncogenic growth factor signaling via LPA in adipocytes, and that this effect extends to surrounding cells, yielding a measurable alteration of miRNAs secreted in plasma, according to the grant's abstract.

Murph's lab previously reported on the discovery that miR-30c-2*, when expressed in ovarian cancer cells, suppressed cell proliferation and viability while downregulating the oncogene BCL9. Specifically, the miRNA was found to participate in a "regulatory feedback loop" inhibiting oncogenic transcripts that are initiated by LPA-mediated receptor activation.

With the NIH funding, the researchers plan to first test their theory in a mouse model of obesity that spontaneously develops cancer, then quantify specific miRNAs in an obese but otherwise healthy human population to see whether miR-30c-2* and other miR-30 family members are altered as a consequence of body mass index and can be used to predict cancer risk.

The grant began on Jan. 6 and runs for two years. It is worth $426,849 in its first year.

Also securing NIH funding is Kazuko Nishikura of the Wistar Institute, who is researching the effect of an Epstein-Barr virus (EBV) miRNA on breast cancer metastasis.

In 2010, she and her colleagues reported that loading of the EBV miRNA miR-BART6 onto a functional RISC is inhibited by A-to-I editing of its primary transcript by ADAR1. "Four binding sites of miR-BART6-5p were identified within the human Dicer mRNA 3'UTR, revealing a unique strategy of EBV to manipulate the host RNAi mechanism," she noted in her grant's abstract.

Recent data from another group showed that two miRNAs, miR-103 and miR-107, helped induce metastasis-promoting epithelial-to-mesenchymal transitions in breast cancer cells by silencing Dicer, which in turn affected levels of the EMT-inhibitory miRNA miR-200.

Given the well-established connection between latent EBV and various cancers including Hodgkin's disease, and that it is frequently detected in breast cancer, Nishikura speculates that miR-BART6-5p and its editing by ADAR1 might control EMT by targeting Dicer, thereby contributing to metastases in EBV-positive breast cancer.

With the NIH funding, she and her team will examine the function of miR-BART6 RNAs on EMT in human breast cancer cell lines; test the significance of RNA editing in the EMT-promoting function of miR-BART6; and study the role of miR-BART6 in vivo in breast cancer metastasis using an orthotopic tumor implantation mouse model, she noted in her grant's abstract. The investigators then plan to look at miR-BART6 and ADAR1 expression levels in human breast tumor specimens and to determine their relevance to metastatic progression.

The four-year grant began on Jan. 1 and is worth $383,875 in the first year.

The NIH also awarded a research grant to Thomas Jefferson University researcher Paul Bray, who is studying miRNA function in megakaryocytes — bone marrow cells that give rise to thrombocytes.

Late last year, Bray and colleagues reported on a study of platelets in 154 healthy subjects, identifying a number of so-called master miRNAs that regulate platelet activity through GPVI, PAR1, PAR4, and P2Y12, leading them to hypothesize that megakaryocyte miRNAs may control mRNAs involved in platelet reactivity and number, according to the grant's abstract.

To extend their findings, Bray and his team will use the NIH funding to functionally characterize candidate master miRNAs that appear to regulate platelet aggregation by transducing them into human megakaryocytes differentiated from CD34+ stem cells and testing them for agonist-induced cell activation. The group will then validate predicted mRNA binding and test the function of novel mRNA targets in megakaryocytes, the abstract states.

Bray noted in the grant's abstract that his lab has generated preliminary data pointing to specific miRNAs associated with platelet number that "target and knock down mRNAs encoding apoptosis-regulating genes also associated with platelet number. As such, the NIH grant will also support the examining of miRNAs in megakaryocyte apoptosis and thrombopoiesis.

His lab has also conducted early experiments indicating that "blood cell type-preferential expression of some miRNAs can dictate cell-preferential transgene expression," the abstract states. To further examine this, miRNAs will be profiled in primary human bone marrow cells and peripheral blood cell lineages from the same subject. Binding sites for cell-preferential miRNAs will be engineered into lentiviral vectors, which will be introduced into hematopoietic stem cells so that transgene expression can be assessed in megakaryocytes and other lineages.

Bray's three-year grant began on Jan. 1 and is worth $393,793 in the first year.

Lastly, Palo Alto Institute for Research and Education's Jorg Goronzy received a four-year grant to study miRNA regulation of T cell senescence.

In 2012, he and his team reported finding that miR-181a expression declines in aging T cells, impacting T cell receptor sensitivity by increasing the activity of the dual specific phosphatase 6 (DUSP6). "DUSP6 calibrates the T cell receptor activation threshold at which stimulation is translated into a productive signal," he wrote in his grant's abstract. "Increased DUSP6 contributes to the lowered sensitivity of elderly T cells to respond."

Building off this work, Goronzy will use the NIH grant to look at the "epigenetic, transcriptional, and post-transcriptional mechanisms that control miR181a/b expression … [in order to] understand what drives the decline in miR181a/b with age and to identify means to upregulate expression," the abstract states.

They will also further study the effect of age on DUSP6, as well as other genes involved in T cell activity and survival, in T cell subsets to determine whether age-related changes in protein expression are caused by the degree of miR181a/b expression and if such effects can be reversed by miR181a/b overexpression. They also plan to study the functional consequences of miR181a/b loss and its relationship to the overexpression of DUSP6 and the other genes.

The grant is worth $429,942 in its first year.

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