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NIH Awards More Than $800K in March to Fund Three miRNA-Related Research Projects

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By Doug Macron

Research into microRNAs has been an area of intense interest to the National Institutes of Health in recent months as far as extramural funding is concerned, and March has been no exception.

So far this month, the National Institutes of Health earmarked more than $800,000 for fiscal year 2010 to fund three new projects investigating the roles the small, non-coding RNAs play in cancer and asthma.

The first grant in March was awarded by the National Cancer Institute to University of Pennsylvania researcher Lin Zhang to support his research into the role of miR-30d in the initiation and progression of ovarian and breast malignancies.

"Our earlier findings that miRNAs exhibit genomic alterations at high frequency and their expression is remarkably deregulated in ovarian and breast cancers strongly suggest that [they] are involved in the initiation and progression of cancer," he wrote in the grant's abstract.

Specifically, "preliminary studies have identified miR-30d as a potential oncogene," he noted. "First, miR-30d plays a critical role in both epithelial transformation and established epithelial tumor growth. Second, miR-30d may directly regulate certain cancer-associated pathways. Third, the DNA copy number of miR-30d is frequently amplified in multiple types of human epithelial tumors."

At the same time, over-expression of the miRNA is "significantly associated" with a poor outcome in ovarian cancer patients, while pre-miR-30d is induced by hypoxia and has been found to prevent tumor cell apoptosis, Zhang added.

Hypothesizing that the miRNA is a key player in ovarian and breast epithelial cell transformation and tumor development, Zhang and his colleague plan to "dissect the transcriptional regulation of miR-30d under hypoxia and map the pro-survival pathways downstream" of the miRNA, according to the grant abstract.

They then aim to examine miR-30d's ability to prevent hypoxia-induced apoptosis in vivo in a novel tetracycline-inducible human tumor xenograft model and a collection of human ovarian and breast tumor specimens. Lastly, the team plans to test whether antisense oligonucleotides targeting miR-30d have a therapeutic effect in animal models of cancer.

Zhang's grant began on March 1 and is worth $331,309 this year. It is set to run until the end of 2014.

The second grant, also from the National Cancer Institute, went to Ricardo Aguiar of the University of Texas Health Science Center, in San Antonio, to fund his investigation of miR-155 and its link to diffuse large B cell lymphoma.

According to Aguiar's grant abstract, the miRNA has been found to be over-expressed in aggressive subtypes of the cancer, and its "oncogenic nature … was confirmed in E5-miR-155 transgenic mice, whereas its key role in lymphocyte biology was shown in loss-of-function animals.

"However, the mechanisms by which miR-155 contributes to lymphomagenesis are still unknown," the abstract notes.

In previous studies, Aguiar and colleagues found that miR-155 directly targets the transcription factor SMAD5 and impairs TGF-beta/BMP-mediated induction of ID2, a "key regulator of the oncogenic transcription factor PAX5," the abstract states. "Furthermore, we found that DLBCL cell lines genetically modified to over-express miR-155 or a SMAD5 shRNA become resistant to the growth inhibitory effects of TGF-beta1 in association with a block in p21 expression."

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Based on these findings, the investigators hypothesize that "SMAD5 targeting, by disrupting multiple downstream effectors of the TGF-beta/BMP signaling module, is at the core of the miR-155 lymphomagenesis."

To test this, they aim to examine the interaction between the miRNA, SMAD5, and TGF-beta/BMP in primary human DLBCLs and mature B cells in miR-155 knockout mice, according to the grant's abstract.

The team will then "characterize in vitro and in vivo the contribution of a defective ID2 regulation to miR-155-mediated lymphomagenesis … define the mechanisms by which SMAD5 regulates p21 expression, and establish in vivo the role of PAX5 in the lymphomas associated with miR-155 over-expression and SMAD5-specific knockdown," it states.

Aguiar's grant runs from March 1 until the end of 2014, and is worth $308,138 this year.

The last grant was awarded by the National Institute of Allergy and Infectious Diseases to Johns Hopkins University's Clifford Takemoto to fund his work examining the role of mast cell miRNAs in asthma.

"Mast cells are major effector cells in the pathogenesis of asthma," he wrote in the grant's abstract. "While specific miRNAs that mediate inflammatory responses have been identified, the role that miRNAs play in mediating … mast cell responses [dependent on the antibody Immunoglobulin E] is unexplored."

Takemoto and his colleagues hypothesize that miRNAs modulate IgE-mediated responses by regulating key inflammatory mediators from mast cells, having found "widespread repression of miRNAs, including let-7 miRNAs," during an array screen for miRNAs regulated by IgE signaling, the abstract states.

To follow up, he plans to "investigate miRNA regulation of IgE activation by examining mast cells globally depleted of miRNAs by genetic targeting and RNAi approaches," and then "determine whether the let-7 miRNAs regulate the expression of IL-13, an interleukin that promotes airway inflammation and responsiveness."

Lastly, with the support of the NIAID funding, Takemoto will "examine the role of IgE-regulated miRNAs in the development of airway inflammation and responsiveness" in mice with mast cells that are either depleted of miRNAs or over-express let-7, the abstract adds.

"The goal of this pilot study will be to establish the miRNA regulatory network in IgE-activated mast cells," it states. "The insights gained from this project may lead to new and innovative strategies for the treatment of asthma."

Takemoto's grant runs from March 1 until Feb. 28, 2012, and is worth $205,000 this year.

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