The National Institutes of Health has earmarked nearly $800,000 in grant funding to support research projects focused on the role of microRNAs in cancer development and immunity, as well as the development of a platform to study miRNA expression data in tumor cells.
The first grant was awarded to University of California, Los Angeles, researcher Dinesh Rao to fund his efforts characterizing the tumor-suppressive functions of two miRNAs — miR-34a and miR-146a — in B cell neoplasia.
In 2010, Rao and colleagues reported a link between miR-34a and the suppression of the B cell oncogene Foxp1. In 2011, along with collaborators from Regulus Therapeutics and the California Institute of Technology, he described the role of miR-146a in the suppression of myeloid cell proliferation and oncogenic transformation.
With the support of the NIH, Rao aims to better understand the developmental roles of miR-34a and miR-146a in B cell activation and to uncover their mechanism of action. Specifically, he and his team will use a combination of genetically defined mouse models, retroviral transduction systems, bone marrow transplantation, high-throughput approaches, bioinformatics, and hypothesis-driven investigation of individual targets to elucidate the miRNAs' roles in development and oncogenesis, according to the grant's abstract.
Through the work, Rao aims to not only improve the understanding of “critical biological and pathological processes,” but also to advance potential miRNA treatments for B cell malignancies, the abstract adds.
The grant runs from Jan. 1 until the end of 2017, and is worth $239,663 in its first year.
The second grant went to Timothy Ratliff of Purdue University, who aims to use miRNA arrays to identify pathways and markers for myeloid-derived suppressor cells, or MDSCs.
MDSCs are a “heterogeneous, ill-defined population of immune regulatory cells that are a critical cell population in suppressing tumor immunity and controlling inflammatory processes,” he noted in his grant's abstract.
“Currently, MDSC function is based on studies of phenotypically defined cell populations that contain both suppressive and non-suppressive cells,” he wrote, adding that clearly defined markers for the cells remain unavailable and functional pathways unique to the cells have yet to be described.
In 2011, Ratliff and colleagues published data showing that active regulatory MDSCs are present only within a tumor or at the site of inflammation, and that only tumor- or inflammation-derived MDSCs express arginase I and inducible nitric oxide synthase, and suppress T cell responses.
A previous gene array analysis of MDSCs identified only two genes that regulate the cells' T cell-suppression activities, and Ratliff and his team hypothesized that identifying miRNAs linked to MDSC function will uncover “new targets that will enable identification and modulation of active MDSC,” according to the grant's abstract. “Additionally, integrating the miRNA analysis with the gene array data will enhance pathway discovery unique to functional MDSCs.”
A miRNA array analysis performed on the same MDSCs from the gene array study revealed a significant up-regulation of 46 of the small, non-coding RNAs, as well as down-regulation of 40 others. With the NIH grant funding, Ratliff plans to take these findings further, combining the miRNA and gene arrays to identify novel MDSC-specific genes and pathways associated with differentiating between functional and precursor MDSCs.
He then aims to validate the biological relevance of certain of the miRNAs identified in the analysis, with the goal of finding new approaches for controlling MDSC function.
The grant began on Jan. 2 and runs until Nov. 30, 2014. It is worth $156,131 in the first year.
The last grant was awarded to Massachusetts Institute of Technology researcher Ron Weiss to help with the creation of a platform for generating live cancer cell miRNA expression data.
“While contemporary platforms such as microarrays and RT-qPCR are capable of measuring aggregate miRNA levels, only limited research has addressed single-cell distributions and no systematically created dataset is available for cancer research,” Weiss wrote in his grant's abstract. “Most significantly, distributions and time-series data are required to identify multimodal miRNAs, characterize expression variability, find significant inter-miRNA correlations, and enable more accurate analysis and classification of cancer cell types and states.”
Additionally, no functional datasets exist characterizing the interaction of miRNAs with genetic circuit elements for use in cancer diagnosis and gene therapy, he added.
To address these issues, Weiss and colleagues plan to use a high-throughput microfluidic platform to assemble libraries of genetic circuits that act as sensors for the expression levels of single and multiple miRNAs in target cell lines.
Data generated from this platform will be experimentally measured in real time from large numbers of individual live cells using a separate microfluidic module, according to the abstract. The resultant miRNA correlation data will be used to increase the precision of cancer cell classifiers, it adds.
The grant began on Jan. 1 and runs until the end of 2017. It is worth $391,973 in its first year.