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NIH Awards Two Grants in February Supporting Research into microRNAs, Cancer

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The National Institutes of Health this month awarded two grants worth nearly $300,000 combined to fund research into the role of microRNAs in cancers.

The first grant was awarded to Dartmouth College's Angeline Andrew, who is investigating miRNA dysregulation in bladder cancer prognosis.

Among patients who develop non-muscle invasive urothelial cancer, more than half experience recurrent disease, with new tumors often refractory to treatment, Andrew wrote in her grant's abstract. With the support of the NIH funding, Andrew and her colleagues aim to identify miRNAs that could help identify patients who will experience tumor recurrence in primary tissue.

Having assembled a population-based tissue bank of bladder tumors with long-term recurrence, progression, and survival data from an epidemiologic cohort of more than 1,000 patients with non-muscle invasive urothelial cell carcinoma, the researchers aim to identify miRNAs associated with rapid disease recurrence by assessing primary tumor tissue specimens for miRNA expression levels using small RNA sequence count analysis.

Prognostic miRNA candidates will be prioritized and confirmed using qRT-PCR, and their distribution in urothelial carcinoma cells versus other cell-types will be examined using in situ hybridization.

The prognostic value of the miRNAs will then be assessed as they relate to recurrence, progression, and survival in the population-based case cohort.

"Successful identification of a prognostic dysregulated miRNA will help tailor management of clinically challenging bladder cancer cases by enabling early detection of rapidly recurrent and refractory phenotypes," Andrew stated in the abstract. "The dysregulated miRNAs that we identify are also potentially viable therapeutic targets and could lead to the future development of novel [miRNA antagonist] or miRNA-replacement therapies for this malignancy."

The grant began on Feb 1 and runs until the end of January 2016. It is worth $246,645 in its first year.

The second grant went to Oregon Heath and Science University researcher Noah Hornick to fund his efforts to study how exosomal miRNAs might drive immune evasion in acute myeloid leukemia (AML).

Several aspects of the development and progression of AML are related to the disease's interaction with bone marrow microenvironment, with the immune system developing a tolerance for the leukemic cells and patients losing hematopoietic function, Hornick noted in his grant's abstract.

"As the diagnoses of both the initial leukemia and relapse are made through cytopenias, a better understanding of the events culminating in the development of leukemia both initially and in relapse could potentially allow for earlier detection of disease and new approaches to therapy," he wrote.

Exosomes have been recently shown to carry RNA and proteins between cancer cells and the tumor microenvironment, contributing to disease progression. Given that miRNAs have also been found in exosomes, Hornick plans to investigate whether exosome-bound miRNAs transferred between AML and surrounding cells contributes to the immune tolerance and erosion of hematopoiesis that are associated with the disease.

He and his colleagues will study the effect of exosomal miRNA transfer on the ability of hematopoietic stem cells to home to and engraft and differentiate in the bone marrow using in vitro exposure of precursors to exosomes isolated under conditions designed to mimic those encountered in the marrow environment. The researchers will also conduct in vivo modeling using immune-deficient mice.

The team will also examine if AML-exosomes can suppress the ability of dendritic cells to develop and initiate an immune response by evaluating the differentiation of mononuclear cells to dendritic cells, the maturation of dendritic cells in response to antigen, and the induction of dendritic cell apoptosis in response to exosome exposure.

The grant began on Feb. 1 and runs for three years. It is worth $47,232 in its first year.

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