The National Institutes of Health this month awarded nearly $1.6 million in research grants to support efforts exploring the role of microRNAs in radiation injury, cancer, psychiatric disorders, and pancreatic cell function.
The first grant was awarded to Dana-Farber Cancer Institute researcher Dipanjan Chowdhury to fund his work examining serum microRNAs as biomarkers for radiation injury to lung and hematopoietic cells.
“Radiation exposure in terrorist events, industrial accidents, or natural disasters ... is a current and continuing threat for the future,” he wrote in his grant's abstract, with symptoms appearing days to months after exposure, which could lead to a delay in treatment.
“Existing biodosimetry techniques and devices do not predict the severity of injury sustained by specific organs and tissues, and thus do not allow for the prompt organ- and tissue-directed medical treatment that might be provided by any available radiation medical countermeasures,” he noted.
Having found that miRNAs can affect the body's response to radiation, Chowdhury and his colleagues speculated that serum miRNA profiles might be used to predict radiation damage to hematopoietic cells and lung tissue.
“In preliminary studies, we used a sub-lethal dose of total body irradiation to cause hematopoietic injury in mice and assessed the serum miRNA profile a day and week after injury,” he wrote. “Histopathological and cellular analysis revealed that specific serum miRNAs correlated with radiation-induced damage to bone marrow and other aspects of the hematopoietic system.”
Further data suggest that certain sets of miRNAs could be used to estimate the time of radiation exposure, he added.
In terms of lung injury, Chowdhury and his team exposed the animals' thoracic regions to localized doses of radiation, and found that specific sets of miRNAs corresponded to the injury in a dose-dependent manner.
“These results suggest that serum miRNA expression may serve as a novel biomarker for acute and delayed radiation injury to the hematopoietic system and lung,” he wrote.
To help him follow up on these findings, the NIH awarded Chowdhury a five-year grant, which began on June 15 and is worth $425,386 in its first year.
The second grant was awarded to University of Maryland School of Medicine investigator Qun Zhou to fund his studies into the role of miR-140 in breast cancer.
According to his grant's abstract, preliminary data indicate that a loss of the miRNA is associated with the development of ductal carcinoma in situ, one of the two main types of breast cancer, and that the chemopreventative nutrient sulforaphane can restore its expression.
“We further observed that reduced miR-140 expression is associated with increased expression of the SIRT1 histone deacetylase that is associated with enhanced cancer stem cell survival,” he wrote, while mice lacking the miRNA spontaneously developed breast cancer early on.
Hypothesizing that miR-140 loss leads to higher SIRT1 expression, which in turn promotes ductal carcinoma in situ development and increased accumulation of breast cancer stem cells, Zhou and his team aim to define the role of the miRNA in this process; determine its effect on cancer stem cell survivial; and characterize how it impacts sulforaphane chemoprevention in vivo.
Zhou's grant runs from June 1 until the end of March 2017, and is worth $318,513 in its first year.
Also investigating the role of miRNAs in cancer is Northwestern University's Xiaozhong Wang, who received a two-year grant to focus on how the tumor suppressor PTEN impacts miRNA expression in stem cells.
“Using a genetic screen, we identified a novel function for the tumor suppressor PTEN as a modifier of the microRNA silencing pathway in embryonic stem cells,” he wrote in the grant's abstract. “Thus, the objectives of this project are to elucidate the molecular mechanisms by which PTEN modulates the efficacy of microRNA silencing machinery in stem cells and to determine the contribution of microRNAs to drive malignant transformation in loss-of-PTEN cancer cells.”
The grant is worth $201,623 in its first year.
The NIH also awarded a grant to Columbia University's Joseph Gogos to assist with his research into the link between miRNA dysregulation and psychiatric and cognitive disorders.
According to the grant's abstract, work in Gogos' lab has revealed “two major components” of the abnormal miRNA processing observed in the brains of mice with a microdeletion in chromosome 22, as well as a “major downstream target” of this miRNA dysregulation.
To advance these findings, he and his colleagues plan to further elucidate how miRNA dysregulation “contributes to the cellular, synaptic, and behavioral phenotypes associated with the … microdeletion in vivo,” and to identify additional key downstream targets.
“Understanding how miRNA-dependent gene regulation disrupted by a structural mutation with unequivocal causal links to schizophrenia and cognitive dysfunction contributes to the emergence of the psychiatric and cognitive phenotypes associated with this genomic imbalance will provide important mechanistic insights and can guide analysis of miRNA contribution to other psychiatric, neurodevelopmental, and cognitive disorders,” he wrote.
The grant runs from June 15 until April 30, 2017. It is worth $396,635 in the first year.
The last grant went to Praveen Sethupathy, a researcher at the University of North Carolina, Chapel Hill, to support his efforts to uncover the roles of miRNAs in human pancreatic islet function, which play a role in metabolic responses to blood sugar levels.
Although it is known that progressive dysfunction of the islet underlies type 2 diabetes, the “gene regulatory networks that drive islet biology are largely uncharacterized,” he wrote in the grant's abstract.
With recent studies linking miRNAs with islet function, he and his team plan to use high-throughput genomic approaches to systematically characterize all miRNAs in resting and glucose-stimulated primary human islets. Then, the researchers aim to identify the regulatory modules that influence their differential expression patterns and targeting activity.
The grant runs from June 1 until May 31, 2015. It is worth $248,575 in the first year.