NEW YORK (GenomeWeb) – The National Institutes of Health this month handed out more than $1.2 million in grant funding to support four microRNA-related research projects.
Among them is one awarded to University of Massachusetts Media School investigator and miRNA pioneer Victor Ambros to study certain fundamental aspects of the role miRNAs, and another issued to startup Chromologic to develop a system that uses the small, non-coding RNAs as biomarkers for radiation exposure.
The other grants focus on miRNAs in systemic lupus erythematosus (SLE) and tuberous sclerosis complex (TSC).
Diet and environment
Since Ambros' lab discovered the first miRNA as part of a broader research effort on the genetic pathways of development timing in C. elegans, understanding the fundamental roles of miRNAs has been one of his major focuses.
In support of this work, he has received a four-year grant from the NIH to study in C. eleganshow miRNAs mediate organismal responses to nutritional and pathogenic properties of an animal's diet, as well as how the non-coding RNAs confer developmental and physiological robustness against environmental change.
The nematode contains more than 150 distinct miRNA families, including more than 20 with human homologs. Despite continued research, the exact functions of these miRNAs is unclear, Ambros noted in his grant's abstract, and it is unknown how miRNA expression is regulated transcriptionally or post-transcriptionally by developmental and physiological signals.
With the support of the NIH grant, which is worth $645,174 in its first year, Ambros and his team aim to create a comprehensive, genome-wide analysis of miRNA gene regulatory networks in C. elegans, with an emphasis on miRNAs that mediate responses to the nutritional and pathogenic qualities of the worms' bacterial diet.
"In-depth functional analysis will be conducted for a set of specific evolutionarily conserved microRNAs that are known to act in pathways that confer developmental and physiological robustness in the context of changing dietary conditions," the abstract notes.
The project began on June 1 and runs until the end of March 2018.
Given the critical need for rapid treatment following radiation exposure, startup Chromologic is developing an optical biodosimeter capable of measuring changes in blood-based miRNAs as biomarkers for acute radiation syndrome (ARS) in around 15 minutes.
The system combines automated magnetic bead based screening for miRNA targets with a proprietary technology called amplified reflectometric interference analysis to enable "highly sensitive and specific quantification of 100s of miRNA radiation biomarkers in parallel," the company said in the abstract.
In pilot studies, the system has been used to measure sub-femtomolar concentrations of miRNA in ovarian cancer serum samples, while experiments in rodent plasma have identified a panel of miRNAs with dose- and time-dependent responses to whole-body irradiation in a dose range relevant to medical triage in case of a radiological event, Chromologic added.
With its two-year grant from the NIH, worth $299,968 in the first year, the company aims to show that the miRNA panel previously identified can be used to measure whole-body irradiation in a clinical setting; that a similar panel can be used to measure radiation doses in non-human primates and humans; and that the miRNAs can be used in a point-of-care blood-based microchip assay to predict ARS within the first week of radiation exposure.
The grant began on June 1 and runs until May 31, 2016.
SLE is an autoimmune disorder that causes inflammation and tissue damage in any part of a patient's body. Although its exact causes are unknown, there is growing evidence of a genetic component.
In light of data linking miRNAs to immune system development and function, Thomas Jefferson University researcher Marianthi Kiriakidou has been studying whether the ncRNAs are implicated in the disease. Now, with the support of an NIH grant, she and her colleagues aim to further study the function of miRNAs in a tri-congenic mouse model of autoimmune disease that closely matches SLE in humans.
In previous studies, she and her team have demonstrated that the expression of a set of miRNAs in the mouse positively correlates with the development and severity of severe lupus manifestations.
With the one-year grant, worth $35,538, the researchers aim to uncover miRNA-dependent signaling pathways that are uniquely affected in the animal model with the goal of identifying novel therapeutic targets for SLE.
TSC is a rare genetic condition in which benign tumors known as cortical tubers grow in the brain, leading to a number of neurological symptoms including epileptic seizures. However, not all tubers are epileptogenic, though the reasons why are unknown.
To address this knowledge gap, Wayne State University's Alan Dombkowski has been awarded a three-year grant to investigate the possibility that aberrant microRNA activity contributes to the epileptogenic potential of cortical tubers in TSC, according to his grant's abstract.
Preliminary work from his lab points to significant perturbations of miRNA expression in epileptogenic tubers, including dysregulated miRNAs predicted to target epilepsy risk genes. Using brain tissue that has been resected to treat intractable epilepsy, Dombkowski and his team aim to compare the expression profiles of miRNAs in epileptogenic tubers and non-epileptogenic tubers.
"Computational analysis and integration of epilepsy risk gene databases will identify target genes known to confer risk of epilepsy, and we will validate key microRNA target interactions using a human neural cell line model to ensure functional relevance to the human disease," the abstract states.
Follow-on work will focus on determining why certain tubers are epileptogenic even in the absence of elevated kynurenine pathway activity, which has been associated with tuber epileptogenicity.
The grant began on June 1 and runs until May 31, 2017. It is worth $332,500 in its first year.