By Doug Macron
The National Institutes of Health this month awarded more than $500,000 in grants to help researchers study the use of microRNAs as biomarkers for various diseases, including obstructive neuropathy and liver and prostate cancers.
The first grant was awarded to Thomas Jefferson University's Hushan Yang to investigate how miRNAs influence how chronic hepatitis B can lead to hepatocellular carcinoma.
While HBV infection is “the most prominent etiologic factor” for hepatocellular carcinoma, only 20 percent of patients with the virus develop the cancer, according to the grant's abstract. This underscores the need for a “clinically acceptable risk-assessment model.”
Because miRNAs have been linked to HBV-related liver cancer and are stable in serum, they are a “valuable resource for miRNA-based biomarker research," the abstract states. This is "especially [the case] in prospective studies that have been followed up for extended time periods but only collected serum samples at the time of study initiation.”
With their NIH grant, Yang and colleagues plan to take a “prospective case-control approach to systematically identify baseline serum miRNA expression signatures that are associated with the risk” of liver cancer among 510 chronic HBV patients, he wrote in the abstract.
The goal, he wrote, is to identify miRNA expression signatures that can predict the development of the disease in those with chronic HBV infection. Specifically, the researchers will examine a “unique and highly homogenous Asian-American population” divided into 30 cases and 30 controls that will be analyzed using an unnamed miRNA microarray platform. The team will also compare miRNA against real-time PCR by studying separate cohorts comprising 150 cases and 300 controls.
“The strict matching between cases and controls as well as the two-stage study design greatly increases the possibility of discovering the bona fide miRNAs,” Yang wrote.
The investigators also aim to develop a multivariate risk-assessment model to “analyze the cumulative and interaction effects between miRNA expression profiles and other important risk factors” that modulate chronic HBV infection to hepatocellular carcinoma transformation, the abstract states.
Finally, they aim to undertake exploratory bioinformatics analyses to help create an in silico network of genes potentially targeted by miRNAs.
The grant began on Sept. 1 and runs until the end of August 2013. It is worth $202,275 in its first year.
Also securing NIH funding is Robert Blelloch of the University of California, San Francisco. His project will study how miRNAs can be used as prognostic biomarkers in prostate cancer patients who are under active surveillance, a standard course used to avoid unnecessary treatment in those with a low-risk form of the disease.
“Patients on active surveillance are monitored through PSA kinetics and serial biopsies followed by radical intervention in the case of disease progression,” but such approaches are only “modest predictors of adverse pathology following radical-prostatectomy," he wrote in the grant's abstract. This suggests "a need for novel biomarkers to detect significant disease.”
Preliminary data from Blelloch's lab suggest that serum miRNA signatures can detect significant disease in prostate cancer patients classified as low risk. Therefore, he and his colleagues aim to discover whether they can accurately predict significant disease to enhance the effectiveness of active surveillance and avoid delays in necessary therapy, the abstract states.
Specifically, the investigators will look for miRNAs associated with significant disease in low-risk prostate cancer patients and evaluate the predictive ability of these miRNAs. A novel multiplex qRT-PCR method will be used to generate preliminary characterization data from miRNA signatures in serum of patients who are candidates for active surveillance but elect to undergo immediate radical prostatectomy.
The accuracy of the miRNAs biomarkers will be evaluated using a novel prediction model designed to distinguish patients who rank differently when assessed through a standard prostate cancer-prognosis evaluation.
“The proposed research is significant because it is expected to improve the detection of significant disease in low-risk patients and directly increase the effectiveness of active surveillance as a management strategy for prostate cancer,” the abstract notes. “Ultimately, such improvements will benefit patients by ensuring treatment to patients with significant disease while decreasing morbidities related to radical interventions.”
Blelloch's grant began on Sept. 1 and runs for one year. It is worth $201,623.
The last grant was awarded to Nationwide Children's Hospital's Susan Ingraham to support her efforts to identify early biomarkers for the diagnosis and prognosis of kidney malformations called congenital obstructive nephropathy that commonly affect young children.
Hypothesizing that miRNAs may play a role in how kidneys respond to congenital urinary obstruction, Ingraham and colleagues will use the megabladder mouse to discover potential miRNA biomarkers. The mouse is a genetic model that develops chronic and end-stage kidney disease secondary to a functional lower urinary tract obstruction.
In the first of the project's two parts, the researchers will preliminarily characterize miRNA expression in the mouse along a range of time points and disease severities, as well as examine the effect of therapeutic cutaneous vesicostomy on the non-coding RNAs, according to the grant's abstract. Next, they will compare the animal results with specific miRNAs in patient samples.
Potential miRNA-targeted therapies will also be examined in the mouse model.
“The anticipated outcome of this work is advancement of our understanding of the role miRNAs play in congenital obstructive nephropathy and the potential of this important class of regulators in biomarker discovery and therapeutics,” Ingraham noted in the abstract.
Her grant began on Sept. 1 and runs until April 30. It is worth $149,472.
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