By Doug Macron
The National Institutes of Health this month set aside nearly $400,000 to fund three research projects focused on microRNAs and the heart, including one issued to a company aiming to develop an miRNA antagonist to prevent cardiac ischemia.
One of the NIH grants was awarded to New Jersey-based Vasade Biosciences, which specializes in developing drugs for cardiovascular diseases, to support its work on an inhibitor of miR-199a.
"Protecting the heart against ischemia or ischemia/reperfusion injury is one of the top health care objectives," according to the company's grant's abstract. "Currently, one of the most effective mechanisms is ischemia preconditioning, which is achieved by intermittent occlusion of the coronary artery via balloon inflation."
But this approach is short-lived and requires knowledge of the time of an ischemic episode, the abstract notes. At the same time, it carries the risk of atherosclerotic emboli.
Company researchers have identified miR-199a as an "obligatory direct regulator" of hypoxia-inducible factor 1-alpha, which is required for preconditioning cells against hypoxia, and Sirt1, which plays a role in cellular longevity.
"By knocking down miR-199a in cultured myocytes or in a transgenic mouse model, we were able to recapitulate the effects of hypoxia preconditioning and protect the cells against hypoxic damage," the abstract notes.
Still, modulating this miRNA in vivo for therapeutic purposes remains a challenge, it adds. As such, Vasade aims to use the NIH funding to experiment with various forms, doses, and delivery approaches of miR-199a antagonists in mice.
"These experiments are a prelude to phase II that will involve testing its effectiveness in protection of the heart against ischemic damage," with the ultimate goal of developing both systemically delivered and locally delivered miR-199a inhibitors as "preventive, preconditioning [measures] for the ischemic heart," the abstract states.
The grant project is set to run from Aug. 16 until Jan. 31, 2011, and is worth $132,191.
The second grant was issued to University of California, San Francisco, researcher Vasanth Vedantham to examine the role of the muscle-specific miRNA miR-1 in the cardiac ventricular conduction system.
According to the grant's abstract, Vedantham has "developed and validated a set of tools to be used to study the ventricular conduction system in mouse models." Already, these tools have been used to demonstrate that miR-1 dosage "profoundly affects" the ventricular conduction system's structure and function.
Using the NIH funding, Vedantham will advance this work to test the hypothesis that miR-1 regulates the development and function of the ventricular conduction system by participating in a set of critical gene regulatory networks, the abstract states.
Specifically, Vedantham plans to assess the architecture, cell number, and proliferation rates during the ventricular conduction system's development in mice with altered miR-1 levels, followed by studies of the system's cellular function in the animal models.
"With this integrated picture of the specific ways in which [ventricular conduction system] biology is sensitive to miR-1 levels," Vedantham will work to define the regulatory networks that mediate the system's effects, as well as lay the groundwork for future research into the role of miR-1 and other miRNAs in the cardiac conduction system.
The grant is set to run from Aug. 6 until the end of April, 2015. It is worth $125,010 in its first year.
The final grant went to the University of Chicago's Gene Ho Kim to support his research into miRNAs in cardiac development.
Kim and colleagues have previously discovered that one particular miRNA, miR-130a, is highly expressed in the developing mouse heart and targets a key transcriptional regulator of cardiac development, FOG-2, he wrote in the grant's abstract. "Given the complex signaling requirements and protein dosage sensitivity in cardiac development, I hypothesize that the levels of microRNA-130a may also be important for normal heart development through its action on other key targets."
To study this, he aims to validate the predicted targets of miR-130a relevant to cardiac development in a mouse model over-expressing the miRNA, according to the abstract.
Next, Kim will "determine the mechanism of ventricular wall hypoplasia and embryonic lethality in the … mice through serial histological staining and assessment of cardiomyocyte apoptosis and proliferation," it adds, after which he will elucidate the regulatory elements controlling miR-130a expression by "defining the temporal-spatial pattern of [the miRNA's] expression, as well as performing both in vitro and in vivo functional promoter assays."
Kim's grant began on Aug. 18 and will run until April 30, 2015. It is worth $124,200 in its first year.