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NIH Awards More than $1M to Fund Cardiovascular-Related miRNA Research

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By Doug Macron

The National Institutes of Health this month handed out more than $1 million in grants to support the work of three researchers investigating the role of microRNAs in cardiovascular disorders and health.

The first grant was awarded to Saint Louis University's Angel Baldan to fund his examination of miRNAs in sterol and lipoprotein homeostasis.

Last year, Baldan and his colleagues reported that miR-33 is encoded within sterol regulatory element binding protein 2, whose increased expression is associated with a reduction in low-density lipoproteins. Additional data from his lab shows that targets of the miRNA include ABCA1, a transporter critical for HDL lipidation and reverse cholesterol transport, and ATP8B1, a phospholipid flippase linked to intrahepatic cholestasis, he wrote in his grant's abstract.

Hypothesizing that miR-33 controls key aspects of sterol mobilization, bile excretion, and high-density lipoprotein metabolism, he aims to determine its role on cholesterol, bile, and lipoprotein homeostasis. Further, because statins increase SREBP-2 levels in the liver, and because these drugs induce the miRNA's expression, “we speculate that statin-treated patients will have elevated levels of miR-33 and persistent down regulation of ABCA1 and ATP8B1 by miR-33,” according to the abstract.

With the NIH funding, Baldan and colleagues specifically aim to determine the role of miR-33 in hepatic sterol homeostasis in primary hepatocytes and in mice by measuring the effect of its over- or under-expression on lipoprotein secretion and bile excretion.

They will also examine the effects of altered macrophage miR-33 expression levels on cholesterol mobilization and the progression of atherosclerotic lesions in mice, and see whether systemic silencing of the miRNA is atheroprotective by “characterizing the composition and biological properties of HDL” and by evaluating whether miR-33 antagonists synergize with the effects of statins.

“There are still multiple aspects of cholesterol homeostasis, cholestasis and atherogenesis that remain obscure,” Baldan wrote. “Our data suggest that the cholesterol-miR-33 axis modulates key aspects of hepatocyte and macrophage biology. We anticipate that our studies will provide new clues into the complex regulatory networks that control intracellular cholesterol levels, bile excretion, and circulating lipoproteins.”

His grant runs from May 1 until then end of March 2016, and is worth $375,000 in its first year.

Eastern Kentucky University's Rebekah Waikel received the second grant, which will support her research into estrogen-mediated regulation of miRNAs in cardiac remodeling.

“Within the last few years, research has shown that miRNAs are highly regulated during cardiac hypertrophy and are capable of regulating cardiac remodeling,” she wrote in her grant's abstract. However, there has been no comparison of sex-dependent cardiac miRNAs despite evidence of sex-specific differences in how the heart responds to certain insults, such as hypertension.

In a pilot study, she and her colleagues found that certain miRNAs are differentially regulated in male and female mice, both at baseline and after being stimulates by cardiac hypertrophy, the abstract states. As such, Waikel aims to test whether “male/female differences in susceptibility to adverse cardiac structural remodeling are due to estrogen mediated regulation of miRNAs.”

Specifically, her research aims to identify miRNAs that are regulated by estrogen in cardiomyocytes during cardiac remodeling; determine the cell-signaling mechanisms by which estrogen regulates miRNAs; and establish a functional role for the miRNAs in estrogen-mediated inhibition of cardiomyocyte hypertrophy.

“Ultimately, the goal of this research is to improve our understanding of the sex specific regulation and downstream targets of miRNAs during cardiomyocyte hypertrophy to improve diagnosis and treatment” of left ventricular hypertrophy, the abstract notes.

Her grant runs from May 15 until April 30, 2014. It is worth $389,445 in its first year.

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The final grant was awarded to Mount Sinai School of Medicine researcher Yong Zhao to investigate the function of miR-1-2 in cardiac-conduction system development and maintenance.

“Disorders of the cardiac-conduction system can cause arrhythmias, which [are] the major causes of sudden cardiac death in ... patients with cardiovascular diseases,” he wrote in his grant's abstract.

In previous studies, Zhao found that miR-1-1 and miR-1-2 are enriched in the cardiac conduction system progenitor cells during cardiogenesis, and that both remain highly expressed throughout the system during development and in adulthood, according to the abstract.

Over-expression of miR-1-2, however, triggered bradycardia and arrhythmias in mice, while mice that are missing the miRNA exhibit bradycardia and develop cardiac-conduction defects after birth despite the lack of “obvious cardiac structural abnormalities.”

Zhao hypothesizes that miR-1-2 plays an important role in restricting the cell cycle progression of cells within the cardiac-conduction system and that it is critical to proper differentiation and maintenance of various cardiac-conduction system lineages, the abstract notes.

As such, he and his colleagues aim to determine the role of miR-1-2 in regulating specification and proliferation of the cardiac-conduction system. Specifically, they will examine “how miR-1-2 establishes a precise level of calcium signaling, ion channels, and connexins during differentiation and maintenance of the system; and identify affected genetic pathways upon loss of miR- 1-2 that are critical for [its] development and maintenance.”

His, which is worth $413,325 in its first year, grant runs from May 2 until the end of April 2016.


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