The National Institutes of Health this month awarded three grants to academic researchers investigating the roles of microRNAs in cocaine addiction, liver development and disease, and sickle cell diseases.
The first grant supports a two-year project headed by Rockefeller University research associate Anne Schaefer, who seeks to build on the discovery that the “development of addiction is associated with aberrant expression of miRNAs,” according to the grant’s abstract. “We will test whether normalization of … miRNA expression, altered by cocaine treatment, will normalize brain function and cure addiction” in mice.
The second grant was awarded to Joshua Friedman, an associate professor of pediatrics at the Children’s Hospital of Philadelphia, to fund a five-year effort to examine the functions of certain liver-specific miRNAs, including miR-30a, and determine whether they play a role in biliary atresia, a rare neonatal condition in which the common bile duct is either obstructed or absent, a defect that can lead to liver failure.
“These studies have the potential to shed light on biliary atresia pathogenesis and may result in new treatments,” the grant’s abstract states. Further, the work is expected to “reveal novel regulatory pathways in normal liver development and in biliary atresia.”
The third grant, which was issued to Duke University assistant professor Jen-Tsan Ashley Chi, funds efforts to examine how erythrocyte miRNAs contribute to sickle cell diseases and susceptibility to malaria.
With the support of the two-year NIH grant, this work “will result in a better understanding of the role of miRNAs in determining erythrocyte phenotypes in hemoglobinpathies and infectious diseases, as well as provide better therapeutic strategies for [sickle cell diseases] and malaria infection,” according to the grant’s abstract.
Amid recent findings that the development of addictive behavior, at least in mice, is associated with stable changes in gene expression, researchers have raised questions about the exact role genes and their regulators play in addiction, Rockefeller’s Schaefer wrote in her grant’s abstract.
“We found that establishment of cocaine addiction in mice is associated with expression changes of numerous miRNAs in the striatum. Given the potent role of miRNAs in regulation of gene expression, we hypothesize that cocaine-regulated miRNAs contribute to the establishment of the gene-expression network that supports addiction.”
“We found that establishment of cocaine addiction in mice is associated with expression changes of numerous miRNAs in the striatum,” she noted. “Given the potent role of miRNAs in regulation of gene expression, we hypothesize that cocaine-regulated miRNAs contribute to the establishment of the gene-expression network that supports addiction.”
To evaluate this hypothesis, Schaefer plans to identify murine miRNAs that are either up-regulated or down-regulated by cocaine. “Inactivation of miRNA that are induced by cocaine treatment will be achieved by injection of … specific miRNA inhibitors into the striatum,” the abstract states. “In turn, striatum-specific normalization of [miRNAs] that are suppressed by cocaine will be achieved by using miRNA-expressing adeno-associated virus.”
According to Schaefer, identifying specific miRNAs that play a role in the development and maintenance of cocaine addiction “may help to reveal molecular networks controlling dopamine signaling in health and disease,” while the development of agents that can target addiction-associated miRNAs may lead to the development of new treatments for addiction.
Despite advances in the miRNA field, “virtually nothing is known regarding the function of miRNA in liver development and disease,” according to Friedman’s grant abstract. At the same time, efforts to identify the cause of biliary atresia, which is typically treated through liver transplantation, remains unknown.
Aiming to fill in this gap, he wrote that he and his colleagues have identified a set of miRNAs whose expression rises significantly during hepatobiliary differentiation and morphogenesis, and are currently localizing their expression using in situ hybridization.
“This approach has yielded the first examples of developmentally regulated miRNAs in the embryonic liver,” including miR-30a, which is expressed in the ductal plate and bile ducts and is believed to be required for biliary development, the abstract notes.
Under the NIH-funded project, Friedman will investigate the function of miR-30a and other hepatic miRNAs, as well as their molecular targets, using cell-culture model of liver differentiation, the abstract states. A mouse model will be used to test the developmental function of miR-30a and other selected miRNAs in vivo.
Having already found that miR-30a is highly expressed in “the proliferating bile ducts characteristic of biliary atresia,” the grant project will also characterize the expression of all miRNAs in both diseased and normal tissue, as well as in a mouse model of the condition.
Susceptible to Infection
While erythrocyte diseases such as anemia and malaria persist, “our understanding of these diseases is rather limited,” Duke’s Chi wrote in his grant’s abstract. “For example, while the genetic cause of sickle cell diseases and the positive selection of them imposed by malaria infection has been long established, much remains to be learned about how [sickle cell disease] erythrocyte phenotypes contribute to diverse clinical manifestations and to altered interaction with malaria parasites.”
According to Chi, he and his colleagues have found that mature human erythrocytes contain abundant miRNAs. “Given the potential regulatory roles of miRNAs during erythropoiesis, the erythrocyte miRNA pool is likely to contain important biological information, indicate developmental history, and show biological phenotypes of erythrocytes.”
Additionally, a number of miRNAs have been found to be translocated in malaria parasites during infection in order to disrupt the growth and replication of the parasites, the abstract notes.
In the grant project, Chi aims to identify erythrocyte miRNAs whose expression can be used to distinguish between normal erythrocytes, various sickle cell disease subtypes, and anemia disorders, which will hold diagnostic value for anemia disorders. The project also will involve determining whether the differences in miRNA composition among different types of erythrocytes contribute to their differing susceptibility to malaria infection.