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April 1, 2010
Using sheep as a model, Professor Russ Anthony is shedding new light on what may cause problems in early pregnancies that may lead to placental insufficiency, a leading risk factor for growth-restricted infants.
Russ Anthony is the Hill Professor of Biotechnology in the Department of Biomedical Sciences.
Having worked in reproductive research for more than 30 years, Russ Anthony has had his share of disappointments and knows all too well that results don’t always reflect hypotheses. In the case of Proline-Rich 15, however, he was dead on target.
“For once, one of my experiments worked just like I drew it on the board,” laughed Anthony, who, like most researchers, knows you learn just as much from supposed research failures as you do from successes, but success is sweeter.
In this particular case, using sheep as a model, Anthony’s success is shedding new light on what may cause problems in early pregnancies that may lead to placental insufficiency, a leading risk factor for growth-restricted infants.
Anthony and his research team are interested in understanding the role of PRR15 in early conceptus (the embryo and its extraembryonic components) development and how it impacts critical windows of fetal and placental development. In both humans and sheep, PRR15 has times of peak expression. Anthony theorized that if PRR15 was ablated, conceptus development would be compromised.
The results of his research were published in December 2009 in Biology of Reproduction, the official journal of the Society for the Study of Reproduction.
“The ruminant conceptus undergoes a period of elongation that is required for maternal recognition of pregnancy, prior to attaching to the endometrium,” said Anthony, who is a professor in the Department of Biomedical Sciences Animal Reproduction and Biotechnology Laboratory.
“We saw that expression of PRR15 corresponded to the elongation of the conceptus, rising as the conceptus changed from a disc shape to a long string, so we theorized that PRR15 was important to this critical process of conceptus development.”
In the cell, messenger ribonucleic acids deliver specific information to the cell’s ribosomes to build certain proteins. By effectively knocking out the PRR15 mRNA, researchers could determine the impact of PRR15 ablation on conceptus development. Using vectors (agents of infection) such as lentivirus and adenovirus, short-hairpin RNA encoding cassettes with guide sequences designed to silence specific mRNAs can be delivered to the cells. These shRNAs multiply, and then target and destroy the specific mRNA of interest, in this case PRR15.
An illustration of a hairpin loop from a pre-mRNA..
Anthony’s study showed that none of the embryos treated with the lentivirus expressing short-hairpin RNA against PRR15 elongated – a factor critical to implantation – and most died.
“RNA interference is a new tool that allows us to better define gene function in livestock,” said Anthony. “Methods that were used in mouse models, particularly homologous recombination (genetic recombination), have not been efficient in livestock species. But the development of our understanding of naturally occurring RNA interference holds great potential for effectively knocking down specific gene function and allowing us to see more clearly what happens when particular mRNAs are suppressed.”
While the success and publishing of the PRR15 research work is a milestone, Anthony and his team have many more questions to investigate, including understanding the role of PRR15 and exactly why it is so important to early conceptus development.
Interruptions to conceptus development are not only important to the livestock producers seeking to optimize production, but also to developing a greater understanding of the human conceptus and the role PRR15 plays in embryonic and placental development.
Anthony and his team have several ongoing projects investigating the early stages of placental development. These investigations may help researchers learn what happens in gestation that may lead to low birth-weight babies who are small for their gestational age. In the United States, 8 percent to 10 percent of babies suffer from clinical intrauterine growth restriction. Worldwide, the number is 17 percent. In 80 percent of these growth-restricted infants, the cause is a functional failure of the placenta to grow, develop, and provide biological sustenance to the baby in utero.
“We are not only concerned about the developing infant. In the last 20 years, epidemiologists have been able to demonstrate that infants born at low birth weights have a higher predisposition to coronary heart disease and hypertension,” said Anthony.”
We are finding that fetal organ systems, if not nourished at the right time, can suffer impaired development that can create lifelong health concerns. By improving our understanding of what may lead to fetal and placental problems, we also improve our chances of developing effective interventions that may prevent or predict functional placental deficiencies.”
Some causes of growth-restricted pregnancies, such as smoking, drug abuse, and high altitude, are apparent. But, Anthony noted, many growth-restricted pregnancies are idiopathic cases with no apparent external or environmental cause.
Understanding the role of PRR15 and other genes expressed during early development may provide keys that can help scientists and doctors improve the odds of a healthy pregnancy and a healthy life for all babies.
Originally published in the Biomedical Science Update, Spring 2010.