michael oreilly           Michael O’Reilly, PhD

Department of Pediatrics

Laboratory Support Center Awardee

 

Dr. O’Reilly received a Laboratory Support Center Award in 2007 for his proposal, “Genome profiling of innate-immune privileged lung epithelial cells.” The research funded by this RFA has led to advances in the study of how premature oxygen exposure affects children throughout life. It has also led to the creation of the Perinatal and Pediatric Origins of Disease (PPOD) Program in the Department of Pediatrics. The PPOD Program will be run by Dr. O’Reilly.

Dr. O’Reilly’s involvement with the CTSI began when his research was becoming translational. He says he saw the opportunity to use the CTSI’s resources in order to help move his research forward. At the time the Laboratory Support RFA was announced, Dr. O’Reilly was considering doing microarrays using the Functional Genomics Center. His lab had done one set of microarrays, but they were very expensive. Dr. O’Reilly says using the core facilities with the CTSI’s laboratory support allowed him to complete those studies.

Research Focus: Why do children born prematurely have increased risk for respiratory viral infections?

Dr. O’Reilly’s research is focused on trying to understand why children born prematurely have increased risk for respiratory viral infections. One of the biggest issues of premature birth is that the lung is not ready to breathe the air the child is exposed to when born. When this happens, the child must be given extra oxygen in order to survive. The combination of the room air and the extra oxygen causes the lung to develop abnormally, which renders it unable to deal well with respiratory viruses.

Treating the effects of premature birth is a life-long process. There are repeated doctor visits, hospitalizations, and the complications of dealing with disorders or diseases like asthma or Bronchopulmonary Dysplasia, a chronic form of lung disease frequently seen in preterm infants with very low birth weight. In 2005, the National Heart Lung Blood Institute (NHLBI) estimated the annual financial cost of treating prematurity to be $26.2 billion. $2.5 billion of that total was designated to treating Bronchopulmonary Dysplasia, which requires supplemental oxygen treatment in premature babies. Dr. O’Reilly says these treatments, as well as other therapies like vaccines, are similar to giving eyeglasses to people who have difficulty seeing. “It helps, but it hasn’t really solved the disease – it has just attenuated the disease,” he said.

Click here for a video of Dr. O’Reilly explaining the eyeglasses analogy

In order to develop therapies to improve the long-term health of children born prematurely, Dr. O’Reilly says he first needs to understand why being born prematurely affects the lung’s ability to properly protect against infection. This was the goal of the project funded by the Laboratory Support Center Award.

The Proposal: “Genome profiling of innate-immune privileged lung epithelial cells”

Dr. O’Reilly’s project focused on identifying genes that were differently expressed in two populations of cells, where one of those populations was depleted in lungs that had been exposed to high levels of oxygen. Dr. O’Reilly says he needed to know what these cells made because it could indicate what was deficient in the lung.

Click here for video of Dr. O’Reilly explaining his CTSI pilot program proposal

In order to determine this, Dr. O’Reilly isolated the two populations of cells and ran gene arrays on each. By looking for the expression of every gene in these cells and comparing them to each other, he found that only 0.5% of all the genes were differently expressed in both populations. Dr. O’Reilly said he targeted a set of these genes and attempted to find relevance in an experimental mouse model that examined how oxygen made the lung more sensitive to infection with respiratory viruses like influenza. He studied two groups of mice: mice born into room air and mice that were given high oxygen at birth. After allowing the mice to grow up, he gave them respiratory viruses. He found that the mice born into room air became sick and then recovered, but the mice who were given high oxygen at birth became sicker than the first group and did not recover as efficiently. After further study, Dr. O’Reilly determined that the depleted cell population was not only missing in the mice exposed to high oxygen, but that those cells actually made an antiviral gene that blocked viral replications.

“So now we had a lung that was deficient in a cell that prevented viruses from replicating in the lung,” Dr. O’Reilly said. “What we wanted to do was take that information and move it forward by restoring and rescuing the phenotype.”

Dr. O’Reilly and a colleague then developed a tool that delivers the depleted gene back into the lung. As a result, it is possible to restore high level expression of this gene, essentially replacing what the cell was supposed to be producing.

“In doing so, now we’ve actually rescued the mice, much like you’d do with a vaccine. The mice don’t get as sick anymore,” Dr. O’Reilly said. “Now we have a new potential candidate to study in children that are born prematurely and we can ask, ‘is this the same gene or is this population of cells deficient? And if it is, can we use these kinds of tools that we’ve started to develop in experimental models to treat children in the future?’”

This study was recently finished and is about to be sent out for peer review.

“We think we really stumbled onto something that’s going to have a lot of translational merit,” Dr. O’Reilly said. “Hopefully, it will help us solve what’s going on with kids that are born prematurely.”

Translational Research: Dialogue across disciplines

Dr. O’Reilly says the next step in his research is to try to understand a spectrum of disorders associated with prematurity and oxygen exposure. It is well known that children born prematurely have deficits in lung and immune function, difficulty dealing with respiratory viruses, and increased risk for asthma. However, recent studies in Australia have shown that children born prematurely have high risk for high blood pressure as well. Other studies show an increased risk for retinopathy, and also neurodevelopmental delay, which often requires children to have extra assistance in the classroom.

Dr. O’Reilly is collaborating with several faculty members in order to gain a better understanding of what causes these disorders. Dr. Deborah Cory-Slechta in Environmental Medicine is studying the cognitive effects of the brain in mice exposed to high oxygen at birth. She has concluded that these mice have deficits in locomotor activity, which suggests that their brains might be wired differently. In addition, Dr. Paige Lawrence in Environmental Medicine has helped Dr. O’Reilly develop the influenza model. Furthermore, Dr. David Dean in Pediatrics and Neonatology has developed a novel method to restore gene expression in the lungs of mice. Dr. O’Reilly is also working with researchers interested in fibrosis because the cells he has identified may play a role in protecting against this scarring disorder.

“Essentially, it’s been able to open up a lot of doors for us by identifying this set of genes in this small population of cells,” he said of the collaborations.

The joint efforts have also led to additional funding. The preliminary data generated from the research supported by the Laboratory Support Center Award led to an individual research grant (R01) from the NIH. The R01 allows the O’Reilly Lab to move forward with the studies on how oxygen affects the aforementioned small population of cells. In addition, Dr. O’Reilly and Dr. Paige Lawrence received a second R01 to study the antiviral properties of this gene (which supports Dr. Lawrence’s interest in studying flu).

“One of the nice things about working at Rochester is that it’s a small enough place to not only go between the CTSI where I can do pilot projects and have interface with using their laboratory support stuff, but I can also walk into the Department of Pediatrics and I can talk to my clinical colleagues.”

Dr. O’Reilly says going from the bench to the bedside keeps him true to form because he can ask if what he is studying will indeed have impact in humans. For instance, his interactions with colleagues in the Department of Environmental Medicine have posed the question of whether children born in major cities with higher levels of urban pollution will be more or less at risk to disorders associated with prematurity. He says he can also walk into a basic science department like Biochemistry and ask researchers studying DNA damage and repair how oxygen affects DNA, if cells respond to damage in DNA because of oxygen, and if that is causing the changes seen in the lung.

“I think it’s an exciting place to be because I can actually go from the bench to the bedside and back again and I can talk to a bunch of different people very easily,” Dr. O’Reilly said. “That’s one of the pluses about staying here in Rochester to do this because you can have the CTSI across the street from basic science.”

Dr. Nina Schor, Chair of the Department of Pediatrics, agrees. She says the CTSI has changed the culture of the University of Rochester Medical Center.

“It really allowed us to dare to think across traditional lines,” Dr. Schor said. “It opened as an institutional policy rather than as an exception to a rule, the dialogue between the clinic and the laboratory. That, to me, really has been a hallmark of the recent advances that we’ve had in medicine. I think every place where we’ve had an advance has come from a dialogue between the researchers and the clinicians.”

Click here for video of Dr. O’Reilly and Dr. Nina Schor explaining the Perinatal and Pediatric Origins of Disease Program

Click here for video of Dr. O’Reilly and Dr. Nina Schor explaining the benefits of working with the CTSI

A Personal Touch: “This may be a reason I’m called to do this – to help my family”

“There’s always a philosophy of why do you do research? I thought about this a lot and we become scientists because we are generally curious people and we want to know how the system works.”

Dr. O’Reilly’s interest in studying prematurity began during his training in the 1980’s. His mentor was interested in surfactant, which is a protein lipid mixture made by the lung. Surfactant allows the lung to open and expand more readily and deliver oxygen more efficiently.

“I still remember being a graduate student when the fellow came running back with the first clinical sample of surfactant that they put into a child who was blue, because they couldn’t get enough oxygen in the lungs,” Dr. O’Reilly said. “It expanded [the child’s] lungs so much, they couldn’t turn the oxygen saturations down fast enough because the child had turned pink so quickly.”

“It saved lots and lots of lives and now we’re dealing with trying to do the follow-up, basically. We saved your life being born prematurely, but now how can we improve the quality of life later on?”

Dr. O’Reilly says the research to which he and thousands of other contributed led to the development of therapies which now serve as standard of care for babies born prematurely: they receive reduced levels of oxygen, milder ventilation, and are treated with surfactant.

“20 years later, I’m a scientist studying how cells respond to oxygen – the same oxygen we worry about because we still have to give oxygen to these preemies – and my son, Thomas, was born prematurely by about seven weeks,” Dr. O’Reilly said.

Thomas was treated in the NICU at Strong Memorial Hospital by Dr. O’Reilly’s colleagues who also study surfactant biology. Fortunately, Thomas did not need high levels of oxygen or excess surfactant.

“I became very intrigued by the concept of what happened 20 years earlier, where I was being trained by somebody interested in surfactant. Now, watching children today being treated with surfactant in the pods around me – around my son, in particular – and I became very interested in what’s going to happen to these children as they grow up, and in particular, what’s going to happen to my son.”

As a result, Dr. O’Reilly then decided to move his research in the direction of neonatal oxygen exposure. His focus is on how oxygen in the early stages of lung development can permanently reprogram how the lung and other organs function late in life.

“I’m excited to actually participate in it because every day I go home and I have to look at my son and I have to say to myself, 'did I do a good job at work today and how could this help Thomas?’”

Dr. O’Reilly’s second child, Kathryn, was also born prematurely.

“This may be a reason why I’m called to do this – to help my family, but also to help all the other children that we now treat all the time so that they can have as best of a possible life in the future,” Dr. O’Reilly said. “As some of my colleagues say, ‘you’ve spent the past ten years studying oxygen simply to get to where you are now.”

Click here for video of Dr. O’Reilly explaining why he believes that studying oxygen is his calling

Click here to visit Dr. O’Reilly's Lab page: http://www.urmc.rochester.edu/pediatrics/research/oreilly-lab/

Related Publications

Child health, developmental plasticity, and epigenetic programming.
Hochberg Z, Feil R, Constancia M, Fraga M, Junien C, Carel JC, Boileau P, Le Bouc Y, Deal CL, Lillycrop K, Scharfmann R, Sheppard A, Skinner M, Szyf M, Waterland RA, Waxman DJ, Whitelaw E, Ong K, Albertsson-Wikland K.
Endocr Rev. 2011 Apr;32(2):159-224. Epub 2010 Oct 22. Review.

Environmental factors and developmental outcomes in the lung.
Kajekar R. Pharmacol Ther. 2007 May;114(2):129-45. Epub 2007 Feb 24. Review.

Strategic plan for pediatric respiratory diseases research: an NHLBI working group report.
Castro M, Ramirez MI, Gern JE, Cutting G, Redding G, Hagood JS, Whitsett J, Abman S, Raj JU, Barst R, Kato GJ, Gozal D, Haddad GG, Prabhakar NR, Gauda E, Martinez FD, Tepper R, Wood RE, Accurso F, Teague WG, Venegas J, Cole FS,
Wright RJ. Proc Am Thorac Soc. 2009 Jan 15;6(1):1-10.

Neonatal hyperoxia causes pulmonary vascular disease and shortens life span in aging mice.
Yee M, White RJ, Awad HA, Bates WA, McGrath-Morrow SA, O'Reilly MA.
Am J Pathol. 2011 Jun;178(6):2601-10. Epub 2011 May 6.

Neonatal oxygen adversely affects lung function in adult mice without altering surfactant composition or activity.
Yee M, Chess PR, McGrath-Morrow SA, Wang Z, Gelein R, Zhou R, Dean DA, Notter RH, O'Reilly MA.
Am J Physiol Lung Cell Mol Physiol. 2009 Oct;297(4):L641-9. Epub 2009 Jul 17.

Neonatal hyperoxia enhances the inflammatory response in adult mice infected with influenza A virus.
O'Reilly MA, Marr SH, Yee M, McGrath-Morrow SA, Lawrence BP.
Am J Respir Crit Care Med. 2008 May 15;177(10):1103-10. Epub 2008 Feb 21

Full publication listing is available here : http://www.urmc.rochester.edu/pediatrics/research/oreilly-lab/publications.cfm

 

NIH Funding Acknowledgement ** Important ** All publications resulting from the utilization of CTSI resources are required to credit the CTSI grant by including the NIH FUNDING ACKNOWLEDGEMENT and must comply with the NIH Public Access Policy.