CHRI Investigator Feature
Eric Peeples, MD, Assistant Professor in Neonatology, has been named the second CHRI Scholar awardee. This competitive award recognizes early-career faculty at Children’s Hospital & Medical Center and University of Nebraska Medical Center (UNMC) who lead promising research programs in pediatric medicine. As a physician-scientist, Dr. Peeples balances academic research with clinical service in the neonatal intensive care units of both Children’s and UNMC.
Joining the Children’s and UNMC faculty in 2016, after Fellowship at the University of Washington (UW), Dr. Peeples already knew Omaha. He had earned bachelor’s and medical degrees at Creighton University. As an undergraduate he spent three summers working in a research lab at UNMC, investigating the effects of organophosphate poisons on neurotransmitters. Although he found bench science stimulating, the experience prompted a shift in career direction. “The piece that I missed with research was the translation – I really wanted to engage in the clinical side. After my first summer it struck me that I wanted to do medicine. For me, the research interest came first, and medicine came later. But I’ve obviously continued that interest in research and carried it through my whole career thus far.”
Dr. Peeples entered his fellowship at UW with a particular interest in hemodynamics (the study of blood circulation), but was convinced to take a plunge into the intricacies of neuroscience. He teamed up with a physicist who wanted to explore clinical applications of a novel, ultrafast ultrasound technology. “We looked at the small vessel brain perfusion in preterm babies who are at risk for hemorrhage, tying in hemodynamics with the brain. I was appropriately intimidated by brain research because of the sheer complexity. That study helped me get a foot into the world of the brain.” Dr. Peeples’ mentor, Dr. Sandra (Sunny) Juul, played a pivotal role in shaping his research path. He recalls her influence “not only in how to ask the appropriate question and get the projects done, but also in exposing me to the world of neuroscience. Sunny would frequently show me ‘These are the really cool things going on brain research; these are the opportunities that could be there if you want to reach for them.’ And I think it opened my eyes to more of what can be really cool about the intricacies of the brain.”
After returning to Omaha, in the very early stages of developing his research program, Dr. Peeples collaborated on the development of an experimental mouse model which he used to study the role of endogenous stem cells in mending tissue damage after neonatal hypoxic ischemic encephalopathy (HIE), i.e. an injury resulting from oxygen deprivation to the brain. The goal was to treat HIE in baby mice, using drugs to trigger the release of stem cells from bone marrow, so they could migrate to the brain (like a “self-transplant”) and promote tissue restoration. “It did seem to be helpful to the overall development of the treated mice, but we didn’t see any big change in the number of activated stem cells in the brain. So a big question was, ‘How was this having that beneficial effect?’ It’s pretty clear from the literature at this point that most of the effects of transplanted stem cells are paracrine effects, meaning that the stem cells aren’t going into the brain and making new cells; they’re going into the circulation and releasing all kinds of soluble mediators that help out. One of those things is probably extracellular vesicles (EVs). The stem cells can ‘design’ what’s contained inside of EVs and release them based on the ‘help signals’ that they’re receiving from the brain. The additional benefit is that EVs are so small that they can easily pass through the blood-brain barrier.”
Dr. Peeples and his lab then turned their attention to these EVs, the intriguingly versatile messengers released by stem cells, as a possible mode of therapy for neonatal brain injury. Joining with collaborators across the UNMC campus, including Shilpa Buch, PhD (Pharmacology & Experimental Neuroscience) and Guru Pendyala, PhD (Anesthesiology), he has explored what sorts of stem cell “experiences” and properties prepare them to release optimal EVs for the injured brain. Experiments showed that stem cells isolated from mice in the aftermath of HIE released EVs with powerful benefits for recipient mice that had the same injury. Compared with EVs from naïve stem cells, these “pre-treated” EVs conferred greater benefits to brains of recipient mice, i.e. fewer ischemic lesions and fewer cells undergoing programmed cell death. “The next step for us,” Dr. Peeples commented, “is to figure out what is the difference between those two signals, and then, can we harness that?”
The team is searching for microRNA (miRNA) molecule(s), packaged inside the pre-treated EVs, which might be conferring the protective signal. miRNAs modulate expression of individual genes or groups of genes by preventing translation of messenger RNA into protein. In the context of HIE, a protective miRNA might, for example, suppress a gene that promotes inflammation or suppress another one that induces apoptosis. Conveniently, available “Dicer-knockout” stem cell lines can be used to produce batches of “empty” EVs that contain no miRNA. “We can infuse the empty EVs with any miRNA we want,” Dr. Peeples explained. “If we find that the injured brain is lacking miRNA that we believe is protective, we can make EVs that have a lot of that particular miRNA. But if we find that the stem cells have too much of a harmful miRNA, let’s say miRNA-210, which is a big hypoxia regulator, we can actually use an antagonist and infuse that into the EVs to minimize its harmful effects.”
To be sure, there are plenty of hurdles to clear between this research stage and a future point where therapeutic EVs could be administered to newborn babies diagnosed with HIE, like those Dr. Peeples treats in the NICU. Presently there is only one active phase I trial evaluating the use of EVs in a neonatal population (as a treatment for chronic lung disease). Yet, the strategy is powerful and simple enough that Peeples can envision a day when EVs tailored to treat HIE are manufactured as an off-the-shelf medicine for hospitals to keep on-hand, ready for rapid treatment of a new HIE patient. “If we can get something like this to every hospital, it could be administered right after birth and theoretically it would decrease the injury. Because we are unable to anticipate prenatally which infants are at the highest risk for HIE, EVs could provide an effective secondary prevention (comparable to hepatitis B immunoglobulin or tetanus toxoid), allowing for a rapid post-exposure intervention to decrease the injury.”
Since his arrival as an early-stage investigator, Dr. Peeples has been a dedicated supporter of CHRI’s goals to foster faculty career development and world-class research. He invests time each month to coordinate the Pediatric Writing Group, where investigators help their peers refine grant proposals and manuscripts through critical reading and constructive feedback. He emphasizes the importance of supporting faculty who fall in two categories – many clinicians who have little protected time for research and others like himself who have more dedicated resources and time. “The core mission of CHRI is something that is absolutely necessary and something that I think could have huge effects on the makeup of our faculty. It has acted and will continue to act as a recruitment tool especially for young investigators. That is 100 percent what we need, because one of the biggest hurdles that we have is building a ‘quorum’ of mid-career and senior investigators,” so that eventually there will be a more balanced ratio of experienced mentors to early-stage mentees. In addition, “There are a lot of my colleagues who see themselves as pure clinicians who are doing a lot of great academic work, but they don’t always see it as that. Inclusion of more of those colleagues in the projects being performed within the greater CHRI is an important challenge and part of how we build the core membership and people’s sense of investment.”
Over a 3-year period the CHRI Scholar award will support Dr. Peeples’ research supplies and salary, while providing a structured program of mentoring and career development training. In the upcoming year, he plans to use this as a springboard to apply for an NIH Mentored Clinical Scientist Research Career Development Award (K08).
by Matthew Sandbulte, CHRI Grant & Scientific Writer | December 6, 2019