The National Institutes of Health (NIH) gave The Children’s Hospital of Philadelphia’s Akiva S. Cohen, PhD, a prestigious award in July 2014, signaling its confidence in his research into using an amino acid-based dietary therapy to mitigate the long-term effects of traumatic brain injuries (TBIs).
The R37, or Method to Extend Research in Time (MERIT), award is designed “to provide long-term grant support to investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner,” according to the NIH. Researchers do not apply for the award. Instead, MERIT awardees are chosen by NIH staff and a review board, who make their recommendations based on researchers’ past successes and productivity.
A concussion and TBI expert, Dr. Cohen’s work focuses on the cellular and molecular mechanisms underlying pathologies caused by head injuries. He is studying the use of a “cocktail” of cellular nutrients to address brain damage associated with TBIs.
Approximately 2 million TBIs occur each year in the U.S, with more than 500,000 TBIs suffered by children age 14 years and younger, according to the Centers for Disease Control and Prevention. While many TBIs are milder forms such as concussions, even “mild” brain injuries can lead to long-term health challenges, such as cognitive and emotional issues.
“I am honored and humbled to be nominated and receive a MERIT award,” Dr. Cohen said. “And I am driven even more to determine the alterations in brain function that contribute to cognitive impairment caused by brain injury.”
In late 2014, Dr. Cohen led a study published in Science Translational Medicine that found dietary therapy improved sleep disturbances caused by brain injuries in mice. He theorized that dietary therapy could have broader applications. As he said at the time, “If this type of dietary treatment is proved to help patients recover function after traumatic brain injury, it could become an important public health benefit.”
In addition to the MERIT award, the NIH recently invited Dr. Cohen to serve a two-year appointment as a member of its Center for Scientific Review’s Brain Injury and Neurovascular Pathologies (BINP) Study Section. Along with other experts on the panel, Dr. Cohen will review grant applications submitted to the NIH that are aimed at “understanding mechanisms of neural injury, related vascular abnormalities, and alterations in the blood brain barrier in stroke,” among other topics.
Dr. Cohen joins a very small, exclusive group of CHOP investigators who have received MERIT awards (including the National Institute of Neurological Disorders and Stroke’s R37, the Javits Neuroscience Investigator Award). Currently, only two other CHOP researchers have active MERIT awards — hematologist Gerd A. Blobel, PhD, and hyperinsulinism expert Charles Stanley, MD. Several other investigators, including Tom Curran, PhD, FRS, and Douglas A. Coulter, PhD, received MERIT/Javits support in the past.
The award provides $700,000 over five years for Dr. Goldberg’s research into neuronal circuit-related epilepsy research, with an eye toward developing new epilepsy therapies. It was one of 12 CAMS awarded in July 2014.
A private grant-making organization based in Research Triangle Park, N.C., BWF is “dedicated to advancing the biomedical sciences by supporting research and other scientific and educational activities,” according to its website. “[The CAMS] funding supports individual scientists poised to become leaders in their fields,” said BWF President John Burris, PhD. “These awards are highly competitive, and we look forward to seeing great things happen.”
An attending physician and neuroscientist, Dr. Goldberg studies cellular neurophysiology, large-scale imaging of neuronal network function, and epilepsy mechanisms in experimental models. He is also an assistant professor of Neurology at the Perelman School of Medicine at the University of Pennsylvania.
“I am thankful to the Burroughs Wellcome Fund for this generous grant,” Dr. Goldberg said. “Gaining a greater understanding of how neuronal circuits function will yield insight into how circuit function goes awry in epilepsy. My work focuses on developing novel treatments for epilepsy in preclinical experimental models by targeting dysfunctional elements of epileptic circuits.”
Epilepsy, a brain disorder marked by seizures of varying intensity and type, affects approximately 2 million Americans. While there is no cure for epilepsy, about 70 percent of those who have the disease can control their seizures with medication, according to the National Institute of Neurological Disorders and Stroke.
CHOP has a robust epilepsy treatment and research program. Part of CHOP’s Division of Neurology, the Pediatric Regional Epilepsy Program’s (PREP) team of clinicians, nurse practitioners, and researchers works with families to design personalized treatment plans that best control epilepsy with as few side effects possible.
With the support of the CAMS grant, Dr. Goldberg will continue his work studying basic mechanisms of inhibition in the hippocampal dentate gyrus, a sub-region of the brain that is critical for normal cognitive operations and is dysfunctional in epilepsy.
His next step will be to attempt to correct epileptic circuit dysfunction by manipulating the activity of a subset of neurons called inhibitory interneurons. One aim of the grant involves collaborating with Stewart Anderson, MD, by using inhibitory interneurons derived from embryonic stem cells generated in Dr. Anderson’s laboratory to treat epilepsy in model systems.
The BWF CAMS award follows the publication of a manuscript by Dr. Goldberg and Douglas A. Coulter, PhD, in Nature Reviews Neuroscience examining recent advances in the field of epileptogenesis that could have an impact on epilepsy treatment. In their paper, Drs. Goldberg and Coulter suggest that “a greater mechanistic understanding of circuit function and circuit-level dysfunction in epilepsy will lead to the development of successful and broadly applicable interventions in epileptogenic processes, which remain a primary unmet need in epilepsy therapy.”
The Children’s Hospital of Philadelphia’s Lacramioara Ivanciu, PhD, has received funding to explore a potential alternative strategy for treating hemophilia, an inherited bleeding disorder that occurs in approximately 400 babies a year in the U.S.
The BHAP Early Career Investigator grant was awarded in August 2014 through the Bayer Hemophilia Awards Program (BHAP), which is administered by Bayer HealthCare, a subsidiary of the German pharmaceutical giant Bayer AG. BHAP is a “unique initiative dedicated to supporting innovative research and educational initiatives that benefit people with hemophilia,” according to the program.
A researcher in CHOP’s Division of Hematology, Dr. Ivanciu is focusing on designing new bypass agents for the treatment of hemophilia. Her research deals with the blood coagulation response, and in particular the coagulation factor IX (FIX). An important part of the coagulation system, deficiency in FIX results in hemophilia B, which is most often treated by replacement FIX therapy.
However, FIX replacement therapy is currently not ideal for patients. Because FIX has a short half-life, FIX replacement therapy requires multiple injections and high doses. Dr. Ivanciu hopes her research on bioengineering FIX will result in an improved therapy for hemophilia B.
“The novel FIX variants are expected to have prolonged half-life and efficacy and thus, be more efficient at lower doses,” Dr. Ivanciu said. “This could greatly benefit the patients with hemophilia by reducing the therapeutic dose, an important goal in the replacement therapy.”
Saying she was “very pleased” to receive the award, Dr. Ivanciu noted that its support will allow her “to advance the understanding of bleeding disorders by developing and applying new systems models and therapeutics to these problems.”
Dr. Ivanciu’s findings have appeared in peer-reviewed journals. She recently published two first author papers in Blood that focused on coagulation factors, factor Xa and factor Va. Additionally, she co-authored a paper published in the same journal examining recombinant activated human Factor VII.
Who is not stressed out at one time or another these days? But chronic stress, whether it is from illness, interpersonal relationships, or other social stressors, can have a major impact on the brain and body.
And yet, only some people develop illnesses such as anxiety, depression, and post-traumatic stress disorder (PTSD) in response to chronic stress. Seema Bhatnagar, PhD, an associate professor in the CHOP Research Institute’s Division of Stress Neurobiology is trying to figure out why.
In a new research project funded in August 2014 by the National Institute of Mental Health, Dr. Bhatnagar and colleagues are studying peptides called orexins and their possible link to a person’s resilience or vulnerability to the effects of stress.
“If we could understand better the brain mechanisms that lead to vulnerability to stress, then we could either prevent the effects of stress from happening or help treat individuals who are sick and even try to identify them before they get sick,” Dr. Bhatnagar pointed out.
While other neurochemicals are being studied for their potential role in controlling an individual’s response to stress, Dr. Bhatnagar’s research project is the first to center on orexins. First described by scientists about 17 years ago, orexins are important neurochemicals related to arousal, sleep, vigilance, and feeding. Orexins are made in the hypothalamus, and increasing evidence indicates that orexins play a role in people’s ability to be alert and respond to stressful stimulus.
Dr. Bhatnagar’s research team is studying the potential link between orexin levels and the different coping strategies used by young adult male rats exposed to repeated social defeat. When exposed for a week to a larger, more aggressive and territorial rat, some rats that show anxiety and depressive-type behaviors will give up quickly and assume a defeat posture. Other rats are more active in resisting the larger rat and appear more resilient. Based on preliminary data, it appears that the resilient rats exhibit lower orexin levels.
“If we’re correct that orexins are important in vulnerability and resilience, you could imagine developing drugs that inhibit orexin release could be used in a situation of chronic stress or trauma to decrease arousal and maybe prevent the effects of stress from happening,” Dr. Bhatnagar said.
The research team will use an emerging technology called DREADDs (designer receptors exclusively activated or inhibited by designer drugs) to modulate orexin release in the rats. These viral vectors, which have mutated receptors that are either stimulatory or inhibitory, are injected into the brain where they enter the orexin cells. Researchers can then target the viral vectors through a drug administered peripherally to stimulate or inhibit the orexin cells.
Researchers will observe whether this manipulation of the orexin cells affects the rats’ behavior during periods of stress and whether it is possible for vulnerable animals to become more resilient, and vice versa.
Initial data the researchers gathered on orexins came from a study supported by the Defense Advanced Research Projects Agency. That early research examined neural substrates of arousal and, in collaborations with the Philadelphia VA Medical Center, focused on clinical studies of military service members with PTSD.
Dr. Bhatnagar also is a co-primary investigator of a National Institutes of Health-funded study on adolescent stress that eventually could provide insights into the specific involvement of orexins.
“There’s very clear literature that stress in early life has long-lasting impact for producing depression and anxiety,” Dr. Bhatnagar said. “We don’t know if the orexin system is important in mediating resilience or vulnerability to early life stress as it develops across the lifespan. We hope to gather enough data to expand our research to look at the pediatric and adolescent periods.”
Allergies are an uncomfortable fact of life for many children and adults around the world. In a new study funded by the National Institute of Allergy and Infectious Diseases (NIAID), researchers at The Children’s Hospital of Philadelphia are hoping to figure out how to activate certain enzymes in the cell to prevent or treat allergic disease.
Chronic allergic disorders affect millions of individuals worldwide, and their frequency is increasing, especially in children and adults living in the U.S. Too often, multiple allergic diseases, such as asthma, food allergies, atopic dermatitis, and some gastrointestinal disorders can occur in a single patient.
Researchers are studying the underlying biological features that could be common from one allergic disease to another. They are particularly interested in how two small adapter proteins, known as Ndfip1 and Ndfip2, activate enzymes called E3 ubiquitin ligases. The solution to this cellular puzzle could play an important role in preventing chronic allergies.
“A small protein, ubiquitin, is the basis for the garbage disposal system of the cell,” explained Paula M. Oliver, PhD, who is part of the Cell Pathology Division at CHOP and an associate professor of Pathology and Laboratory Medicine at the Perelman School of Medicine at the University of Pennsylvania. “When ubiquitin is tagged to a protein, one of the outcomes can be degradation of that protein. So it is the cell’s way of removing unneeded proteins. When you don’t get rid of those proteins, you can get allergic disease.”
Dr. Oliver’s research team is using genetically engineered mice to study E3 ubiquitin ligase function. The researchers previously found that mice in which a particular ligase — aptly named ITCH — cannot function develop an allergic dermatitis-like phenotype that causes them to scratch. The mice also develop an inflammation of the lungs reminiscent of asthma and gastrointestinal disorders that have features similar to food allergies.
Dr. Oliver’s current project, which received NIAID funding in July 2014, builds on previous findings. The research team already has figured out how E3 ubiquitin ligases remain inactive in a closed, “off” position until Ndfip1 and Ndfip2 seem to open them up and turn them “on.”
“We took the next step in thinking that maybe there are some ways of forcing that to happen and that we might design therapeutic strategies to turn on these enzymatic pathways in cells to prevent or treat allergic disease,” Dr. Oliver said.
The ability to turn on cells’ enzymatic pathways would be an exciting alternative to current treatments for allergic disease that globally shut down immune function, Dr. Oliver noted. This potential alternative would disarm only the component of the immune system that drives allergic responses, without affecting its ability to respond to viruses or pathogenic bacterial infections, she explained.
Dr. Oliver’s research team will work to develop therapeutic methods to regulate the activation of E3 ubiquitin ligases. Specifically, the researchers will design small penetrating peptides aimed at catalyzing the transfer of ubiquitin to a substrate protein in the cell. They also will partner with a local company on a second possible approach, creating small molecule activators of the ligases.
“We are quite sure that there are other mechanisms that might control these things as well, so we’re continuing to understand exactly how this happens,” Dr. Oliver said. “We’re also trying to understand what the substrates are that need to be gotten rid of, because that might tell us more about how allergic diseases start or which proteins are important in driving allergic diseases.”
In addition to the NIAID funding, Dr. Oliver’s work is supported by the American Asthma Foundation.
Many parents would love to find a better treatment for childhood obstructive sleep apnea syndrome (OSAS) than surgically removing their child’s tonsils and adenoids. While an adenotonsillectomy, currently the primary therapy for OSAS, is relatively safe, about 3 percent of children have significant post-operative hemorrhaging, and other complications can also occur.
Researchers from the Sleep Center launched the “Steroids for Pediatric Research in Kids (SPARK)” trial in September 2014 to investigate the use of nasal corticosteroids as a possible treatment for OSAS. According to Dr. Marcus, OSAS is seen in 2 to 4 percent of children, but is greatly underdiagnosed.
Usually, a blockage from enlarged tonsils or adenoids obstructs the child’s breathing and disrupts his or her sleep in what is known as apneas and hypopneas. If OSAS is left untreated, it can result in significant complications, ranging from behavioral problems and sleepiness in mild-to-moderate cases, and cognitive abnormalities, high blood pressure, and growth disturbances in more severe cases.
Dr. Marcus said she learned from being a co-investigator on a previous childhood OSAS study that families want better treatments and more therapeutic choices. “Most families were hoping to hold off on surgery because they were scared,” she pointed out. The earlier study, the Childhood Adenotonsillectomy Study for Children With OSAS (CHAT Study), specifically compared the effectiveness of surgery vs. watchful waiting for OSAS.
Nasal steroids may prove to be a viable alternative treatment for pediatric OSAS. Over the past few years, several small, short-term studies reported nasal steroids offered overall benefits for mild OSAS cases. But the studies did not include more severe cases of OSAS, and the results varied tremendously among individuals.
Further, the American Academy of Pediatrics clinical practice guidelines for the diagnosis and management of OSAS, which were issued in 2012 and chaired by Dr. Marcus, included nasal steroids as a treatment option. However, there was not enough evidence about the nasal steroids’ effectiveness for the academy to provide a strong recommendation.
With funding from the National Heart, Lung, and Blood Institute, Dr. Marcus and colleagues launched the SPARK study to increase knowledge about the effect of nasal steroids and to identify which subgroups of patients with OSAS are most likely to benefit. For example, the research team will determine if children with asthma and/or atopy respond better to nasal steroids. Another subgroup they will focus on is African-American children because strong data from the CHAT Study and others found they have more severe OSAS and do not respond as well to surgery.
Sophisticated genetic tests used in the SPARK study will help researchers further characterize responders vs. non-responders. The double-blind, randomized control trial also will assess nasal steroids’ duration of action and possible side effects, which for a small number of children can include growth problems, ocular abnormalities, and adrenal suppression.
Other concerns will also be addressed. “Does the disease recur if you stop nasal steroids?” Dr. Marcus asked. “Is it cured forever? Do you keep doing sleep studies? If kids are on the steroids long-term, are you likely to see complications?”
In order to answer those questions, children will be randomly chosen to receive either nasal steroids or a placebo for three months. After three months, those receiving the nasal steroid will be re-randomized to receive either ongoing steroids or a placebo for another nine months.
The multidisciplinary study team will include investigators from general pediatrics and several specialty areas including sleep medicine, endocrinology, ophthalmology, allergy, and otolaryngology. The team’s goal is to randomize 156 participants from these diverse practice settings.
“I’m hoping we’ll find a nonsurgical alternative for some children but that it also will lead to more personalized medicine,” Dr. Marcus, who is also a professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “One treatment does not fit all.”