Tom Belle Davidson, M.D. Assistant Professor of Pediatrics Division of Pediatric Hematology/Oncology Joyce Wu, M.D. Associate Professor Division of Pediatric Neurology
Childhood epilepsy is a particularly disabling group of chronic disorders. With a 1-percent incidence of epilepsy in the general population, about 50 percent begins in the pediatric years (18 and younger). While the incidence is four-fold that of breast cancer, the 2011 National Institutes of Health funding for pediatric epilepsy was less than one-tenth of that for breast cancer. Furthermore, in a significant 25-30 percent of children, their epilepsy cannot be controlled with anticonvulsants, which means about a half-million youngsters in the United States continue with frequent seizures despite multiple concurrent medications. In addition to disabling seizures, these children often have other epilepsyrelated conditions, such as cognitive impairment and autism, a triple threat that takes an emotional and financial toll on families, as well as schools and society. Despite the introduction of multiple new anticonvulsants over the last decade, the proportion of intractable epilepsy has remained relatively unchanged.
Unfortunately, the causes of medically refractory epilepsy remain largely unknown. A reliable biomarker for epileptogenesis development of epilepsy) that is able to assess, monitor, and even predict the condition is needed; the molecular basis underlying this marker will open the door to new treatment. High-frequency oscillations (HFOs) have emerged as such a potential biomarker. First seen in animal models, HFOs are an ultra-fast brain electrical activity (100-500 Hz), which is localized in the seizure onset zone and predicts which animals will develop epilepsy. Findings from our group advanced this field by first finding HFOs in children with epilepsy. We also were the first to detect HFOs throughout the brain; they were previously limited to one particular structure. Compared to HFO detection with invasive surgical implants inside patients' heads for days to weeks as part of their epilepsy surgery evaluation, our findings significantly reduced that time to about 10 minutes just prior to resection in the operating room, without the risky surgical implantation. We also correlated the complete surgical resection of HFOs with seizure freedom, probably the most resounding feature of such a biomarker.
Our current plan to expand the concept of HFOs as a biomarker is two-fold: 1) to further establish HFOs as a spatially localizing biomarker of the epileptogenic zone, ultimately leading to noninvasive localization with scalp electroencephalographs (EEGs); and 2) to establish HFOs as a temporally predictive biomarker of epileptogenesis, by correlating its presence with later-life epilepsy in preepileptic high-risk children due to birth hypoxia, traumatic brain injury, and tuberous sclerosis complex (formation of tumors in various organs). Additionally, the first objective includes "live" HFO interpretation in the operating room, which will enable brain tissue resected during surgery to be studied, potentially leading to a better understanding of epileptogenesis and new antiepileptic drug design. Both objectives hold promise for future clinical trials for better surgical mapping and potential disease-modifying therapy to prevent epileptogenesis altogether, not merely stopping seizures with anticonvulsant medications. HFO detection requires special equipment and recording parameters, and the analysis is 10 times more time and labor-intensive than traditional EEGs. Thus, both personnel and the EEGs themselves depend heavily on research dollars. Support from Today's and Tomorrow's Children Fund will greatly empower us to move forward on these research objectives, which may establish HFOs as a noninvasive, spatially localizing, and temporally predictive biomarker for pediatric epilepsy - unimaginable just a decade ago.
Julian Martinez-Agosto, M.D., Ph.D. Assistant Professor Department of Human Genetics and Department of Pediatrics
Autism and cancer are the most common causes of illness in children. One out of every 110 children will be diagnosed with autism, and cancer is the leading cause of death in those aged one to 14. Both conditions have been increasing in incidence over the past decade.
Autism can be inherited; siblings of children with this condition are 19 percent at risk of also having it, often because of delays in diagnosis. While recent advances in diagnosis and treatment have enhanced developmental outcomes, the causes for autism remain largely elusive. The study of rare genetic conditions with signs of autism, however, provides some insight. One group of genetic entities that can present with autism is overgrowth syndromes. They are characterized by large size at birth, excessive postnatal growth, and increased weight, length, and/or head circumference for age and also are associated with an increased risk of specific solid tumors and leukemia. A late diagnosis may cause affected children to develop tumors that are too advanced for treatment to be effective. In this sense, a prompt diagnosis could have a significant positive impact.
While the causes in a limited number of cases have been revealed, the genetic basis for the vast majority is unknown. Our laboratory studies focus on genetic conditions in which children experience overgrowth (their bodies grow faster than their peers'). A subset of these children have autism and large head-size. Based on this knowledge, we have developed a clinical website that provides related information to parents of such children and promotes their evaluation at UCLA. We now use the most novel technologies to identify the genetic changes in order to expand our understanding of the causes of autism and, in some cases, predisposition to cancer. Support from Today's and Tomorrow's Children Fund will enable us to use "Next Generation Whole Exome" sequencing and chromosomal microarray analysis to identify mutations in pediatric patients with overgrowth syndromes. This technology will allow us to look at each letter in a patient's genes, sequencing DNA to identify rare mutations that are predicted to cause autism, overgrowth, and/or cancer predisposition. Once we have identified the affected genes, we will be able to pursue additional funding to analyze their function. We collaborate with a psychiatrist, neurologist, and oncologist, who provide genetic services to overgrowth patients.
Our findings are expected to enhance our understanding of the genetic risk factors for autism and the biology of pediatric growth disorders, as well as provide new potential targets for therapies. Revealing the causative genes will immediately lead to a medical test that will allow physicians to identify those children at highest risk. These results also will provide parents with critical information for planning future pregnancies. Finally, clarifying the genetic basis of how our bodies grow and develop will allow for the 1) harnessing of regenerative capabilities of tissues, 2) elucidation of the causes of cancer, and 3) further insight into the process of childhood maturation.
Kuk-Wha Lee, M.D., Ph.D Assistant Professor Division of Pediatric Endocrinology
Type 1 diabetes is an autoimmune disease in which the body's immune system attacks and destroys the insulin-producing cells of the pancreas (beta cells). Its causes are not yet entirely understood. As many as 3-million Americans may have T1D, and each year, more than 15,000 children - approximately 40 per day - are diagnosed in the United States. This disease causes dependence on injected or pumped insulin for life and carries the constant threat of devastating complications.
Despite paying constant attention to maintaining a meal plan and exercise regimen and always injecting the proper amount of insulin, these children face many other factors that can adversely affect efforts to tightly control blood sugar levels. These factors include stress, hormonal changes, periods of growth, physical activity, medications, illness/infection, and fatigue. So we are committed to finding better treatments for T1D and, ultimately, a cure. We, along with others, discovered a unique protein called Humanin (HN). It is one of several proteins that are made from the mitochondrial (not nuclear) genome. It protects nerve cells, blood-derived cells, and muscle cells against stresses (including strokes). We are the only group to investigate 1) its potential use for a pediatric indication and 2) its effects on the pancreas. It is important to note that HN protects pancreatic insulin-producing cells from dying, and when we gave it to a mouse model of T1D, it delayed the onset of diabetes. We propose that HN will protect insulin-producing cells from dying in the process that leads to T1D.
Ours is the only laboratory in the world that can measure HN levels from blood (humans and mice). We think that HN levels will be decreased in patients with T1D compared to age-matched controls and could be utilized as a biomarker to identify those children who will develop T1D. Interval funding of this major project will allow us to apply for large grants from the Juvenile Diabetes Research Foundation (JDRF), which has partnered in a unique relationship with the National Institutes of Health (NIH) to target research for T1D.
Despite the formation of large international clinical trial networks and administered interventions, T1D is still treated with injected insulin. The protection of functional, healthy insulin-producing cells remains a fundamental quest that has implications for the prevention of T1D, the treatment of T1D post-onset, islet transplantation strategies, and a cure. Support from the Today's and Tomorrow's Children Fund will enable us to move forward on this project which has a potential for this new agent Humanin to be rapidly translated into a clinical trial in newly diagnosed children with T1D.
To read more about Dr. Lee's research progress, please see page 3 of our November 2011 newsletter.
Paul Krogstad, M.D. Professor Division of Pediatric Infectious Diseases
The enteroviruses are a group of more than 100 readily transmitted, seasonal viruses that usually produce common cold symptoms, hand-foot-and-mouth diseases, and other mild conditions in adolescents and adults. For newborns, infants, and young children, however, enteroviruses can be deadly. In this vulnerable population, they frequently produce central nervous system infections, hepatitis, and other life-threatening illnesses. Serious consequences are well-known among physicians who work at referral medical centers like UCLA Mattel Children's Hospital, since there are currently no medications to treat enterovirus infections. The survival of infected newborns often depends upon supportive care until the infection resolves. Unfortunately, infections of the heart in infants and older children sometimes cause progressive injury and heart failure despite this care, resulting in the need for heart transplantation. Dismayed by the lack of antiviral medications for treatment, members of my laboratory and I are studying the chemistry of enteroviruses, searching for potential therapeutic targets.
Enteroviruses are intracellular parasites that specialize in taking over the machinery used by cells to make proteins. We have identified a little-used experimental antibiotic that dramatically reduces the growth of enteroviruses in cells. In pursuit of our general goal of being able to produce effective treatments, we now wish to confirm these initial studies in animal models and identify other compounds, as well.
Treatments for enteroviruses are unlikely to arise from the pharmaceutical industry, which in recent years has relied upon Public Sector Research Institutions such as UCLA to perform the initial research needed for development of new products. Support from the Today's and Tomorrow's Children Fund would provide the critical initial push to garner the larger-scale funding needed to optimize lead molecules we identify and turn them into candidate medications to be tested in human clinical trials.
To read more about Dr. Krogstad's research progress, please see page 4 of our November 2011 newsletter.
Yonca Bulut, M.D. Associate Clinical Professor Division of Pediatric Critical Care
Childhood infections and their severe form, sepsis, are major causes of hospital admissions. In the United States, more than 40,000 children develop severe sepsis each year, with a 10% mortality rate, especially among infants. The reasons why some boys and girls develop more severe infections are not well understood. Iron supplementation is a common health practice for the prevention of anemia in children, and it is also used in hospitals, even during severe infections; however, iron is an essential nutrient for bacteria, and its availability is a rate-limiting factor in bacterial growth and their ability to cause disease. Thus, if the current practice of iron supplementation in infected children increases iron availability to bacteria, this practice could be harmful. The aim of our study is to examine if iron supplementation and high body iron stores are risk factors for infection severity and mortality. In other words, we are asking: Is iron supplementation worsening infections?
Our laboratory has been at the forefront of iron research for the last decade. At UCLA, we discovered the critical regulator of iron metabolism, the hormone hepcidin. The discovery has brought on a revolution in our understanding of iron metabolism and its relevance to infection. Hepcidin increases early during infections and causes the disappearance of iron from blood, to keep microbes from getting this essential nutrient. Iron supplementation may subvert hepcidin's effect, enhance iron availability to microbes, and reduce the ability of our body to fight infection. Our proposal highlights a very important question about the safety of iron supplementation during severe infection. Our lab has the cutting-edge methodology as well as the experience to find out if these concerns are warranted.
The ultimate goal is to examine the safety of iron supplementation in healthy and ill children. If iron promotes infections, this result will lead to decreasing the routine use of iron supplements as well as have a major beneficial impact on the frequency and severity of infection and sepsis in hospitalized infants and children. Support from TTCF will allow us to obtain critical preclinical data to lay the framework for human studies.
To read more about Dr. Bulut's research progress, please see page 5 of our November 2011 newsletter.
Christopher C. Giza, M.D. Associate Professor in Residence Department of Neurology and Division of Pediatric Neurology
Traumatic brain injury (TBI) is the #1 cause of death and disability in children and adolescents; however, there is currently no brain-specific therapy for TBI, and its victims struggle with chronic disabilities. The predominant therapeutic strategy for years has been to block neurotransmission in the injured brain, with the goal of providing 'neuroprotection;' unfortunately, this avenue has not led to any effective new treatments. Our work in the basic science laboratory and in young patients indicates that the immature brain actually shows impaired neural activation after TBI, which suggests that promoting (not blocking) neurotransmission is necessary to facilitate recovery.
To read more about Dr. Giza's research progress, read the [Mid-Year Update]
Robert S. Venick, M.D. Assistant Clinical Professor Division of Pediatric Gastroenterology, Hepatology and Nutrition
Children whose intestines do not work must be fed intravenously through parenteral nutrition. While this treatment is often life-sustaining and provides sufficient calories to maintain growth and promote adequate neurodevelopment, it can be associated with life-threatening parenteral nutrition associated liver disease (PNALD). In fact, 100% of infants who develop significant PNALD and remain dependent on parenteral nutrition for more than a year will die unless they receive a timely liver and intestinal l transplant. Such transplants are not a panacea, as donor organs remain in short supply, and challenges with post-transplant infection and rejection mean that the five-year post-transplant survival rates are as low as 50%. Post-transplant care poses a large economic burden to society and the healthcare system as a whole; the cost of a transplant is estimated at $200,000, and post-transplant medications at $15,000/year per child.
To read more about Dr. Venick's research progress,read the [Mid-Year Update]
Gary M. Satou, M.D., FASE Director, Pediatric Echocardiography UCLA Mattel Children's Hospital Associate Clinical Professor, Pediatric Cardiology
Newborn infants with congenital heart defects often require urgent evaluation and lifesaving interventions. This particular problem is in isolated, rural, and frontier areas, where medical resources are limited and infants must quickly be transported to large specialized medical centers for care. Telemedicine with echocardiography (heart ultrasound) for real-time evaluation represents an innovative technology, permitting specialty care to be rendered at a distance to stabilize and treat these critically ill infants until a neonatal aero-medical evacuation team can be sent. In addition, unnecessary transports may be avoided, when the ultrasound shows there is no heart problem or when treatment can be directed and managed remotely by pediatric heart specialists.
To read more about Dr. Satou's research progress, read the [Mid-Year Update]
Noah Federman, M.D. Assistant Professor of Pediatrics Division of Pediatric Hematology/Oncology
Childhood cancer patients often suffer severe side effects with chemotherapy treatment. Strategies that would improve the delivery of anti-cancer agents specifically to tumor cells would not only increase the effectiveness of a chemotherapy, but also would reduce its systemic toxicity. A molecular vehicle is needed that could target tumor cells - nanoparticles provide such a potential vehicle. Dr. Federman will develop and test targeted nanoparticles to treat pediatric sarcomas (aggressive and often lethal bone and soft tissue cancers), in which the survival rate for patients is less than 20% despite incredibly aggressive chemotherapy, surgery, and radiation treatments. This completely novel and high-risk project would be a breakthrough in our current treatment of pediatric cancers, leading to the development of powerful new therapeutic strategies in aggressive childhood malignancies. If successful, we hope to rapidly translate this technology from the laboratory bench to the patient's bedside.
More about Dr. Noah Federman
2008 Jacqueline Casillas, M.D, M.S.H.S. Assistant Professor of Pediatrics Division of Pediatric Hematology/Oncology
Dr. Casillas, Associate Program Director of the UCLA-LIVESTRONG Survivorship Center of Excellence, focuses her research on the various aspects of childhood cancer survivorship. Her study follows how the barriers to long term follow-up care, the pathophysiology of late effects and its increase in mortality, and the psychosocial growth of young adult survivors converge to impact quality of life for survivors.
2007 Theodore B. Moore, M.D. Associate Clinical Professor Division of Pediatric Hematology/Oncology
Dr. Moore, Clinical Director of Pediatric Hematology-Oncology, has developed a new dendritic cell vaccine protocol for children with the usually fatal anaplastic astrocytoma and glioblastoma multiform brain tumors. This new therapy takes stem cells from a patient's blood and develops them into dendritic cells that are professional antigen processing cells. The dendritic cells are incubated with lysates of tumor from the patient, so that they can process the tumor antigens and, when inoculated into the patient, can teach the patient's immune system to attack the cancer.
2006 Daniel S. Levi, M.D. Assistant Professor Division of Pediatric Cardiology
Dr. Levi's research focuses on the design of new devices to help children with heart disease avoid surgery. He is collaborating with UCLA Mechanical and Aerospace Engineering the space-age material thin film Nitinol to create tiny replacement heart valves. These new valves will one day be inserted with a catheter through small incisions in the groin, and will therefore not require the opening of the chest, or the cutting of a little one's heart.
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