Four of the new projects seek to improve the treatment and prognosis of brain tumors in children. Others will set out to understand severe respiratory infections and asthma development, improve the outcomes for children suffering from a range of genetic diseases and expand the potential of regenerative medicine. The new grants raise the total of currently active pediatric studies conducted through the CDI to 50.
Ana Maria Arbelaez, MD, pediatrics, and Christopher Smyser, MD, neurology, seek to understand the neurodevelopmental consequences of malnutrition on children. The researchers and their collaborators will conduct a one-year study in Cali, Colombia, leveraging that city’s high rates of childhood malnutrition. When the 8- to 10-year-old children enrolled in the study are diagnosed with malnutrition, they will be treated and, along with healthy children, given a battery of tests to measure brain structure and cognitive performance. The knowledge gained through this project will help with the design of an expanded study aimed at identifying appropriate cognitive and brain development targets and metrics, bringing researchers closer to large-scale intervention trials.
With their funding, Joshua Blatter, MD, MPH, pediatrics, and David Wang, PhD, molecular microbiology,
hope to discover ways to improve the survival rates of pediatric lung transplant patients, which lag behind other solid organ transplants. This study leverages the largest repository of clinical and biological specimens from children receiving transplants. The multicenter effort is based at the School of Medicine. The investigators will mine it for early microbial biomarkers of disease associated with chronic lung inflammation following transplantation.
Abhinav Diwan, MD, medicine,
will use his CDI funding to study lysosome storage diseases. These genetic defects in cell metabolism are the most common inherited disorders in children. Lysosomes act as cellular waste disposal systems. Lysosomal enzymes break down all kinds of biomolecules, including proteins, carbohydrates and cellular debris. A shortage of these enzymes impacts metabolism, reducing fat stores and causing a significant energy deficit. Dr. Diwan will use animal models to test whether the role of lysosome can be bypassed with alternative nutrients.
Karen Gauvain, MD, MSPH, pediatrics, and David Limbrick, MD, PhD, neurological surgery and pediatrics, take on one of the biggest obstacles to treating pediatric brain tumors: the blood-brain barrier, which keeps chemotherapy drugs from penetrating the brain. A minimally invasive laser procedure, called magnetic resonance imaging-guided laser ablasion (MLA), disrupts the blood-brain barrier in adults, allowing the penetration of chemotherapy drugs into the tumor. The purpose of this study is to examine the outcomes of pediatric brain tumor patients who are treated with MLA and chemotherapy. The study also will test whether MLA’s therapeutic effects are due to enhanced infiltration of immune cells, a result of blood-brain barrier disruption.
Through his CDI funding, Jeffrey Haspel, MD, PhD, medicine,
will employ a combination of animal models, cell culture systems and patient observations to look for novel ways to reduce severe respiratory infections and asthma development in children. Because asthma symptoms are intimately tied to time, Dr. Haspel will study a circadian clock gene called bmal1 to see the extent to which it regulates the lung’s response to common respiratory viruses. In addition, he will determine how a child’s age modifies the impact of bmal1 on lung antiviral responses and asthma-like airway disease.
Rob Mitra, PhD, genetics, will use his CDI funding to study glioblastoma, the most devastating form of brain cancer. A School of Medicine colleague and co-investigator on this study, Joshua Rubin, MD, PhD, pediatrics, recently published studies exploring the observation that females are less likely than males to develop the disease, and when they do, they have better outcomes. He showed that these differences are due to distinct sex-specific cellular responses to chemotherapy drugs and to mutations affecting tumor suppressor genes. Recently, cellular identity has been tightly linked to differences in the activity of super enhancers, DNA regions that regulate the activity of genes in each cell. Dr. Mitra’s study will examine whether differences in super enhancer activity underlie male-versus-female cellular identity and contribute to the sex differences in rates of glioblastoma malignant transformation and treatment responses.
With her CDI funding, Samantha Morris, PhD, developmental biology, will study the potential of regenerative medicine therapy for short bowel syndrome (SBS), a condition arising from the surgical loss of a significant length of small intestine. Dr. Morris previously observed that skin cells of mice could be put into a petri dish and converted to cells that grow into liver and intestine. The CDI study will set out to test whether mouse skin cells can be reprogrammed into mature small intestine cells that can carry out the work of absorbing nutrients.
Shalini Shenoy, MD, pediatrics, will use her CDI funding to test a new approach that may improve outcomes in sickle cell disease patients who undergo hematopoietic cell transplantation (HCT). This procedure involves the infusion of bone marrow stem cells that give rise to healthy blood cells. HCT has been shown to cure sickle cell disease. The problem is that a fully tissue-matched donor can be found only 35 percent of the time. Dr. Shenoy will study whether, with the right therapeutic approach, bone marrow stem cells from half-matched donors can be employed to achieve the same life-saving outcome in sickle cell disease. This approach could also potentially be applied to HCT in pediatric cancer patients.
Reprogramming pediatric brain tumor cells into normal neurons is the ultimate goal of an innovative grant led by Qin Yang, MD, PhD, radiation oncology, and Dennis Hallahan, MD, radiation oncology. In mice, protein inhibitors, called kinases, are able to reprogram brain tumor cells so that they lose their tumor-generating potential. Using cell culture studies, the researchers will try to reprogram human pediatric glioblastoma cells into neurons by combining kinases with small molecules known to prevent cellular resistance to reprogramming. This is the first step toward the development of novel reprogramming treatment strategies that, if successful, will extend the lives of, and potentially cure, children with brain tumors.
Suman Mondal, PhD, biomedical engineering, will use his CDI post-doctoral fellowship under the mentorship of Samuel Achilefu, PhD, to develop a prototype of a wearable goggle system that enables advanced fluorescence-guided surgery. Bioengineers at the School of Medicine devised a way to select the fluorescent molecule that best identifies different types of tumor cells. That key innovation of the new goggle system will enable more precise and effective surgery, thereby increasing survival rates and decreasing the need to treat residual tumors with chemotherapy and radiation.
Sudhir Singh, PhD, medicine, will use his CDI post-doctoral fellowship to advance the work performed in the lab of CDI faculty scholar Ying (Maggie) Chen, MD, PhD. Dr. Chen’s lab studies genetic forms of nephrotic syndrome (NS), a childhood kidney disease that causes an unhealthy abundance of protein in urine called proteinuria and the progressive loss of kidney function. Using cell and mouse models of NS, Dr. Chen’s lab has demonstrated that a genetic mutation of kidney cells called podocytes induces proteinuria by activating a cell stress response in a cellular organelle called endoplasmic reticulum (ER). In mice, Dr. Singh found that a protein called mesencephalic astrocyte-derived factor (MANF) is a reliable biomarker for detecting podocyte stress in the earliest stages. CDI funding will enable Dr. Singh to examine whether MANF also can be relied on to detect podocyte stress in NS patients.
Rounding out the projects supported by this cycle of awarded grants is continued funding of the CDI Summer Undergraduate Research Fellowship program, led by Kathryn Miller, PhD, biology. This program introduces the next generation of pediatric researchers and physician scientists at Washington University to cutting-edge pediatric research and involves them in independent research projects spanning a 10-week period.
For more information about these and other pediatric research studies funded by the CDI, visit childrensdiscovery.org.