The CHEO Research Institute is pleased to announce the results of the 2018 CHEO Research Institute Research Growth Awards (RGA). This internal grant program aims to provide start-up funds for a new project idea or a change in research direction or to fund pilot projects that may lead to future external grants. We would like to thank the CHEO Foundation and our generous community of donors for making this competition possible.
There were 11 applications received and five funded - a 45% success rate. Congratulations go out to the following successful applicants and their teams:
• Shawn Beug ($30,000) – Therapeutic Modulation of the Neuroblastoma Immune Microenvironment for Effective Cancer Immunotherapy.
Neuroblastoma is an often fatal childhood cancer, in part due to the inability to completely eradicate disseminated tumours and due to the development of chemoresistance. Hence, new effective therapies are urgently needed for this type of refractory cancer. It is expected that the maximal benefit of cancer therapies will be derived from combining different treatment approaches that will lead to a full-blown attack against the cancer. The combination of immunotherapies with a class of drugs called Smac mimetics has the potential to kill neuroblastoma cells. This work will decipher the mechanisms required for synergy between Smac mimetics and an antibody that is an immunotherapy used for the treatment for neuroblastoma, called anti-GD2. The study will add insight into the importance of the molecular and cellular components that mediate the efficacy of anticancer combination. The data will improve our understanding of how to more effectively treat cancer and ultimately see the translation of this combination into the clinic for the treatment of neuroblastoma.
• Kevin Cheung ($28,474) – Management of Pediatric Clinical Scaphoid Fractures: A Feasibility Study. Co-Investigators: S. Carsen, K. Smit, K. Highmore, K. Koujok, K. Tang
Children commonly develop wrist pain following a fall on their outstretched hand. When a scaphoid fracture is suspected, but no fracture is seen on X-ray, this is known as a clinical scaphoid fracture. Children diagnosed with a clinical scaphoid fracture are often over-treated with a cast because of the potential for poor long-term outcomes associated with a missed scaphoid fracture. MRI allows for early and accurate diagnosis of a scaphoid fracture. If MRI is used routinely for these patients, many children may avoid unnecessary immobilization. To justify the use of MRI, however, the costs and effectiveness of MRI compared to routine immobilization must be considered. A cost-effectiveness analysis is one way to compare these two management strategies. This study will see if it is feasible to conduct a larger study to determine the cost-effectiveness of MRI compared to immobilization in children with a clinical scaphoid fracture. Patients with a clinical scaphoid fracture will be randomly assigned to receive either an MRI or usual care which involves treatment with a cast. If no fracture is seen on the MRI, no further treatment is required. Patients will be followed at regular intervals until their symptoms resolve. All costs associated with treatment will be collected. Effectiveness will be measured by assessing patients’ quality of life during treatment. The results of this study will help conduct a larger study to determine the best way to manage children that present with a clinical scaphoid fracture. Because clinical scaphoid fractures are extremely common, the potential impact of improving care for children with wrist injuries may be significant.
• Jane Lougheed ($30,000) – Submaximal Cardiopulmonary Exercise Capacity: An Innovative Approach to Understanding Physical Activity among Children with Complex Congenital Heart Disease. Co-Investigators: P. Longmuir, T. Kung
This project will use treadmill exercise to improve the health and care of children with complex congenital heart disease (CHD). More than 90% of children with CHD now survive to adulthood. We need to know which children have the active lifestyles associated with optimal health and who needs additional support. We will determine whether treadmill exercise can estimate home/community physical activity and whether having a “blue” skin colour (due to limited oxygen) before heart surgery enables greater activity later in childhood. Doctors use maximal exercise tests to evaluate heart function and ask patients about physical activity. Patients say they are active, but measurements indicate only 30% are active enough for optimal health. This discrepancy may reflect reduced activity expectations - research indicates that maximal exercise is difficult for patients with complex CHD. However, most childhood play is at only a moderate intensity. Three studies suggest that children with complex CHD are similar to healthy peers during moderate exercise. We think the bodies of “blue” children adapt by learning to exercise more efficiently. Children, 10 to 17 years who were “blue” in infancy will complete a treadmill exercise test while breathing and heart rate are measured. They will then wear a monitor to measure their daily physical activity for seven days. “Blue” children include those born with 1) single ventricle (blue for 2-3 years), 2) tetralogy of Fallot (blue for up to 6-8 months), or 3) transposition of the great arteries (blue for < 1 month). Statistical analyses will examine exercise capacity and daily physical activity, adjusting for “blue” exposure
(based on medical record), age and sex. Results will enable CHEO cardiologists to know which children are at risk for poor health due to inactivity and provide an accurate measure of how much physically active play the child’s heart can perform.
• Robert Slinger ($29,791) – Nanopore Sensors for Infectious Disease Diagnostics: A Pilot Study of Group A Streptococcus Detection Using Solid-State Nanopores. Co-Investigators: V. Tabard-Cossa (Co-PI, uOttawa), A. Carlsen (uOttawa), D. Tessier (uOttawa)
Rapid detection of bacterial infections in children can enable physicians to prescribe the right antibiotic at the point-of-care. Delay in such treatment can have serious consequences, while inappropriately prescribing antibiotics to those who do not have bacterial infections can also lead to negative outcomes, such as antibiotic resistance and allergic reactions. Current point-of-care test devices are costly and fragile, since they rely on expensive optical sensors. Development of rapid, low-cost, rugged infectious disease diagnostic devices is therefore still an urgent need. Researchers at the CHEO Research Institute and the University of Ottawa plan to work together to create a device that meets these requirements, using a novel detection technology called solid-state nanopores. Nanopores are small openings that can detect the passage of individual molecules through a membrane. Since the signal readout from nanopores is electrical in nature, miniaturized (e.g. handheld), less costly measurement instrumentation can be used for signal detection. In addition, the Tabard-Cossa lab has recently patented a simple method that could allow nanopores to be manufactured at low cost. Nanopore detection of Group A Streptococcus (GAS), the cause of “strep throat”, will be the goal of this pilot project. Throat swabs from children will be collected and copies of any GAS genes in the sample will be made through a process called DNA amplification. The changes in electrical current upon passage of the DNA amplification products through the nanopores will then be recorded. Results will be evaluated using optical detection as the gold standard. If this study finds that GAS nanopore detection is both sensitive and specific, the investigators will seek additional funding to develop nanopore sensors for use in small, rugged, lab-on-a-chip devices. Such devices could represent a significant advance in the care of children with infections by allowing for rapid diagnosis and initiation of treatment at the point-of-care.
• Sunita Venkateswaran ($30,000) – In Vitro and in Vivo Lipidomic Analysis of Fatty Acid Hydroxylase Associated Neurodegeneration (FAHN). Co-Principal Investigator: S. Bennett (uOttawa)
FAHN is a very rare disease caused by mutations in the FA2H gene. The symptoms of FAHN are mostly confined to the central nervous system. Patients with FAHN appear to have normal early childhood development. Symptoms usually start to appear during childhood or the teenage years. Patients present with muscle spasticity and dystonia, ocular abnormalities, progressive gait instability, intellectual impairment and seizures. Evidence of iron accumulation on a brain MRI is often an important clue leading to the diagnosis of FAHN. We are currently studying the natural history and neuroimaging features of FAHN in a study supported by the NBIA disorders association. In FAHN there is abnormal hydroxylation of cerebrosides (which are an important content of animal muscle and nerve cell membrane) leading to myelin instability. We do not understand how or why these changes occur in the brain. We wish to understand FAHN better. In order to do this, we will use the unique methodology developed by the Neural Regeneration Laboratory to compare the GalCer composition in plasma samples and fibroblasts (skin samples) from FAHN patients and age-matched and sex-matched controls. We will further use lipidomic methods to profile all lipid species that are associated with the hFA-GalCer network. This profile will represent the first lipidomic assessment of lipid defects in FAHN patients.