Past Fellows

The Impact of the Maternal Metabolome and Neonatal Genotype on Childhood Disorders of Glucose Metabolism

The prevalence of disorders of glucose metabolism including insulin resistance and type 2 diabetes in children is increasing, proportionate with the increasing prevalence of childhood obesity. Identifying children at risk for developing DGM and intervening prior to disease onset is critical. We will be investigating the association of maternal metabolites with development of childhood disorders of glucose metabolism. We will integrate metabolomics and genetics data together with clinical data to develop a predictive model for development of childhood disorders of glucose metabolism. The goal is to identify high-risk newborns and develop preventative interventions early.

An integrative Approach to Identify Pathogenic Genomic Variants in Pediatric Epilepsy

Many pediatric epilepsy patients fail to receive a genetic diagnosis despite extensive genetic testing. We hypothesize that a significant portion of these patients harbor genetic variants missed by exon-focused sequencing technologies. To address this, we will perform genome sequencing and develop a computational framework to identify pathogenic coding variants and candidate non-coding variants to improve the genetic diagnosis of pediatric epilepsy.

Computer-Controlled Pediatric Regional Anesthesia to Improve Patient Safety

Matthieu Chardon, PhD, will be developing a tool to measure the effectiveness of local anesthetic dosage in children with the goal of reducing dosage and increasing safety. “Regional anesthesia in pediatrics has dramatically increased over the past 30 years because it provides localized pain relief, diminishes opioid use and facilitates earlier mobilization, internal feeding and hospital discharge,” Dr. Chardon says. “It is also used frequently due to concerns about the effect of general anesthesia on brain development.” Nonetheless, Dr. Chardon explains that there are several concerns surrounding local anesthesia, and that there are no tools to determine its effectiveness or toxicity in real time. As a result, he is seeking to develop a solution in partnership with his mentors Santhanam Suresh, MD, Professor of Anesthesiology and Pediatrics, and Charles Heckman, MD, Professor of Physiology/Physical Medicine and Rehabilitation and Physical Therapy and Human Movement Sciences.

Determinants of Tobacco use and Barriers to Tobacco Cessation in Sexual and Gender Minority Adolescents

Sexual and gender minority (SGM) adolescents are at high risk for tobacco use. Tobacco use in SGM youth is problematic as it is associated with a higher risk of preventable cancers and ultimately heightened rates of morbidity and mortality. It is critical to understand precursors to, and intervene on, risk behaviors that often begin in adolescence and can ultimately lead to preventable cancer (e.g., tobacco use). Thus, my projects seek to identify determinants of tobacco use and barriers to tobacco cessation in SGM adolescents in order to ultimately inform a technology-based intervention to aid in tobacco-use prevention and cessation efforts in this population.

Novel Non-Invasive cMRI Technique to Estimate Continuous Oxygen Saturations in Pediatric Heart Disease

Despite gains in survival, decreased quality of life and morbidity continue to be challenges in congenital heart disease (CHD). Until recently, blood oxygen content in the heart and central vessels (i.e., "oximetry") has only been measured by an invasive technology: catheterization. However, this technique does not take into account complex streaming effects in complex CHD. The course and extent of deoxygenated blood streaming likely contributes to poor tissue growth and abnormal neurodevelopment. Non-invasive data obtained with cardiac magnetic resonance imaging (cMRI) has improved surveillance capabilities in these children and adults. Lurie Children’s Hospital and Northwestern University are leaders in advanced cMRI. Our long-term goal is to establish an accurate, non-invasive and non-Gadolinium-contrast cMRI technique (T2 mapping) to estimate continuous oxygen saturations in the heart and vasculature.

Gene Targeting and Controlled Release of Therapeutics using SNAs to Treat DIPG

Diffuse intrinsic pediatric glioma (DIPG) is an aggressive, malignant pediatric brain tumor. DIPG is a rare form of pediatric cancer affecting 200-300 patient annually, but is nearly uniformly fatal with a mean survival of only 18 months after diagnosis.1 Due to the tumor anatomic location within the brainstem coupled with its densely infiltrative nature, surgical removal is not possible. Additionally, chemotherapeutics that are effective for adult high-grade glioma, such as temozolomide (TMZ) treatment, are not effective for treating DIPG, while radiation therapy may temporarily alleviate symptoms but has no effect on overall survival. Dr. Figg's project aims to improve DIPG treatment targeting the H2K27M mutation using spherical nucleic acids (SNAs) as potent gene therapy and drug delivery vessels. Dr. Figg recently accepted a faculty position in the chemistry department at Virginia Tech University.

A Novel siRNA Approach for Targeting Immunosuppresive IDO1 in Pediatric Brain Tumors

Alicia Lenzen, MD, will be studying a novel form of treatment for pediatric brain tumors that will use immunotherapy combined with nanotechnology. She will be researching the inflammation-induced expression of indoleamine 2,3 deoxygenase 1 (IDO1), its role in suppressing tumor immunity and therefore its promising therapeutic reactivation of the immune response against brain tumors. Dr. Lenzen will also integrate nanotechnology as a direct delivery mode into central nervous system tumors in order to create precise targeting. “This TL1 training will facilitate the building blocks of that research foundation now, obtaining findings related to the development of novel treatment regimens using mouse brain tumor models, with the possibility of direct translation into patients,” Dr. Lenzen says. “It will also allow me a look into multi-disciplinary work in order to create the best projects.”

Inhibitory Control as a Transdiagnostic Correlate of Psychopathology in Youth

Mental health disorders are among the leading causes of disability among youth worldwide. Given that disorders co-occur more often than they occur independently, it is important that research examines potential transdiagnostic mechanisms that contribute to multiple forms of psychopathology. My project will test whether impaired inhibitory control, which is defined as the ability to override automatic or prepotent responses, is a transdiagnostic correlate of internalizing and externalizing psychopathology among youth using state-of-the art computational modeling and advanced neuroimaging methods. Advanced computational modeling holds the potential to quantify inhibitory processes with greater precision than traditional methods and neural network approaches can help to identify systems of coordinated neural circuitry that mediate specific components of inhibitory control. Ultimately, the goal of this work is to identify treatment targets and inform intervention approaches aimed at ameliorating multiple mental health conditions in youth.

Detecting cardiovascular abnormalities in pediatric bicuspid aortic valve patients using easy, low-cost chest vibration measurements

Cardiovascular abnormalities caused by bicuspid aortic valve, a congenital malformation, are associated with high risk of acquired valve disease and aortopathy. Patients with these conditions require regular clinical monitoring to ensure that disease progression is detected and managed appropriately, but this can entail tests such as diagnostic MRI, which are time- and cost-intensive and can be especially burdensome for pediatric patients. My project will explore the creation of an accessible, easy-to-use technology for detecting cardiovascular abnormalities through measurements of the physical vibrations on the chest’s surface of pediatric patients with aortic valve disease. In previous research using these measurements from adults, we have shown good performance for distinguishing healthy cardiovascular function from abnormal flow function associated with aortic valve disease. We will extend these promising findings to the pediatric population, who may benefit greatly from a low-cost and easy-to-use test that streamlines clinical care.

Dynamic Energy Balance in the ICU

Natalie Roebuck is studying and developing novel energy equations used to estimate calorie and fluid goals at the bedside in the ICU. Current equations can under- or over-estimate calorie goals in the pediatric ICU population by up 400 percent. This level of inaccuracy in energy balance leaves patients vulnerable to malnutrition, infection and prolonged mechanical ventilation. Along with collaborators in Applied Mathematics at Northwestern University, she will be developing and validating a novel equation to predict energy requirements in the pediatric ICU. She will validate this method in the Lurie Pediatric ICU and Pediatric Cardiac ICU while integrating dynamic physiologic data to improve our ability to account for dynamic energy change in critical illness. Natalie seeks to integrate clinical medicine with data science in order to gain usable knowledge at the bedside to improve care during pediatric critical illness.

Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is a devastating monogenic disease that affects ~1 in 3500 males. The disease is caused by mutations in the dystrophin gene that prevent production of the dystrophin protein and lead to progressive skeletal and cardiac muscle degeneration and ultimately death during the mid-twenties. A technique known as exon skipping has emerged as a promising treatment modality for a number of DMD cases that can circumvent disruptive mutations and restore the reading frame of the dystrophin gene to drastically improve the symptoms of the disease. While FDA approved drugs to accomplish exon skipping have recently been approved, they require repeated injections to achieve an effect and are extremely expensive. We have recently developed a gene editing platform termed CRISPR-SKIP that uses CRISPR-Cas9 single base editors to achieve permanent exon skipping by editing DNA directly. We have also developed a platform for delivering these gene editing tools using adeno-associated viral (AAV) vectors, which have proven to be a safe and effective vehicle for gene delivery. This project aims to couple these two advances to develop a one-time gene-editing treatment for DMD that will result in permanent exon skipping and lasting therapeutic benefit for the patient.

Innovative Physiologic Recording Devices Skin Patch Sensors as a Substitute for Continuous Heart Rate and Blood Pressure Monitoring in the Neonatal Intensive Care Unit

Millions of premature infants worldwide suffer from infant respiratory distress syndrome, which could be fatal. It is important to be able to detect the vital signals, such as blood oxygenation, blood pressure and heart rate, in a safe and continuous manner. Current methods in the detection of neonatal blood flow are invasive, cumbersome and difficult to operate. In this project, I am developing a wearable, non-invasive skin patch for continuous monitoring of blood flow that could be mounted on the skin of neonates.

Non-contrast Fibrosis Quantification CMR Sequence

Tetralogy of Fallot (TOF) is the most common cyanotic heart condition in children. The most frequent and deadly complication in late childhood and young adulthood for TOF patients is ventricular tachycardia (VT), which is caused by myocardial fibrosis. The best treatment for VT is ablation, during which areas of fibrosis can be detected and ablated, but current methods are not robust. Prior studies have shown that pre-ablation assessment of myocardial fibrosis using cardiovascular MRI (CMR) improves procedural success for VT ablation. However, current CMR fibrosis imaging techniques require the use of a gadolinium contrast agent, which may have adverse health effects. Therefore, my project aims to develop a non-contrast fibrosis quantification CMR sequence using T1ρ mapping for measuring fibrosis in TOF patients.

Peptide amphiphile nanofibers extend and enhance BMP4 function for improved therapeutic efficacy on pediatric high grade gliomas

Among pediatric brain tumors, high-grade gliomas are the most devastating. Therapeutic resistance in pediatric gliomas is primarily due to a population of glioma cells with stem-like features, referred to as glioma stem cells (GSCs). The growth factor bone morphogenetic protein 4 (BMP4) is known to promote GSC differentiation, which increases cell sensitivity to cytotoxic therapies. We hypothesize that BMP4 is a promising adjuvant for glioma treatment. However, due to the relatively short half-life of BMP4 in vivo, a delivery system needs to be developed for administering BMP4 in a clinical setting. We propose delivering BMP4 to the site of the glioma using peptide amphiphile (PA) nanostructures, which are known to extend the biological function of bound growth factors. The primary goal of this project is twofold: 1) to evaluate the clinical potential of a BMP4 nanostructure delivery platform for treating pediatric malignant glioma, and 2) create and test a new PA nanostructure containing relevant chemotherapeutic agents that can be used in combination with the BMP4 nanostructure.

Separate Neurodevelopmental Risk Pathways for Depression and Comorbid Anxiety

Depression and anxiety are among the most prevalent mental health disorders in youth. Before the age of 18, 20% will meet the criteria for at least one depressive or anxiety disorder, and over 10% will meet the criteria for both. Co-occurring depression and anxiety worsen prognosis and treatment outcomes compared with either condition alone, leading to greater impairment, symptom severity, and recurrence. Although one of the most robust risk factors for depression in youth is a family history of depression, the neurodevelopmental mechanisms of this familial transmission are unclear. For example, offspring of mothers with a history of depression are also more likely to develop comorbid anxiety disorders, making it particularly difficult to separate familial risk for unipolar depression from risk for comorbid depression and anxiety. Prior work suggests the pathway from maternal depression to offspring with and without comorbid anxiety disorders may depend on distinct patterns of neural activity to positive and negative laboratory stimuli. Specifically, symptom dimensions unique to depression are associated with neural hypoactivation to rewards while shared symptom dimensions are associated with neural hyperactivation to making errors. My project uses an electroencephalogram to examine neural responses to rewards and errors among siblings and mother/daughter dyads. The objective of my project is to test the hypothesis that blunted response to rewards is a mechanism for familial risk for depression and abnormal error processing is a mechanism for familial risk for comorbid depression and anxiety. Results will help identify early risk factors for depression and anxiety to facilitate preventative interventions that specifically target underlying neural dysfunction in one or both domains.

Investigating the role of stromal cells in folliculogenesis supported by a transplantable scaffold

Chemotherapeutic regimens delivered to pediatric patients can result in premature ovarian insufficiency (POI) and lead to reduced ovarian hormone production and infertility. Currently, the only fertility preservation option for prepubescent female patients is ovarian tissue cryopreservation (OTC). Autotransplantation of cryopreserved ovarian tissue can restore hormone production and fertility. The Laronda Lab seeks to bioengineer a transplantable ovarian scaffold that will restore fertility in patients who survive pediatric cancer but develop POI and infertility from treatment. Stromal cells are essential components to folliculogenesis in vivo as they are the source of theca, hormone-producing cells, and modulate vessel formation and immune responses within the ovary. We aim to further delineate the role of stromal cells in folliculogenesis within our bioengineered and transplantable system. Specifically, our goal is to (1) investigate if stromal cells produce matrisome proteins that match the ovarian compartment from which they came, (2) delineate what paracrine factors are secreted by stromal cells, and (3) investigate if direct contact with stromal cells is required for in vitro primordial follicle growth.

Defining and Reducing Waste in the Operating Room-An Effort to Combat Climate Change

Climate change, driven by greenhouse gases (GHGs) in the atmosphere, represents the planet's greatest public health crisis. Links between climate change and health problems include excessive heat-related illnesses, waterborne infectious diseases, and exacerbation of cardiovascular and respiratory diseases due to declining air quality. Children are particularly vulnerable to climate change-related health concerns. The healthcare sector is responsible for an estimated 10% of U.S. GHG emissions Specifically operating rooms (ORs) are estimated to produce 70% of hospital waste. There is a lack of consensus on the methods to quantify waste/environmental impact or report costs/cost savings. This lack of consensus in reporting is a major gap in our ability to implement quality and process improvement efforts to reduce GHGs and improve sustainability. As hospitals navigate changes in processes, such as the institution of recycling and reprocessing programs, it is imperative to evaluate outcomes (e.g., waste reduction, cost-savings) as well as barriers and facilitators of implementation (e.g., adoption, adherence, fidelity Our aim is to 1) Define a generalizable method to quantify waste and environmental impact and 2) Evaluate implementation of a waste reduction program within the children's hospital.