Current TL1 Fellows
Current TL1 Fellows
Monica E. Bianco, MD
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.
Combined Effects of Chemotherapy and Antibiotics on the Intestinal Microbiome in Children
The human microbiome plays a critical role in gastrointestinal, immunological, and metabolic development and homeostasis. Children and adolescents receiving intensive cancer treatments are at an increased risk for developing health complications associated with microbiome dysbiosis (e.g., diabetes, asthma, obesity) and antibiotic-resistant invasive infections. To advance potential treatment strategies that mitigate such risks, our project aims to determine the impacts of chemotherapeutics and antibiotics on the gut microbiome in children using in vitro (synthetic community) and in vivo (murine) experimental systems. Using molecular biology and multi-omic methods, we will test the hypothesis that different forms of combination therapy may have overlapping and synergistic impacts on microbiome function and its potential resiliency post-treatment.
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.
Electronic Medical Record Integration of Genomic Testing Results
Bimal Chaudhari, MD, MPH, is developing a knowledge base that will deliver genomic testing results to non-geneticist clinicians via an electronic medical record. Many patients may benefit from genomic testing, but not all physicians feel prepared to take action based on the results of genetic testing. However, this new knowledge base will address this problem by offering clinical decision support that is patient specific and compatible with a physician’s workflow. “Right now, methods for DNA sequencing are fairly robust and well-developed but methods of sequence interpretation are evolving,” Dr. Chaudhari says. “The result is that, unlike an X-ray or blood culture, the interpretation of a sequencing test result can change over time. Results may also be more or less relevant at different points in time. The TL-1 program provides me the support I need to develop my knowledge base in this area and gain practical experience. I'm developing collaborations in fields I didn't even know existed a year ago. My hope is that this relatively novel collaboration is the foundation for sustained extra-mural research funding.”
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 Spherical Nucleic Acids to Treat Diffuse Intrinsic Pontine Gliomas
Diffuse intrinsic pontine glioma (DIPG) is a rare, aggressive, and malignant pediatric brain tumor that most commonly results from a mutation of the histone 3.1 or 3.3 isoforms. Due to the anatomic location of the tumor within the brain stem and the infiltrative nature of the tumors, surgical removal is not an option. Additionally, chemotherapeutics used for high-grade adult gliomas have no effect on DIPG tumor growth, and radiotherapy has not increased survival rates. In this project, we will utilize spherical nucleic acids (SNAs) composed of a synthetic polymer core coated with a highly-orientated and specific mRNA sequence to study DIPG gene regulation, which could lead to a powerful new nanoparticle-based treatment. The polymer core functions as a degradable cargo vehicle to deliver specific protein inhibitors, while the mRNA sequence targets locations on the genome to induce gene knockdown of proteins hypothesized to lead to malignancy. Ultimately, our goal is to integrate polymer and nanoparticle engineering to develop specific and powerful clinical treatments for rare and/or incurable pediatric diseases.
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.”
Yen-Sheng Lin, MS, PhD
The Effects of tDCS on Abnormal Synergistic Coupling in Children with CP
Gait deviations in children with hemiplegic cerebral palsy are multifactorial including sagittal plane impairments at the ankle and knee combined with hip hiking and circumduction. These kinematic patterns are metabolically inefficient and may lead to significant musculoskeletal comorbidities, including joint diseases. While it has been proposed that weakness, spasticity and leg length discrepancy may contribute, the underlying factors remain unknown. We argue that these impairments may be a manifestation of aberrant motor coordination. The goal of this project is to construct a training paradigm to help shape the underlying motor sequence during gait in children with cerebral palsy with hemiparesis. The technique will leverage our understanding of the motor control of hemiparetic gait and neuromodulation for locomotor training.
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.
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.
Current Affiliate Fellows
Khalid K. Alam, PhD
TxDx: A Platform for Diagnostics Powered by Transcription
Ribonucleic acid (RNA) is a unique biomolecule with a diversity of functions. RNA can store and propagate genetic information, sense compounds in the environment (aptamers), regulate gene expression (riboswitches) and perform chemical reactions (ribozymes). RNA is also highly engineerable and can be evolved for a variety of new functions. Transcription, the conversion of a static DNA template to a dynamic RNA molecule, is therefore the key reaction that unlocks an assortment of biological function. Through the regulation of transcription and careful design of the functional end product, elaborate biological circuits can be constructed to sense and respond to a variety of compounds, including those for which current diagnostic paradigms fall short. The TxDx (Transcription Diagnostic) platform seeks to develop, validate and apply such RNA-based sensors for resource-limited settings and detection of medically relevant compounds. As a TL1 participant and father of two, Khalid is looking forward to collaborating with pediatric fellows to identify diagnostic challenges in child and adolescent health and apply the TxDx platform toward them.
Detecting Speech Motor Disruptions in Adolescents at High Risk for Psychotic Disorders
Disruptions to cortico-cerebellar pathways in schizophrenia are argued to be a common source for certain cognitive, behavioral and motor abnormalities in the disorder. Tracking cerebellar motor dysfunctions has been a promising diagnostic tool for assessing adolescents who are at high risk for psychosis but have not yet received a diagnosis. However, current motor assessments rely on specialized equipment and are not easily employed in non-research settings, restricting their clinical utility. Emily's project investigates whether subtle disruptions to speech motor control (a highly-regulated motor behavior that relies on the cerebellum) can also signal early risk in this population. They are developing signal processing tools for to enable fast, automatic processing of recorded speech and will apply them to the assessment of speech acoustics as a potential biomarker for psychosis risk.
Ethan M. Johnson, PhD
- Mozziyar Etemadi, MD, PhD
- Michael Markl, PhD
Exploration of noninvasive cardiac monitoring by ballistocardiogram sensing in pregnancy to improve child health
Cardiac diseases that occur during pregnancy, such as preeclampsia, can have negative effects on the health of a child exposed in utero. New insights gained into cardiac disease progression can potentially point to disease management strategies that mitigate health consequences for the child. This research aims to explain key aspects of cardiac disease progression through noninvasive physiological monitoring, using an innovative research device that integrates accelerometers and electrodes into a wearable ballistocardiogram (BCG)-electrocardiogram (ECG) sensing package. The BCG signal arises out of mechanical recoil created by the heart circulating blood, and the well-known ECG signal shows electrical activity of the heart. Together, they give detailed insights into cardiac and hemodynamic function, and as such can paint a much richer portrait of cardiac disease progression.
Tyler Ray, PhD
Epifluidic Platform for Clinical Diagnostics via the Stimulation, Collection and Analysis of Sweat
Sweat chloride testing is the gold standard technique for diagnosis of cystic fibrosis, a fatal, genetic disease affecting over 30,000 people in the United States. Current FDA-approved screening technologies are cumbersome, have high rates of failure in collecting sufficient sample volumes, are prone to chloride contamination and are time consuming in both collection and lab analysis. The main objective of Tyler's work is to develop a superior diagnostic approach that integrates stimulation, collection and analysis into a single epidermal platform providing both an improvement in diagnostic capabilities by decreasing analysis time, eliminating sources of contamination, improving repeatability and reliability.
Development of a Virtual Flow Cytometry for use on Longitudinal Large Cohort Studies
Michael Sherenian, MD, will be studying the association between whole methylome sequencing and T-cell subsets to identify and establish differences between these cells. In doing so, Dr. Sherenian wants to develop alternative ways to examine T-cell development and pathology in allergic diseases. “The skills that I develop through the program will promote my learning of asthma, allergic disease and the immunologic basis of these conditions,” Dr. Sherenian says. “The experience will increase my knowledge of important research gaps, relevant epidemiological approaches and understanding of data science.”
Hongchul Sohn, PhD
Influence of Rapid Sensory Feedback on Motor Learning After Neural Injury
Motor learning is an essential component of functional recovery after neurological injury, as patients must adapt to a changed nervous system to generate desired movements. Vision and proprioception are integral to motor learning, providing feedback for evaluating performance and guiding corrective responses. As such, recent evidence from healthy individuals suggests that visual and proprioceptive pathways that generate rapid sensory-evoked motor responses, defined as those occurring prior to volitional reactions, play a key role in learning. However, the importance of rapid motor responses in motor learning following neural injury has not been explored, limiting our ability to exploit this neurophysiological mechanism of motor learning to guide rehabilitation. This project thus seeks to quantify impairments in rapid visual and proprioceptive pathways, and to determine how such impairments affect motor learning after neural injury, initially using stroke as a model population.