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Current TL1 Fellows

Current TL1 Fellows

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.

Ashley Kraus, PhD

Mentors:

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.

Improving Data Capacity and Predictive Capability of NSQIP-P Using Design of Experiment Methodology

Dr. Ingram is applying novel industrial engineering and management science methodologies to assess quality outcomes for children undergoing surgery. The American College of Surgeons National Surgical Quality Improvement Project-Pediatric (NSQIP-P) is considered the premiere quality improvement program for children undergoing surgery. The biggest limitation to expanding this beneficial program is rooted in the burden of data collection. By using innovative engineering methodologies, Dr. Ingram and her mentoring team will reduce the data collection burden and expand the impact of the program.

Siam Racharaks, PhD

Mentors:

Engineering a CRISPRi Phagemid System to Better Treat Infection in Young Children with Cystic Fibrosis

Cystic fibrosis (CF) is an autosomal recessive disease that affects approximately 30,000 people in the United States, of whom 75% were diagnosed by age 2. As a result of diminished lung function, roughly 50% of all people with CF have chronic Pseudomonas aeruginosa (Pa) infections which are associated with increased morbidity and mortality. To improve infection treatment in young children with CF, we propose the development of a novel phagemid-based therapy to combat Pa infections. Phagemids—synthetic plasmids packaged into a functional infectious phage particle—are highly specific and have unique characteristics which mitigate the release of endotoxins and prevent escape of progeny phages into the surrounding environment. To create an effective therapy, phagemids will be engineered to repress Pa genes involved in biofilm and antibiotic resistance development by utilizing CRISPR interference (CRISPRi) technology. The proposed studies will provide the foundation to design desperately needed new treatments for lung infections in children with CF.

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.

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.

Suvai Gunasekaran, PhD

Mentors:

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.

Participating Institutions: