Current TL1 Fellows
Current TL1 Fellows
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.
Ethan Johnson, PhD
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.
Allison Letkiewicz, PhD
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.
Characterization of atypical corticospinal tract development and hand motor impairments in early-onset pediatric hemiplegia
Unilateral brain injuries occurring before, at, or shortly after full-term can result in pediatric hemiplegia (PH), which accounts for one-third of cerebral palsy cases. The effects of PH are non-progressive but last throughout the lifespan and require countless hours of specialized healthcare in forms such as physical and occupational therapy, orthopedic surgery, and neurology. A thorough understanding of changes in neural morphology and the link with motor impairments is needed to better design treatment strategies for functional deficits. This project aims to quantify and compare atypical corticospinal tract development in both hemispheres of the brain and typical motor impairments (paretic hand weakness, mirroring grasp force, and lack of finger dexterity) in early-onset pediatric hemiplegia. This will be done using a combination of diffusion-weighted MRI techniques and quantitative kinematic and kinetic motor assessments.