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.
NIR spectrometers to detect difference in molecular/spectroscopic signatures of MIH teeth
Molar incisor hypomineralization (MIH) is a dental congenital disease with a prevalence thought to be as high as 40% with uncertainty due to widespread underdiagnosis caused by no standard diagnosis procedure. Even with preventative measures, MIH teeth still suffer from rapid dental decay. Many children with MIH have other preexisting illnesses and further suffer from the dental sensitivity, pain and cosmetic issues caused by MIH. The mechanism behind the condition is not well understood and difficult to study because few teeth are available for scientists to investigate because of a good policy of restoring teeth until extraction is the only option. Due to the high impact and the need for further knowledge of this condition, MIH needs to be further studied non-destructively, intra-orally and painlessly. One exciting possibility is the use of NIR spectrometers to detect difference in molecular/spectroscopic signatures of MIH teeth. Working closely with residents at Lurie’s Children Hospital, the device will be used to obtain spectra from clinical spaces that can be added to a library of known spectra. Machine and human learning will be used to then develop a protocol for identifying MIH teeth using the spectra obtained. If this technique is successful, this may lead to a comprehensive approach to diagnosing MIH lesions. Further, the information extracted from the spectra may lead to more knowledge about the etiology of MIH.
Kathryn McElhinney, MD
Utilizing 3D Bioengineering to Study the Biochemical and Environmental Triggers of Ovarian Follicle Growth
Lifesaving chemotherapy treatments in the pediatric population frequently induce premature ovarian insufficiency (POI) leading to reduced ovarian hormones and infertility. Giving survivors of pediatric cancers the option to have biological children is a key quality of life improvement measure. Women with POI also experience comorbidites related to loss of ovarian hormones and a shorter life expectancy. Ovarian tissue cryopreservation is the only fertility preserving option for children who are not mature enough to ovulate. This preserved tissue can then be transplanted back into the patient in order to restore hormone function and fertility. However, premature activation and depletion of primordial follicles within cryopreserved ovarian tissue leads to this truncated function of transplanted ovarian tissue. We hypothesize that both biochemical and physical cues control primordial follicle activation. We will use bovine ovaries as a mono-ovulatory model of human ovaries to test the the role of EMILIN1, an ovarian glycoprotein, in maintaining quiescence in isolated primordial follicles. We will also investigate the role of the ovarian microenvironment stiffness on primordial follicle activation and growth using a 3D printed gelatin scaffold.
Steven Papastefan, MD
In utero gene therapy via an endogenous, placenta-specific mRNA delivery system
In utero gene therapy (IUGT) is an ideal treatment for placental and developmental disease due to the potential to prevent irreversible damage that develops within the womb. Clinical translation of IUGT is limited by inadequate delivery strategies which lack target specificity and carry risk of immunogenicity and insertional mutagenesis. IUGT is particularly well suited for the treatment of fetal growth restriction, a leading cause of infant mortality that incurs lifelong susceptibility to cardiopulmonary and neurological disease. My project will investigate a delivery system composed of the endogenous retroelement PEG10 that recapitulates natural processes of mRNA transfer within the placenta, via packaging of cargo mRNA within virus-like particles. We aim to study the fundamental mechanisms by which PEG10 mediates mRNA transfer to placental trophoblasts during fetal development, and subsequently to repurpose this technology for targeted, minimally-immunogenic gene therapy delivery to the placenta. Our ultimate objective is to design a gene therapy delivery system capable of delivering therapeutic mRNA for the treatment of a wide range of placental and fetal diseases, including fetal growth restriction.
Sarah Walker, MD
Machine Learning to Predict Fluid Responsiveness in Hypotensive Children
Over 600,000 children worldwide are diagnosed with sepsis-induced shock each year, and many more suffer hypotension and shock from varied etiologies including dehydration, trauma, surgery, and other forms of dysregulated inflammation. Associated mortality rates for septic shock are as high as 50% and mortality from other shock etiologies is poorly quantified. Though pediatric shock management guidelines for resuscitation focus on early, rapid fluid administration, all patients in shock do not respond to this form of management. Identification of children who experience sustained clinical improvement after fluid bolus administration (“fluid responders”) would allow for personalized intervention and avert prolonged shock and excessive fluid administration that can lead to end-organ damage and mortality. Our preliminary research shows that most known adult predictors of fluid response perform poorly in children or have technical challenges that impede widespread use at the bedside. Consequently, we have a critical need for easily-deployed, real-time prediction of fluid response to personalize and improve resuscitation for children in shock. Our central hypothesis is that a machine learning-based prediction model which combines both continuous physiologic monitor data and patient-level clinical variables will accurately predict which children will be “fluid responders” with sustained response to fluid bolus.
Meredith Taylor, MD
Elucidating the Role of Mitophagy in Preservation and Reperfusion during Solid Organ Transplantation
To date, there have been little to no advances in organ preservation prior to implantation. One such strategy can be to pre-treat donor organs prior to implantation. Microvascular endothelial cells (ECs) lining the vessels of the graft are the first to be affected by the ischemic and hypoxic conditions in cold preservation solution as well as by reperfusion injury once the graft is implanted. This ischemic-reperfusion injury (IRI) damages the EC barrier and activates the ECs to trigger a robust adaptive immunity response. Therefore, pre-treating the donor organ during the preservation phase to target the ECs is a viable strategy to dampen the activation of ECs and minimize immune allograft recognition. This is critical in the setting of pediatric and adolescent transplant, as durable organs, longevity, and the minimization of the toxic effects of pharmacological immunosuppression is of utmost importance. Recent data shows inhibiting mitochondrial fission and promoting mitochondrial fusion has a protective effect and significantly reduces EC immunogenicity. The exact mechanism(s) of this protective effect is unknown. Our goal is to assess the impact of mito morphology on autophagy and mitophagy in ECs during IRI with the goal for a translational pre-treatment solution model for transplant organs.