Current Fellows
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.
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
Postdoctoral Trainee
Mentor:
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.
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.
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.
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.
