Current Pilot Projects

2024-2025 Pilot Investigators

Delaware Data Science Awardees

Nancy Lennon, DPT, MS, PT Research Physical Therapist Institution: Nemours Children’s Hospital  Website Project Title:  Outcomes of High and Low Dose Multi-Level Surgery in Youth with Cerebral Palsy Summary: Cerebral palsy (CP) is a group of movement and posture disorders resulting from nonprogressive disturbances to the fetal or neonatal brain. The overall prevalence of CP worldwide is 2.11 per 1000 live births and it affects approximately 10,000 babies born in the United States each year. Much of the specialized care for youth with CP aims to minimize the impact of musculoskeletal impairments. Multilevel orthopedic surgery (MLS), including soft-tissue muscle lengthening, bony reconstructive osteotomies, or both, is frequently utilized to correct gait deviations in youth with CP. MLS improves the mechanics or kinematic patterns of movement, as measured by three-dimensional motion capture; however, findings are mixed regarding improvements in function such as walking speed, gross motor capacity, walking activity (WA), and daily living skills. It is not clear why some children make functional gains and some experience a decline in function. A lack of evidence about the potential for functional change, leaves parents without crucial information when making decisions about MLS for their child. The broad goal of this research is to identify how surgical factors and patient factors affect functional outcomes so that families can make better informed decisions and surgeons/therapists can set appropriate goals. Differences in functional gains after MLS might be explained by the ‘dose’ of MLS, which can be ‘low burden,’ soft tissue surgery with or without a single boney osteotomy or ‘high burden,’ soft tissue surgery with two or more boney osteotomies. This project will examine kinematic and functional measures 1 year before and 2 years after MLS, utilizing existing data. Our primary aim is to examine differences in kinematic and functional outcomes between groups of youth with CP who had low burden and high burden MLS.
Chijioke Ikomi, MD Clinical Assistant Professor, Pediatrics, endocrinology Institution: Nemours Children’s Hospital  Website Project Title: Improving timing of diagnosis and equitable care in children with Turner syndrome  Summary: Turner syndrome (45,X), is a genetic condition that affects 1:2000 females. It includes several organ systems (cardiac, endocrine, gastrointestinal, neurodevelopment, ENT) and requires multiple evaluations and treatments through an affected individual’s life course. Early diagnosis enables timely intervention providing standardized and guideline-concordant care with potential for improved outcomes. Health disparities are prevalent across various populations and diseases, with higher incidence among individuals with socioeconomic disadvantage and within racial and ethnic minority groups. Knowledge about children with sex chromosome variations including Turner syndrome are increasing with the recommendation of noninvasive prenatal testing (NIPT) of pregnant women as standard of care in the US irrespective of age or risk factors. Despite this, limited studies exist in the literature that include children with sex chromosome variations across racial, ethnic, and socioeconomic groups. In addition, the effect of NIPT and the most recent Turner syndrome guidelines on timing of diagnosis of Turner syndrome is unknown. This study aims to identify temporal changes and factors associated with age at TS diagnosis, including whether early diagnosis rates have improved with increased recommendation of NIPT and following the most recent Turner syndrome guidelines published in 2017. In addition, we will assess associations between age at diagnosis and race, ethnicity, and socio-economic status. At the completion of the proposed research, we will have identified key factors associated with timing of diagnosis of TS, an important step in developing effective intervention strategies to enable timely diagnosis and improved outcomes in this population. Results of this investigation will provide the necessary pilot data for subsequent application for NIH funding, in addition to dissemination of knowledge through publications with the long-term potential for informing clinical care of children with SCA.
David Chen, MD, MPH Physician Hospitalist Institution: ChristianaCare  Website Project Title: Developing a Common Data Model for Cost and Intent of Firearm Injuries in Delaware  Summary: In 2020, firearm homicides were the leading cause of death in the United States for persons 1-19 years of age. Yet the total morbidity and cost of care of firearm injuries is likely underestimated in most analyses due to inaccuracies of ICD-10 coding for intent of injury, often misrepresenting assault injuries as accidental. Fragmented, siloed, and protected data precludes real-time epidemiologic surveillance that could inform and measure interventions. With recent public guidance and tools for chart-level analysis of EHR data, we will develop and test a Common Data Model to independently examine EHR data from 2018 – 2021 at both a Level 1 trauma center and through Delaware Medicaid Claims & Encounters data to determine health utilization patterns and costs. This will establish a baseline measurement and data framework of firearm injury incidence and costs of care by which to measure future impact from program implementation and policy changes that can be more rapidly deployed within institutions to evaluate shared longitudinal outcomes. Aim 1: Determine the number of persons 12 years of age and older with assault-related and firearm injury associated ICD-10 codes, as well as those with episodes of care of all healthcare encounters, from January 1, 2018 – December 31, 2021 at CCHS and in the Delaware Division of Medicaid and Medical Assistance (DMMA) databases Aim 2: Perform a chart review of identified patients with firearm injuries occurring at CCHS during the study period to determine accuracy of ICD-10 classifications of injury intent, and characterize factors related to misclassification. Then create standard definitions for ICD-10 related variables that describe initial injuries coded by mechanism and intent for the Common Data Model. Aim 3: Utilize the Common Data Model definitions originated in Aim 2 to query and summarize incidence of initial injuries by characteristics among CCHS records and DMMA firearm injury claims from 2018-2021.  Compare frequency and distributions of intent and injury to determine representative concordance. Calculate charges and total cost of care per person and service.

Take-off Awardees

Katie Butera, DPT, PhD Assistant Professor, Physical Therapy  Institution: University of Delaware   Website Project Title: Neurological-based low back pain subgrouping to advance a personalized care pathway for optimizing patient outcomes  Summary: Low back pain (LBP) is a complex disorder that can change an individual’s neural processing of pain. Evidence supports conceptualization and treatment of LBP as a neurological disorder, but it is rarely studied as such. Thus, despite substantial efforts to mitigate this pain condition, cost expenditures continue to increase, and patient outcomes remain poor. I will address these major scientific gaps by establishing a valid, neurological-based subgrouping method that could be used to enhance LBP prognosis and personalize LBP treatment. In preliminary work, we show that a neurological-based approach to subgrouping adults with LBP is not only possibly, but also clinically meaningful. We identified two distinct subgroups independent of age, sex, and chronicity. There was an “Adaptive” subgroup exhibiting more favorable neurological responses (i.e., high pain modulation, high pain coping, typical motor activation); and a “Maladaptive” subgroup exhibiting less favorable neurological responses (i.e., low pain modulation, high pain coping, atypical motor activation). The Maladaptive subgroup also demonstrated worse walking performance and higher pain and disability. A critical next step for advancing this line of work is to conduct a prospective, longitudinal cohort study of >200 adults with LBP that aims to a) confirm the neurological-based subgroups in a separate LBP cohort; b) evaluate whether subgroup classification predicts differential, longitudinal outcomes; and c) inform development and efficacy testing of a personalized, subgroup-matched intervention for improving LBP outcomes. However, additional longitudinal data is required to augment preliminary findings and optimize the potential to successfully compete for R01-level funding from the National Institutes of Health (NIH). Thus, the proposed pilot project will evaluate changes in pain-related neurological responses, as well as their contributions to clinical outcomes among 20 individuals with LBP across three timepoints (baseline, 1-month follow-up, 3-months follow-up). Specific aims are to: 1) evaluate changes in neurological responses—sensory pain modulation, psychological pain coping, and trunk motor activation—among individuals with LBP over 3 months; 2) determine whether worse neurological responses at baseline (e.g., lower pain modulation, lower pain coping, and atypical motor activation) are associated with higher pain and lower function at 3-months follow-up; and 3) use prior cross-sectional findings and new, pilot longitudinal data to develop and submit a competitive research proposal to NIH for conductance of a prospective, longitudinal cohort study of >200 adults with LBP. The culmination of this pilot project will be development of a rigorous, multi-timepoint study protocol that includes effective recruitment strategies and efficient testing procedures. Informed by the results and experiences acquired via completion of Aims 1 and 2, we will be well-positioned to launch a large-scale LBP cohort study and successfully advance an important line of research.
Dayan Knox, PhD  Assistant Professor, Psychological and Brain Sciences Department Institution: University of Delaware   Website Project Title: Understanding sex differences in traumatic stress reactivity  Summary:  Traumatic stress can lead to psychiatric disorders such as Post Traumatic Stress Disorder (PTSD) and women are twice as likely as men to develop psychiatric disorders after traumatic stress. However, reasons for this discrepancy are not well understood. Neural function within key nodes of the fear circuit show sex differences, which could underlie sex differences in sensitivity to traumatic stress. Unfortunately, this relationship has not been sufficiently explored, especially in animal models where neurobiological mechanisms can be readily examined. In male rats, conditioned freezing is elevated after extinction training (i.e. persistent fear memory) in animals previously exposed to single prolonged stress (SPS, a validated animal model of traumatic stress). Using fMRI techniques, data from our lab indicate that SPS decreases resting state functional connectivity (rsFConn) between the anterior cingulate cortex (ACC) and prelimbic cortex (PL) (ACCPL), as well as between ACC and infralimbic cortex (IL) (ACCIL) in male rats. The ACC, PL, and IL have been implicated in emotional regulation with the ACC and PL being critical for expressing fear memory and the IL being critical for inhibitory extinction memory. Previous studies suggest that persistent fear memory driven by SPS is linked to SPS effects on IL, not PL, function in male rats. Furthermore, ACC neurons have direct projections to the IL. These findings raise the possibility that SPS effects on IL-projecting ACC neurons lead to persistent fear memory in male rats. In female rats, SPS leads to persistent fear memory, but data from our lab indicate that SPS has no effect on PFC rsFConn (i.e. ACCPL and ACCIL) in females. These findings suggest that in female rats, persistent fear memory induced by SPS is not driven by changes in PFC circuits. The overarching hypothesis is traumatic stress-induced changes in PFC circuits leads to persistent fear memory in male, but not female, rats. In Aim 1 we use tract-tracing and double labeling immunohistochemistry to test the hypothesis that IL-projecting ACC neurons are excited with SPS exposure in male, but not female, rats. In Aim 2 we will employ chemogenetic techniques to show that reversing the impact of SPS on IL-projecting ACC neurons prevents persistent fear memory in male rats, but has no effects on persistent fear memory in female rats. The results from Aims 1 and 2 may reveal differences in how PFC circuits contribute to traumatic stress-induced changes in persistent fear memory in males and females. In Aim 3, we will use a combination of algorithms and clustering analyses to identify how rsFConn changes across the entire brain with SPS in male and female rats in order to identify a more comprehensive network of circuits that are sensitive to SPS in male and female rats. We anticipate that the network of circuits that are sensitive to SPS will be substantially different between male and female rats, with the male sensitive circuits involving PFC regions, but the female sensitive circuits not involving PFC regions.
Jennifer Peterson, PhD Assistant Professor & Medical Entomologist, Department of Entomology and Wildlife Ecology Institution: University of Delaware  Website Project Title: Harnessing a multi-scale One Health framework to estimate disease risk across human land use types in Delaware Summary: Chagas disease is a zoonotic, vector-borne infection caused by the parasite Trypanosoma cruzi. The disease is lifelong and can lead to potentially fatal cardiac or gastrointestinal alterations. Trypanosoma cruzi is spread between animals and humans by insect vectors called ‘triatomine bugs.’ The most widely distributed triatomine bug species in the United States is Triatoma sanguisuga. This species has never been formally studied in Delaware or any neighboring states, but numerous reports of the bug invading human homes exist from commercial areas, human homes, and recreational sites. In 2019, an adult T. sanguisuga bit a child on the face in her bedroom in Kent county. In July of 2023, a woman found an adult T. sanguisuga on her pillow inside her bedroom in New Castle county. She later found a second bug in her kitchen. Together, these events suggest that T. sanguisuga does make contact with humans in Delaware, but the extent to which contact occurs and in turn the epidemiological risk for T. cruzi transmission to humans is unknown. In this project, we will conduct the first study of Chagas disease vector species, Triatoma sanguisuga, in Delaware. Using a multi-scale One Health approach, we aim to, (1) determine T. cruzi infection prevalence and feeding behavior of T. sanguisuga across human-use types; (2) identify plant species associated with T. sanguisuga breeding and resting sites, which are currently unknown; and (3) use data collected in aims 1 and 2 to estimate risk factors for T. sanguisuga presence both within and across land use types. Methods used will include active and passive vector sampling, bloodmeal analysis, chloroplast DNA analysis, and statistical risk modeling. Results from this project will lay the groundwork for outreach and extension projects in our group that raise awareness about T. sanguisuga, provide vector education, and form connections with community stakeholders. In addition, this project is the first step in a longterm study that will include components such as (i) determination of sentinel animal species for T. sanguisuga presence; (ii) identification of breeding and resting spots of T. sanguisuga through vector geotagging; (iii) sampling across a representative portion of Delaware with site selection informed by data collected in this study; (iv) development of powerful computational methods trained on large datasets such as geospatial Bayesian hierarchical models for predicting vector and parasite presence as well as species distribution models for the state of Delaware and the greater Mid-Atlantic region.
Rosaria Formisano, PhD  Institution: Delaware State University   Project Title: Investigating the role of TRP-4 in modulating dopaminergic synaptic homeostasis in C.elegans  Summary: The overall goal of our research is to understand how neuronal functions and behavior are regulated by the molecular interactions that maintain levels of synaptic dopamine (DA). We utilized C.elegans as model organisms to better understand the cellular roles of two synaptic DA modulators: the presynaptic DA autoreceptor DOP-2 and the DA membrane transporter DAT-1. Based on functional imaging of individual synaptic termini, our previous work has shown that both the D2-like autoreceptor DOP-2 and the DA transporter DAT-1 provide a feedback loop in modulating synaptic DA levels. Our research has focused on exploring how DAT-1 and DOP-2 proteins interact to regulate DA release and reuptake in C.elegans. Regulation of DAT in vertebrates has been shown to be regulated by many mechanisms. One potential mechanism is that mediated by pre-synaptic D2 receptors. Electrophysiological and pharmacological in vivo studies have in fact shown a reduced activity of the dopamine transporter DAT in the absence of presynaptic D2 receptors. In addition, it has been shown that DAT activity is voltage-dependent therefore suggesting that either the DOP-2 autoreceptor or some other gene could act on DAT-1 activity by altering membrane potential. Based on these assumptions and on our results, we are now interested in investigating the involvement of a transient receptor potential (TRP) channel, trp-4, as a gene that could work together with DOP-2 and DAT-1 in mediating DA synaptic homeostasis in C.elegans. Our overall hypothesis is that TRP-4 activity is regulated by DOP-2 and contributes to the regulation of extracellular DA levels by decreasing DAT-1 activity. We propose the following aims to test this hypothesis: 1) Define genetic interactions between dop-2, trp-4 and dat-1 deletion worms through pharmacological manipulation 2) Verify the specificity of DOP-2 drugs in trp-4 and dat-1 mutants.
Shaukat Khan, PhD Research Scientist, Orthopedics, Skeletal Dysplasia Lab Institution: Nemours Children’s Health   Project Title: Novel Small Activating RNA Therapy for Moriquio A  Summary: Morquio A syndrome (mucopolysaccharidosis type IVA, MPS IVA) a lysosomal storage disease with an autosomal recessive trait is caused by the deficiency of the N-acetylglucosamine-6-sulfate sulfatase (GALNS). Deficiency of this enzyme leads to accumulation of specific glycosaminoglycans (GAGs): chondroitin-6-sulfate (C6S) and keratan sulfate (KS). The undegraded substrates are stored primarily in cartilage and in its extracellular matrix (ECM), leading to a direct impact on cartilage and bone development, and successive systemic skeletal dysplasia. In patients with MPS IVA, the cartilage is disrupted at birth as a consequence of abnormal chondrogenesis and/or endochondral ossification. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and various surgical interventions are available in practice. However, neither of the treatments completely restore skeletal system. Therefore, more effective, and affordable therapeutics are urgently needed to improve skeletal manifestations in MPS. We propose developing a small activating RNA (saRNA) therapeutic approach to test the central hypothesis that targeted overexpression of gene products corrects abnormal systems biology and ameliorates brain and bone lesions. saRNAs are chemically synthesized double-strand RNA oligonucleotides, which are highly selective and activate specific genes, leading to increased production of target proteins. saRNA has several advantages over ERT; single injection, longer half-life (6h but effect 6-8 weeks), no immune response, reaches to brain and bone, removes GAGs, and cost effective. In collaboration with Dr. Vikash Reebye (MiNA Therapeutic Limited, London UK), who is an expert in developing saRNA therapy this project will have long-term impact on MPS VI A population.
David Blauvelt, MD Institution: Nemours Children’s Hospital   Project Title: Perfluorochemical Therapies for Lung Injury Requiring Extracorporeal Life Support  Summary: Acute respiratory distress syndrome (ARDS) is associated with a mortality as high as 46%. Extracorporeal life support (ECLS) is an advanced therapy for severe respiratory failure that may improve outcomes by allowing the lungs to rest and recover from an acute lung injury. Unfortunately, the optimal respiratory support during ECLS is controversial, and conventional mechanical ventilation may cause further damage to the lungs. Furthermore, ECLS is a high-risk therapy that carries the potential of life-threatening complications such as bleeding, thrombosis, device failure, and infection. For this reason, it is important to identify strategies to enhance lung recovery on ECLS to enable separation from ECLS as soon as possible. ECLS offers a unique opportunity to deliver direct therapies to the lungs to enhance lung recovery. For patients supported on an ELCS circuit, the lungs are not needed for gas exchange. It thus becomes possible to fill the lungs with liquid therapies, which may otherwise impair efficient gas transfer. Unlike gas, liquid has the ability to more evenly fill the lung alveoli in a manner which may prevent further lung injury via alveolar overdistension or collapse. In this proposal, we hypothesize that liquid perfluorochemical (PFC) therapies will enable more homogenous lung recruitment, thereby improving recovery of lung mechanics. Furthermore, we hypothesize that this will translate into biochemical and histological evidence of reduced lung injury and decreased inflammation. We plan to test these hypotheses in an oleic acid lung injury model of severe ARDS in pigs. The results of this study may offer a new therapy for severe ARDS to improve outcomes and ultimately save lives.
Susan Birkhoff, PhD, MSN, BSN Program Director of Technology Research and Education Institution: ChristianaCare  Website Project Title: Mitigating Nurse Burnout: Implementing Evidence into Practice  Summary: Burnout is a significant problem in healthcare, especially among inpatient nurses. Although burnout has been studied extensively in nurses, it continues to plague the profession and perpetuates increased turnover and intention to leave the profession. Nurses and physicians have indicated that broader changes to their environment such as the need for uninterrupted breaks, a way to address poor management/clinical relationships, and improvement of the work environment. The purpose of this pilot implementation science proposal will be to evaluate the implementation of three interventions addressing critical needs identified by nurses that significantly contribute to their perceptions of burnout and increased turnover. The long-term goal of this pilot study is to obtain funding from the NINR after the foundational data has been collecting. The study seeks to reflect the success of interventions targeting elements directly responsible for increasing burnout rather than by providing psychological resources.

Booster Awardees

Jaclyn Schwarz, PhD Associate Professor, Psychological & Brain Sciences Department  Institution: University of Delaware Website Project Title: Transgenerational and Developmental Consequences of Maternal Postpartum Mood Disorder  Summary: Nearly 70% of women experience the “baby blues: or feelings of sadness, anhedonia or other mood disturbances in the weeks following the birth of a child. Fortunately, many women begin to feel better over the next few weeks, but approximately 20-30% of these women may continue to develop more severe, persistent postpartum depression (PPD). Postpartum Depression is one of the most common complications of childbearing, and suicide is one of the leading causes of death in new mothers in the United States -indicating that doctors may be unable to diagnose or effectively treat PPD within the relatively short timeframe that it emerges. Sadly, PPD is also associated with poor attachment and poor interactions with infants during the first year of their life, an effect that can have significant lifelong consequences for these babies. Previous studies have shown that both trauma, stress and associated depression in parents can affect the likelihood of depression in the offspring, particularly in rodent models. Yet, to date, no studies have examined whether vulnerability to PPD persists from generation to generation, via these maternal-infant interactions. Our lab has identified a rat model of individual vulnerability to postpartum mood disorder as measured by a significant and persistent decrease in sucrose preference in ~40% of new rat moms, an effect that we have replicated many times. Additionally, we have identified increases in anxiety and altered maternal care in these susceptible dams. The present study aims to examine whether these phenotypes persist into the subsequent generations of female offspring. The goal of these experiments is to leverage our unique model of individual differences to identify the generational effects of susceptibility to postpartum anhedonia. Moreover, we can leverage our unique model to examine the behavioral and peripheral factors, both immune and endocrine, as well as epigenetic marks that may predict or be a causal mechanism of the susceptibility or the resilience to postpartum anhedonia from mom to baby. Our hope is that these data can provide novel insights into the generational risk of postpartum depression, thus allowing for early intervention throughout pregnancy and identification of potential therapeutic targets.
William Kenkel, PhD  Assistant Professor, Psychological & Brain Sciences Department  Institution: University of Delaware  Website Project Title:  Gut Dysfunction Following Cesarean Delivery  Summary: Delivery by cesarean section has been associated with certain negative health outcomes in later life, including increased rates of childhood obesity. However, the causal mechanisms for this association remain unknown and virtually untestable in human populations. One mechanism for this increased susceptibility to obesity seen in children delivered via cesarean section is gut dysfunction, which has been suggested by our preliminary findings. We will therefore investigate the impact of cesarean delivery on metabolic health throughout the lifespan using an experimental study and animal model. Delivery by cesarean section results in lower levels of several ‘birth-signaling hormones’ and manipulations of these hormones in early life affects their regulation in later life. These ‘birth-signaling hormones’, namely oxytocin and vasopressin, are themselves important regulators of intestinal function and metabolism throughout the rest of life. We hypothesize that by altering levels of oxytocin and vasopressin during the sensitive period of delivery, cesarean section alters the developmental trajectory of oxytocin and vasopressin in ways that increase the offspring’s risk of gut dysfunction and obesity. To test this, we will measure gut anatomy and physiology in prairie voles delivered via either cesarean section or spontaneous vaginal delivery. In particular, we will focus on disruptions to the oxytocin and vasopressin systems of the gut and whether we can ameliorate any developmental consequences by treating cesarean-delivered offspring with ‘hormone rescue’ -a cocktail of oxytocin and vasopressin intended to stand in for the missing surge in birth-signaling hormones experienced by neonates during vaginal delivery. Understanding the long-term consequences of delivery by cesarean section in a translationally appropriate animal model would offer substantial gains to public health.
Erica Selva, PhD Associate Professor, Biological Sciences Department Institution: University of Delaware  Website Project Title: Structural and Mechanistic Exploration of Wnt Ligand Maturation  Summary: Wnt signal transduction is fundamental for the development of all animals and is responsible for the homeostasis of renewable cell populations in adults. During development, reduced or absent Wnt signaling results in a wide range of developmental defects and aberrant signaling in adults is recognized as a primary driver of cancers. While the numerous Wnt ligands and target receptors in receiving cells have been extensively studied, the maturation of virtually all Wnt ligands within sending cells is relegated to highly conserved yet understudied components, Porcupine (Por) and Wntless (Wls). Our initial characterization of Por and Wls function within the model organism Drosophila melanogaster to produce functional Wnt has informed much of our understanding of Wnt ligand maturation. Further characterization of the mechanisms by which these players interact to produce mature, active Wnt ligand is essential to better define how Wnt signaling is regulated. We discovered that Wls forms homo-dimers dependent upon intermolecular disulfide bridge formation, and these Wls dimers interact with Wg (2:1, Wls-Wg). Remarkably, this provides a universal mechanism for Wls dimerization and a possible explanation for the uncharacterized Wnt hand-off between Por and Wls in early ER Wnt processing. Our overarching project goal is two-fold: to characterize disulfide bonded Wls dimer interactions in forming Wnt maturation complexes, and to characterize disulfide bonded Wls dimer importance in Wnt post-translational modification, secretion, and signaling. We have generated various tagged forms of Drosophila Por and Wls wild-type and conserved cysteine mutants that will be used in co-immunoprecipitation experiments to examine the importance of Wls disulfide bonds in forming early Wnt maturation complexes. To determine if Wls cysteine mutants affect post-translational modification, secretion, and signaling, we will use readouts of Wg N-glycosylation by western blot, palmitoylation by click-chemistry, intramolecular disulfide bond formation by high molecular weight maleimide derivative labeling, secretion into media by western blot, and canonical Wnt signaling activity indicated by ß-catenin levels in western blot and in luciferase reporter assays. This work will lead to an understanding of how Wls dimers function within a cell to produce functional Wnt ligand, impacting our comprehension of Wnt cellular dynamics, processing, and secretion mechanisms. Results from this study have the potential to identify targeted therapeutics for diseases fueled by abnormal Wnt signaling.
Matthew Butchbach, PhD Research Scientist, Neurology  Institution: Nemours Children’s Hospital   Website Project Title: Multi-indication therapeutic strategies of early-onset motor neuron diseases   Summary: Neuromuscular diseases (NMDs) result in chronic, severe disability as well as early mortality and a high burden of disease. Motor neuron diseases (MNDs) are a type of NMDs where the spinal motor neurons— either the cell bodies themselves or their axons—are the primary cells affected. They also display clinical and genetic heterogeneity with at least 120 genes to date that are linked to these disorders. Most of these childhood-onset disorders, aside from spinal muscular atrophy (SMA), lack viable therapeutic options. Previous research on MNDs has focused on a single disorder, like SMA, which has led to therapeutic options for this rare disease. Unfortunately, therapies specific for SMA have not been effective against other pediatric-onset MNDs. This project proposed to determine the common and interacting molecular pathways and mechanisms involved in pediatric-onset MNDs using a systems biology approach. We hypothesize that there are common molecular and cellular pathways differentially affected in early-onset MNDs that would be amenable for therapeutics development. Using AR-42 as a small molecule agent, we will first demonstrate in Specific Aim 1 that AR-42 provides therapeutic efficacy against multiple, genetically distinct early-onset MNDs; in other words, AR-42 is multi-indication neuroprotective agent. In Specific Aim 2, we will demonstrate that AR-42 exerts its neuroprotective effects on early-onset MNDs by regulating distinct and interacting pathways, i.e. it is a multi-target neuroprotective agent. This study provides novel insights into early-onset MNDs as perturbations in complex adaptive biological networks. This project will also expand the therapeutic repertoire for many, if not all, of these disorders.
Xuyi ‘Kevin’ Yue, PhD Research Scientist  Institution: Nemours Children’s Health   Website Project Title: Development of PET imaging probes targeting VEGFR3 in the glymphatic-lymphatic system Summary: The glymphatic-lymphatic system plays an essential role in immune surveillance and clearance of metabolic waste. While the existence of brain lymphatic vessels (mLVs) was proposed more than 200 years ago, it was only reliably confirmed with solid experimental evidence in 2015. Fluorescent imaging and gadolinium-based contrast agents (GBCA) have since been used to probe the brain’s glymphatic-lymphatic system in rodents and nonhuman primates. In addition, various MRI methods have been developed to study the human glymphatic-lymphatic system. However, current strategies for imaging the glymphatic-lymphatic system have several limitations that preclude their use for in vivo imaging and application in the clinical setting. The vascular endothelial growth factor receptor 3 (VEGFR3), a tyrosine kinase receptor, is expressed exclusively by the lymphatic endothelium. Deletion of VEGFR3 in mouse pups led to a nearly complete lack of mLVs and compromised waste clearance. Positron Emission Tomography (PET) is a sensitive and noninvasive imaging modality (nM to pM) used to clinically assess metabolism, enzymes, receptors, and transporters at the molecular level. Here, we hypothesize that fluorine-18 labeled VEGFR3-specific radiotracers can be used for real-time PET imaging of the whole brain meningeal lymphatic system. To test our hypothesis, we propose three aims: 1) design and synthesize a series of fluorine-containing compounds targeting VEGR3; 2) identify radioligands with optimal binding affinity and selectivity; 3) preliminarily evaluate the new radiotracers to image the mouse glymphatic-lymphatic system. The project’s long-term goal is to achieve real-time measurement of the whole-brain glymphatic-lymphatic system function in vivo in normal and diseased conditions of clinical settings and study malfunction of the glymphatic-lymphatic system- related diseases, including multiple sclerosis, epilepsy, stroke, autism, and dementia. Our proposed preclinical study will thus be the first to design, characterize, and evaluate novel PET radiotracers targeted to VEGFR3 for functional imaging of the glymphatic-lymphatic system.