Duke University

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY/ABSTRACT Pediatric Crohn's Disease (CD) is a chronic, progressive disease which can have a severe impact on a child's growth, and development. Children are more likely to develop advanced forms of the disease within years of diagnosis. Treating pediatric Crohn's cases requires careful consideration as powerful anti-inflammatory treatments may have adverse effects and may not be necessary depending on severity of disease. Therefore, risk stratifying pediatric Crohn's populations, and predicting future subtypes, including structural manifestations of disease and a lack of response to treatments, is an urgent unmet need. While genomic markers of disease have been studied at length, exploration of the metabolic signature of pediatric Crohn's is less developed. Studies in recent years have identified metabolic changes which occur during Crohn's, including changes in lipid, amino acid, tricarboxylic acid and sulfur metabolism. But metabolic shifts have not been studied in enough detail or in large enough cohorts to become clinical biomarkers, especially for delineating subtypes of disease rather than Crohn's versus normal tissue. And although metabolic pathways are targetable and there are preliminary findings that blocking metabolic pathways (i.e., the mevalonate pathway), can be beneficial for Crohn's outcome, targeting metabolism has not become a widespread phenomenon. In this proposal, we will leverage computational methods to analyze transcriptomics data from large pediatric CD cohorts and map this data onto mathematical metabolic reconstructions to assess metabolic shifts. We hypothesize that identification of unique metabolic shifts in population-based cohorts will inform prediction of Crohn's subtypes, both structural and treatment-based. In Aim 1, we propose to build a novel computational metabolic network reconstruction that will be specific to the metabolic functioning of the ileum, a primary site of Crohn's pathology. This model will serve as a reference for understanding CD metabolic shifts but can also serve as a resource for other groups studying metabolism shifts in the small bowel. In Aim 2, we will leverage existing data from the large pediatric CD cohort, to computationally overlay transcriptomics from a range of subtypes onto our metabolic network reconstruction to assess shifts in metabolism. We will also recruit a prospective cohort of CD patients from both the University of Virginia and Emory University, collect tissue, perform RNA sequencing, and repeat our computational metabolic modeling to validate our analysis of archived data. These results will be further validated by mass spectrometry metabolomics and lipidomics. Finally, in Aim 3, we will profile the transcriptomic and metabolomic signatures of pediatric Crohn's-patient derived ileal organoids, to test if organoids are a valuable proxy for studying metabolic shifts in vivo for mechanistic intervention experiments. Together, these experiments will pave the way towards using high-throughput metabolic data to risk stratify pediatric Crohn's patient subtypes, which can facilitate personalized medicine treatment paradigms.

NSF Awards · FY 2025 · 2025-04

This NSF award supports the 2025 Association of Environmental Engineering and Science Professors Research and Education bi-annual conference. The event will take place in Durham, North Carolina, May 20-22, 2025. The conference focuses on human-environmental systems under global change. It will bring together roughly 700 environmental engineering researchers and educators to share ideas and to form new partnerships. The conference will feature workshops, technical presentations, a plenary program, and networking opportunities. The goal aims at spreading research and innovation. The event encourages participation from diverse communities. North Carolina consortium of universities (Duke, North Carolina A&T State University, NC State, UNC-Chapel Hill, UNC-Charlotte) will host the 2025 Research and Education Conference for the Association of Environmental Engineering and Science Professors (AEESP) in Durham, North Carolina on Duke University’s campus. Approximately 700 attendees will participate in this conference. The 2025 Conference theme is “Information and Engineering for the Public Sector: Data-driven stewardship of human-environmental systems under global change”. Its program features innovations by the AEESP community in research and education to develop and translate information for the public good. The conference will strengthen the connections between the AEESP research and education community with governmental agencies and diverse stakeholders. The conference format, including Workshops, Technical Sessions, Poster Sessions, Plenary Program, External Liaison, Social and Networking, Postdoc and Graduate Networking, provides ideal means for the dissemination of research results, through close interaction of participants from industry, government laboratories, and academia. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-04

Emotion dysregulation in pregnancy is an impairing transdiagnostic vulnerability factor that has critical implications for two generations. Although mental health in pregnancy has been a focus of basic and translational research, most studies have focused on maternal depression or anxiety, neglecting other severe clinical disorders characterized primarily by emotion dysregulation (e.g., personality disorders; self-injurious thoughts and behaviors). The proposed study will test the premise that targeting emotion dysregulation may have transformational benefits for pregnant women and, importantly, may function as a prenatal intervention to affect infant health prior to birth. This innovative R61/R33 proposal proposes a novel group skills intervention that will address the unique emotional needs of pregnancy by applying effective elements of dialectical behavior therapy skills—a treatment that is ideally suited for improving emotion regulation. We expect that reducing maternal prenatal emotion dysregulation will in turn improve infant neurobehavioral and self-regulation at birth and 6 months, making this a novel preventive intervention for infants. Data from our laboratories supports the premise that high prenatal emotion dysregulation associates with blunted maternal physiology and infant neurobehavioral dysregulation. Unknown is whether it is possible to improve maternal and infant health with a unique, emotion-focused intervention designed to engage two key targets: maternal emotion regulation skills or physiological regulation via respiratory sinus arrhythmia (RSA). In the R61 phase, participants will be randomized to our newly developed perinatal DBT skills (DBT-P) compared with an assessment only (AO) control (N=40/group) to establish target engagement of increased emotion regulation skills or resting-state RSA. In the R33 phase, findings will be extended by comparing DBT-P with an active control (Moms2B), an established prenatal group health-based intervention to improve nutrition (N=50/group), to determine whether DBT-P improves newborn and infant behavior regulation. Across both phases, women will be enrolled based upon high emotion dysregulation scores (≥88) on the Difficulties with Emotion Regulation Scale (DERS) and outcomes will be assessed with a pre-post, intent-to-treat design. Target engagement is defined as increases in clinician-assessed emotion regulation skills (clinical target) or resting-state RSA (biological target). To accomplish these innovative aims, we will use our established protocols to recruit, enroll, and retain dysregulated pregnant women and our existing strategies for assessing newborn neurodevelopment using the Neonatal Network Neurobehavioral Scale (NNNS) and infant self-regulation. This study capitalizes on the talents of the investigative team, which unites experts in maternal-infant mental health, clinical trials management, and DBT. Our study is significant because it will result in a novel intervention targeted specifically for emotionally dysregulated pregnant women with the innovative potential to improve infant regulation prior to birth.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY G protein-coupled receptors (GPCRs) shape neuronal function in response to various neuromodulators and neurotransmitters. Conversely, dysregulation of their signaling pathways has been linked to neurological and neurodevelopmental disorders. This highlights the physiological significance of these cascades and the pressing need to better understand their cellular regulation. Here, we focus on RNA binding motif protein 12 (RBM12), a novel mediator of neuronal GPCR signaling that we identified through a functional genomic screen for regulators of the pathway. RBM12 is a poorly understood and understudied factor genetically linked to neurodevelopmental and neuropsychiatric disorders. This proposal will build on preliminary data demonstrating that RBM12 is a repressor of GPCR/cAMP/PKA signaling and test the central model that RBM12 is an RNA-binding protein that regulates GPCR signaling post-transcriptionally. We will apply complementary RNA genomics, biochemistry, cell signaling, and electrophysiology assays in human induced pluripotent stem cell-derived neurons in order to 1) define the mechanisms governing the RBM12-dependent regulation of neuronal GPCR signaling, 2) delineate the RBM12 sequence features that underlie the regulation and determine whether these are disrupted by disease-associated human polymorphisms, and 3) characterize the role of the RBM12-GPCR interplay in shaping neuronal activity. Successful completion of the studies will yield an integrated mechanistic and functional understanding of RBM12’s role in receptor-dependent neuronal function. Additionally, our analyses could pave the way for in vivo characterization of this interplay to establish RBM12-dependent dysregulation of GPCR/PKA cascades as a tentative novel mechanism underlying neuronal disorders associated with rare human mutations in that gene.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY/ABSTRACT Humans prefer foods to which they have been exposed early in life. This has significant implications for obesity as early exposure to foods with excess sugar can lead to unhealthy food choices later in life. However, the mechanism by which early food exposure leads to long-term changes in food preferences is unclear. Recently, it has been established that specialized sensory cells in the gut epithelium called neuropod cells respond to sugar within the small intestine. Further, neuropod cells are essential for driving choices for sucrose over artificial sweetener. Therefore, it stands to reason that neuropod cells could be involved in long-term food preferences. However, enteroendocrine cells, a class of cells in the gut epithelium that includes neuropod cells, are believed to turn over rapidly with some studies suggesting a lifespan as short as three-to-five days. Therefore, it is unclear if the longevity of neuropod cells supports a role in long-term food preferences. Preliminary data included in this proposal finds a population of neuropod cells, called long-lived neuropod cells, that can live up to six months—a quarter of the life of the animal. Further, these preliminary data show that long-lived neuropods have more connections with sensory neurons than their less mature counterparts. Because in other sensory systems like olfaction, active receptors survive, and it has been established that neuropod cells reliably respond to sugar in the small intestine, this proposal hypothesizes that response to sugar leads to increased connections with neurons that facilitate survival. The first aim of this proposal will test this hypothesis using a 2D gut organoid model to evaluate the effect of supplemental sugar and the presence of neurons on neuropod cell activity and survival. The second aim of this proposal will focus on the function of long-lived neuropods with regards to sugar preferences. Using a combination of targeted ablation and optogenetic inhibition, this proposal aims to show that long-lived neuropods are necessary for the establishment and maintenance of long-term sugar preferences. Overall, this proposal will seek to characterize a long-lived gut-brain pathway and define its role in terms of long-term gustatory behavior. This has significant implications for obesity, but since chronic gastrointestinal disorders such as the Disorders of Gut-Brain Interaction (DGBI), which include irritable bowel syndrome and chronic constipation, are also believed to act via a gut-brain mechanism, defining a functional long-lived gut-brain circuit is essential for the study of these diseases as well. In addition to making a significant contribution to the study of gut-brain interactions, this fellowship includes critical technical and knowledge-based training in sensory biology for Dr. Zachary Lorsch. Combined with training in leadership, mentorship, and communications provided by sponsor Dr. Diego Bohórquez and co-sponsor Dr. Rodger Liddle, this fellowship will allow Dr. Lorsch to fuse his background in molecular neuroscience with his clinical training in gastroenterology and become a successful physician- scientist researcher at the intersection of neuroscience and gastroenterology.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY / ABSTRACT Our goal is to enable the investigation of interactions between the skin microbiome and skin cell populations using genetically modified 3D in vitro models. The human skin microbiome – encompassing hundreds of bacterial and fungal species – has essential roles in maintaining skin health. Skin microbiome dysfunction or pathobiont expansion can contribute to diverse skin infections, inflammatory disorders, and skin cancer. It is important to identify the interactions that could go awry in skin disease and to evaluate the impact of potential therapeutic approaches for skin diseases. However, a detailed mechanistic understanding of how these various microbes interact with host cells to maintain skin health or promote skin disease is lacking. This knowledge gap is exacerbated due to an inability to examine host-microbe interactions at the scale needed to probe potentially hundreds of microbes and host genes of interest involved in these mechanisms. Here, we will leverage 3D human reconstructed epidermis (RHE) cultures built from keratinocytes and fibroblasts in an air- liquid interface (ALI) to develop a platform that allows us to knock out human gene function and colonize with diverse skin microbiota. We have previously used the RHE model to examine the effects of colonization of 180 genetically diverse skin staphylococci on skin barrier and innate immunity. Using single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST), we were able to pinpoint cell-type-specific interactions in our model. However, a major gap was the ability to interrogate host mechanisms, most effectively by gene knockout or knockdown. Recently, we built 3D ALI cultures with CRISPR/Cas9 KOs in primary bronchial epithelial cells to investigate the innate immune response to microbial colonization. We propose using a similar approach to build KO keratinocytes and fibroblasts to generate multi-cell type 3D KO RHEs that will enable us to investigate skin's host-microbiome interactions. In Aim 1, we will create 3D RHE ALI cultures with CRISPR/Cas9 knockouts (KO RHE) in a panel of skin barrier and innate immunity genes in immortalized N/TERT keratinocytes, which we will then colonize with commensal and pathogenic skin microbes. In Aim 2, we will add an immortalized hTERT fibroblast layer to the KO RHE model (F-RHE) and similarly colonize with the microbial panel. We will use immunohistochemistry, RNA-seq, scRNA-seq, and ST to characterize KO RHEs' effect on fibroblasts to pinpoint microbial and keratinocyte-fibroblast interactions that change with KO of important skin barrier and immune components. By developing a 3D skin KO model coupled with a cutting-edge `omics approach, this proof-of- principle study will enable the construction of large-scale, high-resolution spatial and functional maps of skin microbiome-host cell interactions. Given the extensive biodiversity of the human skin microbiome, this platform will be valuable for deconstructing and pinpointing interactions that could be disrupted in skin disease and for evaluating the impact of potential therapeutic approaches for skin diseases.

NIH Research Projects · FY 2026 · 2025-04

Tobacco smoking is extremely addictive and remains a leading cause of preventable death. Individuals with chronic pain are approximately twice as likely to smoke cigarettes as those without pain, and smoking cessation among people with comorbid pain is more difficult to achieve. Smoking and pain have been proposed to influence each other through a maladaptive reciprocal positive feedback loop, in which pain increases motivation to smoke and smoking worsens pain over time. Moreover, smoking withdrawal exacerbates pain, thus presenting an additional barrier to smoking cessation. However, the mechanisms underlying withdrawal- induced exacerbation of pain (hyperalgesia) and the real-world impact of withdrawal-induced hyperalgesia among people attempting to stop smoking, remain unclear. To fill this important scientific gap, we will evaluate among people who smoke (PWS) with and without chronic pain: 1) the impact of smoking withdrawal on brain fMRI-based response to noxious heat stimuli (Aim 1); and 2) the influences of withdrawal-induced hyperalgesia on the ability to abstain from smoking (Aim 2). Adults who smoke daily with (n=48) and without (n=48) chronic pain will each complete 2 fMRI scans with counterbalanced conditions: after smoking ad libitum, and after 24- hrs biochemically verified abstinence. During the fMRI scans, participants will experience and provide pain ratings to a pseudorandom series of neutral and noxious heat stimuli. Participants will complete a 1-week abstinence test with a descending reinforcement schedule previously used by our group, accompanied by ecological momentary assessment (EMA) of pain, affect, and smoking urge. We hypothesize based on our preliminary data that: 1) increased pain during smoking withdrawal will correlate with decreased activation of the bilateral inferior frontal gyrus (IFG) indicating reduced cognitive-affective regulation of pain; 2) PWS with chronic pain will exhibit greater withdrawal-induced deficits in IFG activation; and 3) Chronic pain status and withdrawal-induced changes in pain ratings and pain-related brain activation will predict shorter time to lapse. By addressing a critical gap in scientific knowledge regarding the neural basis and behavioral impact of smoking withdrawal-induced hyperalgesia, the project will provide a foundation for development of targeted behavioral, pharmacological, and neurostimulation interventions to aid smoking cessation.

NIH Research Projects · FY 2026 · 2025-04

Abstract The ability to learn which action strategies produce positive outcomes is a central process for adaptive behaviors. Through repetition, action strategies naturally evolve from a flexible (goal-directed) phase into an automatic (habitual) phase. The dorsal striatum is required for the transition between goal-directed and habitual action strategies. Studies over the past two decades have demonstrated that dorsomedial striatum (DMS) is required for goal behavior whereas the dorsolateral striatum (DLS) is required for habitual behavior. Numerous studies have associated long-lasting modifications of DLS circuitry with habitual behavior, but all these plasticity observations were from bulk stimulation of unidentified cortical inputs to striatum. Therefore, it is unknown which cortical inputs to striatum undergo long-lasting modifications over the course of habit formation nor the role these plasticity sites play in habit expression. This project employs two unique strategies to fill this gap. First, we will genetically isolate the two major types of cortical inputs to striatum, the pyramidal tract (PT) and intratelencephalic tract (IT). PT circuits are selectively active during movement; therefore, it is possible long-term modifications of PT circuits sustain motor output for habit expression. Second, we will identify novel cortical regions whose activity is modulated by behavioral transitioning from goal to habit states using Fos-TRAP2 technology. Aim 1 will test the hypothesis that habit expression is accompanied by selective plasticity of PT inputs, and not IT, using optogenetic approaches to activate and quantitatively measure the synaptic strength (whole cell patch clamp and 2-photon imaging of GCaMPs) of PT and IT inputs to striatum in acute brain slices from behaviorally defined mice. I will target orbitofrontal cortex (OFC) inputs to DMS and secondary motor cortex (M2) input to DLS based on preliminary data and published studies suggesting habit is associated with weakening of OFC circuits and strengthening of M2 circuits. Outcomes will provide the first measure of these specific synapses in goal and habit states. Aim 2 will test the hypothesis that weakening OFC pyramidal tract inputs to DMS speeds habit, whereas weakening M2 pyramidal tract inputs to DLS delays habit. I will test this using cell specific pharmacology (DART technology) to dampen glutamatergic input to PT or IT cortical circuits that innervate striatum, thus establishing causal contributions of defined corticostriatal circuits to the expression of habitual behavior. Aim 3 will construct a state-dependent map of neuronal activity across cortical regions that innervate DMS and DLS using molecular genetic capture of activity ensembles (Fos-TRAP2 technology) and immuno-staining. Outcomes are expected to identify novel cortical regions associated with habitual behavior. Collectively, completion of this proposal will identify circuit-specific plasticity mechanisms involved in habitual behavior, producing a detailed plasticity model to better understand neural basis of adaptive habit formation and how disruptions in this process may accompany numerous neuropsychiatric disorders.

NSF Awards · FY 2025 · 2025-04

Understanding the relationship between protein structure and function remains a major challenge. This knowledge would benefit drug design, recycling, and chemical production. This project is designed to learn how to create proteins that will facilitate reactions seen in nature. Artificial intelligence will interpret the data generated by experiments. Two classes of enzymes will be modified to facilitate novel reactions. To help diversify the STEM workforce, workshops in machine learning will be offered to students interested in protein design. Summer research opportunities will be offered to high school and undergraduate students traditionally underrepresented in STEM fields. In this project, protein engineering is treated as a Bayesian optimization problem, with the objective to explore sequence space for improved specific activity. This approach models both the expected activity and the uncertainty of the prediction made. Training deep learning models is data intensive. A convolution neural net (CNN) using transformer architecture will use simulated sequence-function data to pretrain. The simulated data will be generated using Rosetta. Pretrained CNN will be refined with experimental data generated using combinatorial codon mutagenesis (CCM). Enzyme activity in single bacterial cells will be monitored using GFP expression, FACS-based screening, and next-generation DNA sequencing to determine the corresponding amino acid sequences. Biosensor screening can suffer from crosstalk when multiple cells are present. A picoliter-scale microdroplet screening technology developed in the Romero lab will be utilized to avoid this issue. A simulated annealing algorithm to randomly search over sequence positions and degenerate codons for libraries with high values for the expected batch BO objective will be developed. In addition, a probabilistic program using sampling-based inference to estimate the optimal combination of codons will be designed and implemented. This project is jointly supported by the Division of Chemical, Bioengineering, Environmental and Transport Systems (CBET), the Division of Chemistry (CHE), and the Division of Information and Intelligent Systems (IIS). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-04

Abstract Dynamics of Olfactory Processing: Segmentation in the Piriform Cortex The proposed research aims to uncover fundamental principles of sensory processing by examining how the piriform cortex (PCx) in the mammalian brain encodes and represents olfactory information. This work is critical for advancing our understanding of neural coding, which has broad implications for sensory neuroscience and can inform approaches to neurological disorders that affect sensory perception and processing. Our study leverages innovative techniques to record from hundreds of PCx neurons in awake, head-fixed mice while using optogenetics to stimulate the olfactory bulb (OB) in precise, spatiotemporally defined patterns and manipulate neural circuits with novel tools to reveal underlying mechanisms. These methods will allow us to test our overarching hypothesis that the PCx segments incoming OB input into discrete temporal packets within a respiratory cycle. To this end, we propose the following aims: Aim 1: Determine the temporal selectivity of PCx responses to OB stimulation. We hypothesize that PCx neurons jointly encode both OB input and respiration phase. We will test this aim by delivering brief single light pulses to different dorsal OB spots, aligning stimulation with the respiration phase. We predict that PCx cells are tuned to respiration phase, showing varying amplitudes but invariant phase preferences across OB inputs. Aim 2: Investigate the neural circuit mechanisms underlying PCx respiration phase preferences. By performing various targeted circuit perturbations, we will test the following hypotheses: We hypothesize that phase tuning is reafferent, that feedback inhibition modulates response gain and sharpens tuning, and recurrent circuitry redistributes phase preferences to uniformly tile the sniff cycle. Aim 3: Assess whether PCx responses to odors are phase-locked. Ultimately, we need to test the hypothesis that PCx responses to odors are segmented and exhibit phase tuning. Therefore, we will (3.1) deliver multiple odors using 1-sec. odor puffs. Unlike the OB, we hypothesize that cells responding to multiple odors should show different amplitudes but identical latencies. Achieving these aims, our research will reveal, characterize, and mechanistically probe a novel framework for understanding how odor information is encoded in the PCx. This knowledge could eventually lead to novel strategies for diagnosing and treating sensory processing disorders and enhance our ability to develop artificial sensory systems.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY/ABSTRACT Pediatric Crohn's disease presents as a chronic, relapsing inflammatory condition of the gastrointestinal tract, leading to malabsorption, anemia, and psychosocial decline. The incidence rate of Crohn's disease has been growing in the 10- to 18-year age group. Crohn’s disease exists on a spectrum of clinical severity, ranging from mild disease responsive to standard anti-TNFɑ therapy to severe, treatment-resistant disease with stricturing (B2) or penetrating (B3) complications often requiring surgical intervention. Distinguishing which patients will progress to more severe disease from patients who will require minimal intervention at the time of diagnosis is an urgent unmet need. Accurate and automated prediction of disease outcomes will significantly improve patient health by informing personalized interventions for individual patients. Previous attempts at generating predictive models of Crohn’s disease relying solely on clinical features of the disease and patient biodata have demonstrated promising, yet inadequate accuracies for clinical practice applications. This proposal addresses these limitations by leveraging large cohorts of archival and prospective patient clinical metadata, ‘omics, and machine learning derived tissue features to build and test machine learning models for predicting specific Crohn's disease outcomes. In Aim 1, we will build, test, and validate predictive models of Crohn’s disease using computational image analysis of gold-standard biopsy histopathology slides. We will use saliency maps and gene correlations analysis to validate our models by visualizing the tissue features of importance to our predictive models and identify specific transcriptomic changes associated with these features. In Aim 2, we will generate a clinically-relevant predictive model of Crohn’s disease by integrating the deep features extracted from histology image analysis with other patient metadata collected as part of standard clincal care. Additionally, we will collate a thorough list of published predictive models of Crohn's disease to benchmark the performance of our proposed and future predictive models. Lastly, in Aim 3 we will use cutting edge single-cell RNA sequencing and spatial transcriptomics approaches to elucidate a transcriptomic signature of Crohn's disease and characterize specific genetic profiles associated with the hallmark morphological changes in diseased tissue. These data will provide a framework for studying the subtypes and clinical outcomes of Crohn’s disease and other gastrointestinal diseases, thus driving the clinical adaptation of personalized therapy and precision medicine. This proposed research will increase the resolution of both diagnostic and prognostic information to better manage Crohn’s disease in patients and significantly shft clinical management to an individualized treatment paradigm.

NSF Awards · FY 2025 · 2025-03

Language and language expertise have a role in the criminal legal system, whether it be through the interpretation and meaning of documents or testimonies, the treatment of the defendants, witnesses, and experts, or the processes through which juries and judges interpret and understand the evidence they are presented. Forensic linguistics, which focuses on criminal investigation, has had a significant impact, but other approaches in the scientific study of language generally have had less prominent engagement. This conference brings together language scientists who are working on issues in criminal science with lawyers and other social and behavioral scientists to explore and promote new lines of interdisciplinary research on language in criminal legal contexts to advance practice in the U.S. criminal justice system. This conference advances scientific domains at the intersection of linguistics, law and science, and other social and behavioral sciences. Other benefits to society include educational opportunities for students in addition to early career and established researchers. The conference brings together experts and practitioners to identify current areas of successful collaboration and areas where linguistics can have greater impacts. Many experts contribute talks and panel sessions, and an open poster session showcases current empirical projects. The conference provides guidance and support to students and early career scholars with interests in addressing language in criminal legal contexts. The conference is co-located with a large, established gathering of language scientists to enhance the opportunity to advance work at this intersection, by hosting these activities in a setting that is accessible to a wide range of faculty and students. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-03

ABSTRACT: Preterm birth is the leading cause of life-long neurodevelopmental impairment (NDI) in infants. Common complications of prematurity such as intestinal perforation confer a significant risk for diffuse myelination deficits and NDI. Diffuse hypomyelination can reliably detected after affected infants reach term corrected ages however, this is often months after the intestinal perforation has occurred. Using our mouse neonatal modeled intestinal perforation (MIP) model, we discovered a previously unrecognized injury to the multiciliated ependymal cell layer that forms the ventricular border of the subventricular zone (SVZ) neural stem cell niche. The functional role the multiciliated ependyma extends beyond controlling CSF flow and barrier formation but is known to involve the regulation of SVZ progenitor populations within the niche. In our MIP model, disruption of the ependyma was associated with increased echogenicity on cranial ultrasound. Our animal research led us to interrogate the SVZ and germinal matrix of preterm infants using cranial ultrasound following intestinal perforation leading to the novel discovery that a subset (~40%) of preterm infants develop subventricular zone echogenicity (SVE) as early as 48 hours after intestinal perforation. Importantly, the development of SVE was a predictor of NDI on the 2- year Bayley test suggesting that SVZ injury is an early mechanism of brain injury and NDI in human preterm infants. Our preliminary data comprising of both single cell and spatial transcriptomic approaches, support the hypothesis that NFkB-enriched IL-1b producing peripheral monocytes traffic onto the ependymal surface of the lateral ventricles via the choroid plexus where they seed the surface of the SVZ. Our preliminary data identified a unique role for IL-1b at disrupting ependymal cell survival relative to TNFa or IL-6. Our preliminary data also revealed that the LXR agonist, 20-aHydroxychoelsterol, suppresses NFkB signaling and IL-1b production in the monocyte/macrophage lineage and appears to prevent MIP-induced SVZ injury. Our central hypothesis is that blood-born monocytes infiltrate the SVZ and increase localized IL-1b production leading to the disruption of the ependymal barrier and collapse of this critical stem cell niche’s functions. Aim 1 will use scavenged blood samples from preterm infants with intestinal perforation to define immune signatures associated with the development of SVE using a scRNAseq approach. Aim 2 will define immune signatures that are associated with murine SVE and compare our findings to the human data generated in Aim 1. We will also investigate the role of monocyte/macrophage accumulation in the choroid plexus and their role in SVZ injury. Aim 3 will utilize genetic approaches to interrogate the specific role of monocytic-derived IL-1b on SVZ injury and determine if 20HC is a viable therapeutic approach to brain injury in preterm infants.

NIH Research Projects · FY 2026 · 2025-03

Project Summary/Abstract Hepatocellular carcinoma (HCC) is on track to surpass breast, prostate, and colorectal cancer to become the third-leading cause of cancer death in the United States by 2040. HCC-related deaths in men outnumber those in women by more than 3:1 and this is thought to be due to male hormone signaling mediated by the transcription factor androgen receptor (AR). AR is commonly expressed in HCC and increased AR activity corresponds with worse HCC outcomes. AR inhibition is highly effective for the treatment of prostate cancer, but clinical trials to inhibit AR signaling in advanced HCC have been unsuccessful to date. Here, we study a new genetically engi- neered mouse model of HCC (Alb-Cre;Trp53fl/fl;Tsc1fl/fl) that recapitulates the sex differences observed in human HCC. Resultant liver tumors are AR positive and tumor growth is responsive to hormonal manipulations, making the model an ideal platform to functionally assess the role of AR in HCC. We hypothesize that AR is a required mediator of mTOR-driven growth in HCC and propose combinatorial AR and mTOR inhibition may be an effective therapeutic strategy to treat advanced HCC. Our preliminary data demonstrate that AR inhibition via surgical castration prevents the development of liver tumors while treatment with AR agonist dihydrotestosterone pro- motes liver tumors in this mTOR-driven model. To test our central hypothesis, we propose the following aims: 1) measure the effect of AR signaling on the oncogenic traits of HCC models, 2) define the transcriptional profile of the AR in HCC, and 3) determine the therapeutic potential of AR inhibition in patient-derived HCC xenografts and a genetically defined autochthonous mouse model of HCC. The accompanying training plan incorporates a broad range of experimental methods to orthogonally assess the role of AR in HCC while cultivating critical problem-solving skills and immersing the trainee in a highly productive multi-disciplinary scientific laboratory environment combined with focused clinical training in clinical oncology.

NSF Awards · FY 2025 · 2025-03

Forest fires profoundly alter the ecological communities that inhabit affected areas and may have played a significant evolutionary role among multiple animal lineages including primates. The role of fires in the ecology and evolution of primates is not well understood, because most current primate species live in tropical forests where fire studies are rare. This doctoral dissertation research assesses how forest fires affect primate species that have different diets. The research provides context for studies of primate and human evolution since wildfires may have played a significant role in the transition from forest to savannah environments when hominins were first emerging. Results from this study are relevant to the assessment of current conservation efforts. Additionally, the project provides training and educational opportunities for K-12, undergraduate and graduate students. This study assesses how forest fires affect primates with different dietary traits, by focusing on two food sources suggested to benefit primates after fires: new foliage and insects. Applying surveys and distance sampling methods, this research measures and compares the post-fire population densities of seven non-human primate species across dietary niches. The study evaluates changes in the availability and nutritional content (water, protein, fiber, and condensed tannin) of leaves from known food species in burned and adjacent unburned forest. Additionally, resource abundance and isotopic niches among sympatric species are analyzed to determine whether fire-induced changes lead to dietary overlap among them. The study informs primate conservation and primate evolution. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY Child abuse and neglect are common among US children and consequential for later-life health and wellbeing, including hypertension, obesity, cardiovascular functioning, substance use, and depression. Foster care placement, which is an important strategy through which Child Protective Services (CPS) remedy the risk of future harm, is also associated with myriad deleterious outcomes. Because each of these experiences— child maltreatment and foster care placement—are unevenly distributed by race and socio-economic status, they may contribute to health disparities. Unfortunately, prior research on the effects of both of these childhood experiences is generally limited to the study of health in adolescence or early adulthood and does not differentiate health consequences due to maltreatment from health consequences due to foster care placement. Indeed, few studies consider the potentially moderating effects of maltreatment dosage on health outcomes or control for well-established determinants of health, such as genetic disposition, personal behavior, and environmental contexts. These limitations significantly diminish knowledge about the potentially heterogeneous effects of childhood traumatic events on health and wellbeing, the persistence of those effects throughout the life-course, and the potentially remedial or additive effects of important state interventions in family life. This in turn constricts the ability to design policies that reduce long-term health disadvantages among vulnerable children without introducing new sources of social vulnerability. Our project closes this knowledge gap by leveraging the unique advantages of the National Longitudinal Study of Adolescent to Adult Health (Add Health), which tracks a national cohort from childhood into mid-life and includes detailed measures of childhood victimization as well as unique biomarker data and information on core social determinants of health. The project uses these data to (1) extend the scope of existing associational studies of health outcomes from early adulthood until mid-life, (2) study the persistence of health disadvantages among maltreated and fostered children, (3) disaggregate the effects of maltreatment and foster care on health outcomes, and (4) assess how such effects differ across socio-demographic categories and the dosage of childhood abuse and neglect.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY/ABSTRACT The measurement of intraocular pressure (IOP) is an integral part of the standard eye exam and elevated IOP is the greatest risk factor for the development of glaucoma, the most common cause of irreversible blindness. While the measurement of IOP, called tonometry, is frequently represented as a single number, the IOP is quite dynamic with pulsations due to the cardiac cycle: the IOP peaks during systole and troughs during diastole. The difference between the systolic and diastolic IOP is called the ocular pulse amplitude (OPA). Clinicians have long been aware of these ocular pulsations and the presence of these pulsations can make it difficult to measure the IOP: a large OPA is associated with significant IOP measurement variability. Fundamentally, the historical method of using a single, snapshot IOP to represent such a dynamic element, results in greater variability than desired and ignores much of the physiology of IOP and its effect on the eye. Prior studies have reported reduced OPA in eyes with glaucoma compared with controls and that reduced OPA was associated with worse glaucoma severity and a higher risk for glaucoma progression. Reduced OPA has been observed in biopsy-proven, giant cell artieritis, exudative age-related macular degeneration and diabetic retinopathy. While there are many preliminary studies that suggest the importance of OPA in the health of the eye, further study and has been hampered by the lack of devices to measure OPA. The rationale for this project is to develop a novel and validated method for measuring the OPA. This objective will be achieved by pursuing two specific aims: 1) validate applanation-based OPA measurements on nonhuman primates implanted with an IOP telemetry system in normotensive and hypertensive eyes; and 2) assess repeatability and reproducibility of OPA measurements in normotensive and hypertensive eyes. Under the first aim, the algorithm for two previously developed applanation-based tonometers will be modified to allow calculation of the OPA. Measurements with both devices will be acquired on implanted non-human primates and the device measurements will be compared to the telemetrically recorded values. Following algorithm optimization, a repeatability study with both devices will be conducted on normal and hypertensive eyes in the implanted nonhuman primates. Under the second aim, the previously optimized algorithm will be used first in a pilot study to assess proper performance in humans, followed by a study to assess the repeatability and reproducibility of both devices in normal and hypertensive human eyes. The proposed research is technically innovative because it proposes a novel technique for measuring the OPA using applanation that will be uniquely validated against manometrically-derived, ground truth IOP and OPA measurements. This innovation improves clinical care by improving reliability and accuracy of tonometry and opens new research horizons to allow improved understanding of the role of OPA in normal and abnormal ocular physiology.

NIH Research Projects · FY 2026 · 2025-02

Abstract: Sturge Weber Syndrome (SWS) is a sporadic (non-inherited), developmental, neuro-cutaneous syndrome characterized by a capillary vascular malformation affecting the skin of the face, and abnormal capillary venous vessels in the leptomeninges of the brain and choroid. The choroidal vascular malformations lead to glaucoma, and the leptomeningeal vascular malformations lead to epilepsy, stroke-like episodes, and cognitive impairment. In 2013 we (a multi-institutional team) identified the cause of SWS by whole genome sequence analysis. The identical somatic mutation (c.548G→A, p.R183Q) in GNAQ (encoding Gαq) was identified in affected tissue that was absent in unaffected tissue from the same patients. Despite this discovery over a decade ago, to date, no fully faithful animal model of the disease has been developed. We hypothesize that the lack of a robust mouse model is due to two significant gaps in knowledge that need to be answered before any truly faithful animal model can be generated. Our central hypothesis is that SWS occurs 1) only if the causative somatic mutation occurs in a particular fetal cell type during development and 2) only when it occurs within a specific developmental time window. We recently published a mouse model of SWS, using conditional allele integrated into the endogenous locus that expresses the mutant version of GNAQ only upon Cre recombination. These mice develop vascular malformations in the embryo but are embryonic lethal. We propose to address the two gaps in knowledge listed above using our novel transgenic model to identify the developmental time window when the embryonic vascular malformations form, and then using transcriptomics, to identify the cell type in the earliest developing lesions that expresses mutation. These experiments will provide critical information about SWS pathogenesis, that will in future studies, us to then integrate this knowledge to generate a faithful mouse model - or different, organ-specific models - of the disease. In future work beyond the scope of this study, our mouse models will enable mechanistic studies on SWS pathology in the various organs affected.

NIH Research Projects · FY 2026 · 2025-02

Background/Significance: Pulse oximetry is the most common method to monitor arterial oxygen saturation in patients in modern medicine. This technology reflects light off oxygenated blood to approximate the more accurate arterial blood gas (ABG) tests. Recent findings demonstrate that pulse oximeters are more inaccurate in patients with darker skin tones, likely due to interference by skin tone. Minority patients consequently experience disproportionately more hidden hypoxemia (HH), which occurs when pulse oximetry overestimates oxygen levels as within the normal range (≥ 88%) but demonstrate hypoxemia by the more accurate ABGs. However, ABGs are painful to administer and only provide episodic data, so they are used less frequently than pulse oximetry. Furthermore, minority patients are less likely to receive ABG tests, making it even more likely that the problem is underestimated. Innovation: Replacing our pulse oximeters will require significant investment and time. However, a two- stage alternative solution is possible now, leveraging existing pulse oximetry hardware. HH causes patients to have internal organ malfunction, which is reflected in abnormal vitals and laboratory values. We will develop solutions in this multi-health system study (Duke Health, Emory Healthcare) spanning 9 hospitals. In Aim 1, we use routinely-collected electronic health record (EHR) data to develop a machine learning (ML) model to predict which patients are at high risk for HH. Furthermore, we use informative sampling to identify which patients may best benefit from an ABG. Some of these informative patients may benefit from skin tone measurement. In Aim 2a, we measure skin tone using multiple methods - administered visual scales (Fitzpatrick, Monk) and color measurement devices (colorimeters, spectrophotometers, mobile phone cameras) - across patients in hospitals to predict the degree of pulse oximetry bias in critical illness. Using informative sampling in Aim 2b, we build on Aim 2a patients to iteratively identify and test which factors best identify skin tones that will best improve our ML models. Finally, we prospectively perform silent validation for Aims 1 and 2 models in Year 5. Next steps: The results of this proposal will build silently validated, implementation-ready ML models that can mitigate the impact of HH using current pulse oximetry hardware and EHR data. Furthermore, by measuring skin tone, it can mitigate the impact of skin tone on pulse oximetry bias through new ML models when combined with EHR data. Finally, this project will conduct silent validation to ensure temporal validity and understand the impact within current workflows. Completing this project will form the foundation for two future R01 proposals to conduct cluster randomized trials to test the implementation of EHR-only (Aim 1) and skin-tone augmented EHR ML models (Aim 2) to mitigate the effects of pulse oximetry inequity in current clinical practice.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract Pompe disease is a rare autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase (GAA) – a lysosomal enzyme that hydrolyzes glycogen. GAA deficiency results in glycogen accumulation in the lysosomes of cardiac, skeletal, and smooth muscle as well as motor neurons1-3. Despite treatment with enzyme replacement therapy (ERT), many patients develop recurrent respiratory infections, restrictive lung disease, and respiratory insufficiency4,5. As a result, respiratory failure is still the leading cause of death6. Respiratory compromise was previously attributed to failure to protect the upper airway, diaphragm muscle weakness, motor neuron pathology, and airway smooth muscle pathology7-10. However, recent findings from our laboratory identified significant pathology in alveolar type 1 and type 2 (AT1 and AT2) cells as a result of GAA deficiency and glycogen accumulation. Specifically, we found that GAA deficiency in Pompe disease resulted in engorged lysosomes which significantly disrupted AT1 and AT2 cellular architecture. Lysosomes are an essential component of autophagy which is important for maintaining cellular homeostasis. We also found that GAA deficiency resulted in reduced surfactant protein D gene (SP-D) expression and abnormal surfactant accumulation11. Building on these novel findings, the central hypothesis of this proposal is that GAA deficiency disrupts alveolar repair after lung injury and impairs autophagy, and AAV-GAA gene therapy will enhance lung damage repair and reverse alveolar pathology. Three specific aims will be accomplished using the Pompe disease mouse – the Gaa-/- mouse. Aim 1 will determine if Gaa-/- AT2 cells successfully differentiate, repair and repopulate damaged alveolar cells following lung injury. Aim 2 will elucidate the impact of GAA deficiency on autophagy and cellular homeostasis in AT2 cells. Finally, aim 3 will treat alveolar pathology using AAV therapy and to combine airway and systemic therapy to treat the global disease. The proposed experiments will evaluate AT2 cellular function in alveolar repair following a lung injury. We will use a series of ex vivo and in vivo studies, biochemical and histological assessments of lungs, as well as functional and behavioral studies. This proposal will uniquely combine the respiratory physiology and Pompe disease mouse model experience of the PI (ElMallah), with Co-PI Tata’s alveolar stem cell, genetic and epigenetic expertise. This work is innovative because the impact of GAA deficiency on alveolar repair following lung injury has not been evaluated and will provide clinically relevant information for future therapeutic interventions. Finally, defining the impact of GAA deficiency on alveolar differentiation and proliferation in Pompe disease will impact clinical care and inform clinicians about deficits in lung repair following infectious and aspiration injuries.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT Urinary stone disease (USD) is on the rise and represents the second most costly urologic condition in the United States, with a healthcare expenditure over $2 billion per year. Most notably, the landscape of ureteroscopy (URS) via laser lithotripsy (LL) - the leading treatment option for USD is experiencing a rapid and dramatic technological evolution, driven primarily by the launch of the Thulium Fiber Laser (TFL) in 2020 and its growing clinical applications, but also heightened by the introduction of the Dornier Thulio laser in 2022. However, despite the great clinical enthusiasm about these new laser technologies, there is no consensus among urologists regarding the optimal settings for TFL in LL. In addition, because the TFL is much more strongly absorbed in water than the Holmium (Ho):YAG laser, the temperature can rise rapidly, especially when treating impacted stones in the ureter. Therefore, in this new era of LL, there is a pressing need to better understand the mechanism of action for TFL, and to distinguish its similarities and differences from the Ho:YAG lasers in terms of stone ablation capability and tissue injury risk. To address these fundamental challenges/unmet clinical needs, we propose three specific aims: 1) To determine the optimal settings of TFL - in vitro studies to explore a wide range of parameters; 2) To elucidate the mechanisms of action by TFL via experimental and numerical investigations; and 3) To define the best clinical LL strategy using TFL in artificial kidney/ureter phantoms and swine model. Altogether, we strive to unravel the intricate laser-fluid-bubble-stone interactions and their interconnections that cannot be easily observed or appreciated during clinical laser lithotripsy. Through such a grand effort, we hope to develop the best treatment strategy for achieving the most desirable outcomes (i.e., the highest stone ablation efficiency, lowest heat-induced injury risk, and shortest procedure time) for urinary stone treatment using the burgeoning TFL technology. Considering the growing epidemic of USD, coupled with the rapid advance in LL technology and techniques, the proposed investigation is timely and well justified. The outcome of the project is anticipated to impact the long-term surgical management of USD and advance of future LL technology.

NIH Research Projects · FY 2026 · 2025-01

Project Summary Syncytial cells have multiple nuclei in a shared cytoplasm and are common in the biosphere. These cells are found in fungal pathogens and symbionts, during embryogenesis of plants and animals, and in bone, blood, placenta, muscle, and tumor cells of humans. Nuclei sharing a syncytium can differ in genotype, or in gene expression profile, so that these single cells can approach the functional complexity of a multicellular tissue, especially when they grow to a large and complex shape. What functions emerge with this form of cell organization that are distinct from a multicellular tissue? How can a single cell be spatially organized to support different nuclear identities and functions in a common cytoplasm? My lab’s long-term goal is to discover the functions of syncytia and to uncover fundamental cell biology that emerges from this unique cell organization. We have made foundational discoveries in understanding how the nuclear division cycle is spatially compartmentalized in syncytia. We deciphered how cyclin mRNAs drive the formation of biomolecular condensates in the vicinity of nuclei and defined fundamental rules for how cells control the location, size and composition of condensates. The nuclear division cycle is also in part controlled locally by cortical septin cytoskeleton assemblies that act as signaling scaffolds, controlling the concentrations of cell cycle regulators in their vicinity. Our recent focus has been on how septins assemble at specific locations in cells. We discovered that septins preferentially assemble on micron-scale curved membranes, leading them to enrich at specific locations where cells change shape. The proposed future research in a model filamentous fungus addresses gaps in understanding how condensates and septins create functional zones for cell cycle signaling within syncytial cells but also extends to new areas for the lab. In theme 1, we will examine how condensates regulate translation of cyclin proteins in time and space, dissecting how the material state and composition of condensates controls protein synthesis. In theme 2, we will determine how different types of septin assemblies recruit sets of effector proteins to locally control signaling to the cell cycle. This is critical as vanishingly little is known about the molecular basis for septins as scaffolds. In theme 3, we will examine how the number of nuclei is kept in balance with the volume of cytoplasm in large multinucleate cells. This is important because pathologies are associated with aberrant ratios and how all cells sense their size remains a challenging cell cycle puzzle. Finally, in theme 4, to better understand the functions that emerge from syncytial cell organization, we will assess to what extent nuclei share or subdivide tasks within the communal cytosol. The flexibility in where and when genes are expressed, combined with the ability of nuclei to move between different parts of a cell, may be in part the basis for the wide-spread existence of syncytial cells in the biosphere. In this work, we will enrich our understanding on form and function of syncytia and illuminate cell organization mechanisms relevant to all cells.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract Critically ill infants, including those with heart disease, suffer significant morbidity and mortality due to low cardiac output (CO) states. Inotropes such as milrinone are used to improve CO, but current dosing strategies lead to frequent therapeutic failures and toxicities. Therapeutic failures occur because current dosing is based on drug disposition (pharmacokinetics; PK) assessed at a single time point, and fails to account for the substantial, time-varying physiologic alterations that affect drug PK in critical illness, variability in drug response (pharmacodynamics; PD) based on hemodynamic factors, and the reciprocal effects of PD on PK. Identifying systematic approaches to optimize drug dosing based on time-varying PK/PD relationships in critically ill infants are urgently needed. Dr. Thompson proposes to meet this need, using milrinone in critically ill infants with heart disease as a pilot population, by: 1) identifying the optimal milrinone population PK model using a systematic approach to external validation and prospectively collected real world data (RWD) in an independent cohort, 2) developing an advanced PK/PD model to evaluate the complex interplay between milrinone dose, exposure, and response, accounting for time-varying covariates characterized by high frequency RWD, and 3) prospectively validating the observed PK/PD relationships in a multicenter, observational cohort. This Mentored Patient-Oriented Research Career Development Award will provide structured training and expert mentorship to enable Dr. Thompson to develop into an independent investigator and future leader in the field of clinical pharmacology in children with critical illness, including those with heart disease. Her overarching career goal is to design and lead innovative, PK/PD- and RWD-enabled clinical trials to optimize drug dosing in critically ill children. To achieve this goal, Dr. Thompson created a career development plan that capitalizes on the longstanding collaboration between Duke University, where she will transition to faculty in the Department of Pediatrics/Duke Clinical Research Institute, and the University of North Carolina Eshelman School of Pharmacy, where she is pursuing a PhD in Pharmaceutical Sciences. In addition, she will enhance her training in the regulatory conduct of clinical trials through the Intergovernmental Personnel Act (IPA) Scholars program at the FDA Office of Pediatric Therapeutics. Her short-term goals for the K23 program are: 1) to acquire knowledge using RWD to develop advanced PK/PD models; 2) develop the professional skills and techniques to lead a research program; and 3) generate a critical mass of preliminary data and publications to support R01 grant applications. She has assembled a mentorship team with expertise in pediatric pharmacology in critically ill children, advanced PK/PD modeling, the use of high frequency RWD, and novel, regulatory-compliant, clinical trials who have history of successfully mentoring junior faculty. Upon completion of this proposal, Dr. Thompson will have acquired the necessary skillset to pursue a lifelong career developing safe and effective drugs for critically ill children.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT This Mentored Patient-Oriented Research Career Development Award will provide a structured environment with the training and expert mentorship needed to enable Dr. Angelique Boutzoukas to develop as an independent investigator and leader in the field of pediatric antimicrobial stewardship. Excess antibiotic use in preterm infants is common and causes morbidity and mortality. Identification of methods to safely limit unnecessary antibiotic exposures represents an urgent, unmet need in neonatal antibiotic stewardship. Due to differences in preterm infant physiology, current empiric ampicillin courses may provide prolonged levels of drug exposure beyond the intended duration. Dr. Boutzoukas hypothesizes that short-course empiric ampicillin (24 hours) will provide therapeutic exposures for 48 hours in select preterm infants, is safe, and represents a potential way to substantially reduce unnecessary antibiotic exposures in this population. Building on preliminary data, Dr. Boutzoukas aims to study the PK and safety of short-course ampicillin in preterm infants. She will accomplish this through population PK modeling and dosing simulation of ampicillin in preterm infants and conducting a pilot clinical trial to confirm that short-course ampicillin regimens provide the intended antibiotic exposures when accounting for post-discontinuation exposures. This work will advance the concept of post-discontinuation exposures, which may be applicable to other drugs and populations. Additionally, she will develop a novel desirability of outcome ranking endpoint that includes neonatal-specific outcomes and incorporates both the benefits and harms of antibiotic therapy in this population. This endpoint can be leveraged to study safety alongside efficacy and increase the efficiency of future neonatal clinical trials that compare antimicrobial regimens or durations. Dr. Boutzoukas is a pediatric infectious diseases physician with a proven commitment to patient-oriented research and a desire to acquire advanced skills in pharmacometrics, pediatric clinical trial conduct, and endpoint development and selection. The candidate’s short-term goals for the K23 program are to: 1) complete didactic training and practical experiences in population PK modeling and simulation; 2) characterize the PK of ampicillin in preterm infants and simulate optimal dosing regimens that account for post-discontinuation exposures; 3) obtain experiences in the conduct of interventional pediatric clinical trials; and 4) develop and apply a novel neonatal hierarchical ordinal endpoint to increase the efficiency of antibiotic trials in neonates. This proposal will capitalize on unique opportunities provided by the Duke Clinical Research Institute (Zimmerman, primary mentor; Cohen-Wolkowiez, co-mentor) and the University of North Carolina School of Pharmacy. The mentorship team assembled is uniquely qualified, with internationally recognized thought leadership in pediatric trial design and conduct, clinical pharmacology, and a successful history of mentorship of junior faculty. At the conclusion of this program, Dr. Boutzoukas will be well positioned to be an independent physician-scientist and leader in pediatric antibiotic stewardship research.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT The objective of this proposal is to determine how cardiac and skeletal muscle myocytes, mitochondrially dense and highly oxidative cells, manage succinyl-CoA (SucCoA). SucCoA serves three conditionally essential metabolic fates: forward tricarboxylic acid cycle (TCAC) flux, heme synthesis, and ketone oxidation. Indeed, sucCoA is a limiting metabolite for the rate-determining enzymes in heme synthesis and ketone oxidation, Delta-aminolevulinate synthase 1 (ALAS1) and Succinyl-CoA:3-ketoacid CoA transferase (SCOT), respectively. In myocytes ketones are a major fasting energy source and heme is the primary oxygen carrier in the form of myoglobin. Heme is also a cofactor for multiple proteins, including several in the electron transport system, rendering it essential for mitochondrial biogenesis. We identified a nutrient dependent reciprocal regulation of ALAS1 and SCOT, that we hypothesize serves to prevent dual pulls on the sucCoA pool. Interestingly, this regulation is lost in heart failure (HF) and sucCoA is depleted. HF is a disease characterized by a progressive deterioration in cardiac pumping capacity concomitant with alterations to oxidative metabolism, including a stark increase in reliance on ketone oxidation at the level of SCOT and β- hydroxybutyrate dehydrogenase 1 (BDH1). While increased ketone oxidation is an emerging hallmark of HF, far less is known regarding heme or the intersection of heme and ketone metabolism in HF. We hypothesize that the unique demands of hypertrophic and failing hearts, which grow increasingly dependent on both ketone oxidation and heme biosynthesis, result in a dual pull on the sucCoA pool, thereby limiting substrate flux through both SCOT and ALAS1. In accordance, we propose two aims to test our hypotheses that: 1) sucCoA availability for heme biosynthesis in myocytes depends on carbon source, nutritional status, and ALAS1 interactome, and 2) that sucCoA availability limits heme synthesis and mitochondrial biogenesis in hypertrophied and failing hearts. To test this model, we will combine state-of-the-art molecular profiling tools, Langendorff perfused hearts, and metabolic flux analysis with stable isotope tracers, ultimately filling fundamental gaps in knowledge of myocyte heme biology and furthering our understanding of HF pathophysiology. These studies will employ primary human myocytes for flux and interactome analysis and a novel myocyte specific double SCOT and BDH1 knockout mouse (MCK-DKO). The training environment at DMPI is uniquely suited to support these studies due to its robust core facilities and trainee support. In fulfilling the aims proposed herein, the applicant will simultaneously expand their technical skillset and integrate their computational and basic science skills. This supports the applicant’s long-term goal of becoming an academic investigator. The proposed work will expand our fundamental understanding of heme biology and cardiovascular physiology, ultimately contributing to new therapeutic approaches for HF.