Vanderbilt University

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Recurrence remains a significant challenge for triple negative breast cancer (TNBC) patients despite treatment with surgery, chemotherapy, and radiotherapy (RT). Although irradiation of the resected tumor bed decreases recurrence in most patients, patients with chronic lymphopenia and a high neutrophil-to-lymphocyte ratio (NLR) following RT experience relapse at high rates. The mechanisms underlying this association of high NLR with recurrence are poorly understood. However, a growing body of literature shows that irradiation of mammary adipose tissue initiates an innate immune cell-driven program that facilitates tumor cell reseeding. Additionally, preliminary evidence suggests that irradiation promotes recurrence via neutrophil-mediated vascular remodeling and senescence. Therefore, the central hypothesis of this proposal is that neutrophils facilitate formation of a pro-recurrent niche in irradiated mammary adipose tissue through release of pro-inflammatory proteins and in- duction of vascular remodeling when primed by senescent cells. The rationale for the proposed research is that understanding the impact of post-therapy immune cell infiltration on tumor cell reseeding and vascular remodel- ing will identify candidates for targeted therapies. The central hypothesis will be tested by pursuing two specific aims: 1) Determine neutrophil phenotypes and functions associated with tumor cell reseeding in irradiated adi- pose tissue; and 2) identify the effect of neutrophil activation on pro-angiogenic signaling and vascular remodel- ing. In Aim 1, I will use a lymphopenic mouse model to represent at-risk patient populations and establish how neutrophil infiltration to irradiated mammary adipose tissue facilitates recurrence. To confirm that neutrophils are necessary and sufficient for tumor cell recruitment into adipose tissue, I will develop a neutrophil-depleted mouse model. In Aim 2, I will determine the influence of the senescent endothelial cell secretome on neutrophil activa- tion, using a well-characterized microfluidic model of the mammary vasculature to analyze how this activation promotes NF-κB and pro-angiogenic signaling in endothelial cells. I will then evaluate the impact of neutrophil proteins on NF-κB signaling and vascular remodeling as well as on tumor cell recruitment to irradiated adipose tissue in vivo. These studies will identify mechanisms of neutrophil-mediated vascular remodeling and tumor cell reseeding after RT, providing two potential points of intervention to prevent recurrence in patients with TNBC.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY An animal’s nervous system enables it to detect and respond to stimuli to navigate its environment. To enhance sensory acquisition, animals can actively position sensors, altering how they extract information from the external world. However, active sensing, and movement in general, produces stimuli that feeds back onto these same sensory systems – requiring mechanisms for integrating predictive motor signals with externally-generated sensations. Despite the importance of these mechanisms for guiding coordinated behavior, the cellular and circuit basis of motor control and sensation during active movements are not fully understood. This proposal aims to determine how mechanosensory information controls motor output in the Drosophila antenna, an active sensor that can be passively deflected or actively positioned. Previous work shows that APN2, a class of antennal mechanosensory and motor center projection neurons, contributes to an afferent sensory pathway. However, my preliminary connectomics and optogenetic behavior data support that APN2 also lies presynaptic to antennal motor neurons, suggesting a role beyond mechanosensory afference. I hypothesize that APN2, as a premotor class of neurons receiving direct mechanosensory input, enable active antennal positioning via integration of sensory and higher-order motor signals. In Aim 1, I will use electrophysiology and quantitative behavior to characterize the activity of APN2 during different active and passive antennal movements. In Aim 2, I will measure the relative influence of sensory input on APN2 activity during behavior with electrophysiology and machine-learning assisted antennal tracking. By defining APN2’s role in antennal motor control, this proposal will uncover the functional logic of a sensory-motor circuit controlling an active sensor.

NSF Awards · FY 2025 · 2025-09

Quantum computing offers to transform the way engineering computations are performed and promises to allow the engineering community to solve very large and complex mechanics problems that are intractable with classical computers. Using quantum mechanics principles such as superposition and entanglement, quantum computing could lead to both an exponential growth in memory capacity, and algorithmic speed-ups compared to existing “classical” computers. This study looks to devise new quantum computing algorithms for solving mechanics problems that involve rate-dependent, history-dependent and nonlinear materials. Such materials are frequently used in a wide range of applications such as soft robotics, micro-architected structures, and biomedical systems. Increasing predictive modeling and simulation of such important applications is critical to ensuring American competitiveness from commercial and security perspectives. The quantum computing algorithms that look to be devised in this research will be rigorously tested in quantum simulators and real quantum devices to establish the promise and limitations of quantum computing for solving nonlinear mechanics problems. As a part of this study, a computational mechanics community will be established, whose members are collectively committed to advancing quantum computing for mechanics. This community building will be performed in collaboration with existing technical and professional organizations. This study seeks to (1) develop and characterize variational quantum algorithms to simulate the deformation response of hyperelastic and elasto-viscoplastic solids; and (2) implement, verify and validate these algorithms and understand the relationships between the characteristics of the quantum algorithms and their performance in terms of accuracy and efficiency. The research looks to establish the computational and algorithmic complexity of the algorithms and quantify the computational speedup possible over classical solvers. This research aims to discover quantum algorithms integrated with nonlinear finite element method, which will account for the Lagrangian nature of the solid mechanics problems and the morphological complexity of typical problem domains. This research also intends to uncover efficient solution methodologies for incorporating the complex nonlinear constitutive forms associated with hyperelastic and elasto-viscoplastic material behavior, and account for the presence of history variables in quantum setting. 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 2025 · 2025-09

PROJECT SUMMARY This proposal will elucidate connections between bacterial aerobic respiration and flagellar motility in uropathogenic Escherichia coli (UPEC), the primary cause of urinary tract infections. A major focus of our lab is investigating the pathways that are essential for UPEC pathogenesis to aid in the development of new therapeutic strategies. therapeutic strategies. Through our work, we have established that aerobic respiration is crucial for UPEC's survival in the hypoxic environment of the bladder, with the quinol oxidase cytochrome bd specifically required for colonization and proliferation inside bladder cells. Additionally, we observed that cytochrome bd is essential for flagellar motility, a key fitness factor in UPEC. The requirement of cytochrome bd for motility is surprising because UPEC encodes two other cytochrome oxidases that are functionally redundant. Therefore, this proposal aims to elucidate the mechanism of how cytochrome bd supports flagellar rotation in UPEC. My preliminary data suggests that cytochrome bd is required to support overall respiratory flux as mutants lacking cytochrome bd have impaired proton flux across the membrane. Additionally, a prevailing unknown in the field is whether enzymes are localized near the flagella to direcUy power flagellar rotation possibly through interacting with the stator proteins MoWMotB. I hypothesize that cytochrome bd sustains flagellar motility either through support of overall respiratory flux or physical interaction with the flagellar motor. This hypothesis will be tested in two specific aims: Aim 1 will determine how loss of cytochrome bd affects respiratory efficiency and Aim 2 will address the spatiotemporal relationship between cytochrome bd and the flagella. This study will be the first to define a role for cytochrome bd in flagellar motility and address a critical gap in knowledge of how flagellar rotation is energized. Given that cytochrome bd plays an essential role in infection, this information will be vital in the development of novel antimicrobials.

NSF Awards · FY 2025 · 2025-09

This proposal aims to unlock a deeper understanding of how intelligent minds communicate, delivering potentially transformational insights into how we talk and listen in day-to-day life, including when communicating with artificial intelligence (AI) systems. By studying how people remember and use language in everyday conversations, the proposal explores the distinct cognitive processes of speakers and listeners. Through a combination of empirical data collection and computational modeling, this work provides critical insights into when and why communication fails and how we can change the way we communicate in order to achieve success. These insights can support efforts to define new goals for advancing artificial intelligence systems, and critical insights needed to develop computer dialog systems that mimic human interaction more closely. These novel insights can also be leveraged to improve educational outcomes in the classroom by offering evidence-based insights to improve communication. Multiple students will gain hands-on research experience, inspiring the next generation of scientists. The project investigates cognitive processes governing language use and memory during conversation. The aim of the work is to test predictions of a proposal which argues that the way you use language shapes how you remember it, in turn guiding future language use. Data from thirteen behavioral experiments are analyzed using advanced statistical methods. In addition, computational modeling of key predictions using artificial neural networks make explicit precisely which theoretical assumptions are made and test the implications of these assumptions. This rare combination of the study of unscripted language use with computational models provides insights into real-time language processing which can be leveraged to advance AI dialog systems and offer evidence-based approaches for pedagogy and mediation. This project is jointly funded by the Perception, Action and Cognition program and the Linguistics program. 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.

NSF Awards · FY 2025 · 2025-09

This project is co-funded by the Chemical Mechanism, Function, and Properties Program, the Chemistry of Life Processes Program in the Chemistry Division, and the NSF Office of Advanced Cyberinfrastructure. In this project, Professor Zhongyue John Yang of the Department of Chemistry at Vanderbilt University is investigating the origins of wrapping chirality in lasso peptides, which are a class of knotted, interlocked molecules with growing promise in biotechnology and therapeutics. Although lasso peptides can theoretically form in either left- or right-handed wrapping configurations, nature has exclusively selected the right-handed form, a phenomenon that remains mechanistically unclear. This project combines cutting-edge high-throughput protein modeling and machine learning to uncover why this chiral preference exists and whether it can be re-engineered. Lasso peptides are ribosomally synthesized and post-translationally modified peptides that adopt a mechanically interlocked “lariat” shape. Despite the theoretical possibility of both left- and right-handed wrapping topologies (l-LaPs and r-LaPs), only right-handed forms have been identified in nature. This research investigates two hypotheses: (1) that r-LaPs are thermodynamically and kinetically preferred over l-LaPs, and (2) that lasso peptide cyclases selectively catalyze right-handed pre-lasso conformations. To evaluate these hypotheses, the project will develop high-throughput quantum mechanics (QM) and classical molecular dynamics (cMD) workflows to quantify the energy landscapes and entropy profiles of both l- and r-LaPs (Aim 1), and apply multiscale QM/MM and machine learning techniques to model enzyme-substrate interactions and identify cyclase mutants that can potentially generate l-LaPs (Aim 2). These computational pipelines are built on the PI’s previously developed modeling tool, LassoHTP and LassoPred, enabling systematic benchmarking across diverse lasso peptide-enzyme systems. The results will advance understanding of molecular determinants of peptide chirality and refine multiscale modeling strategies for complex, topologically unique biomolecules. 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.

NSF Awards · FY 2025 · 2025-09

With the support of the Chemical Catalysis Program in the Division of Chemistry, Professor Schley at Vanderbilt University is developing new synthetic methods for the synthesis of organic molecules containing bicyclic groups. These methods will equip synthetic chemists with the means to craft molecules of increasingly complex three-dimensional shape and structure, contributing techniques to enhance innovation in the US fine chemical and specialty chemical industries. Members in Prof. Schley’s team will receive training in advanced chemistry techniques necessary to become part of a skilled and competitive workforce. Researchers at Vanderbilt University will partner with local community colleges in the greater Nashville area to establish undergraduate research and training opportunities for local Tennessee community college students to conduct research at Vanderbilt University. With the support of the Chemical Catalysis Program in the Division of Chemistry, Professor Schley at Vanderbilt University is developing methods for the synthesis of organometallic compounds of strained bicyclic groups via radical hydrometalation of the corresponding propellanes. The resulting bicycloalkyl organometallics will be applied as nucleophilic coupling partners in palladium-catalyzed cross-coupling chemistry, and as reagents in 1,2-hydrometalation chemistry of carbonyl derivatives. Whereas existing methods primarily allow for difunctionalization of propellanes via radical reactions, the proposed methods will provide synthetic chemists with the means to introduce bicycloalkyl substituents as terminal groups through transition-metal catalyzed processes already familiar to and broadly applied in chemical industry. The conformational inflexibility of bicycloalkyl substituents accessible by this approach will be applied in the synthesis of bicycloalkyl phosphines, aiding in development of phosphine ligands for chemical catalysis. 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 2025 · 2025-09

Project Summary Addiction is a debilitating disorder that affects ~20 million people and incurs an annual economic burden of $740 billion in the United States alone. However, despite intensive drug discovery efforts, we still lack highly effective therapies for addiction, emphasizing the need for a better understanding of the pathophysiology of the disease and a paradigm-shift in drug design. Towards this end, recent technological advances in neuroscience have allowed us to interrogate the neural circuits that underlie addiction with high precision. We can map the spatial organization of neural circuits, detect and manipulate the firing of selected neurons, and measure the dynamics of neural signal release. However, what is missing is a deep understanding of the molecular effects of neural signals once they are released — rather than simply connecting one neuron to another, neural signals encode complex information by controlling multiple, functionally distinct receptors and their various downstream signaling molecules at once. For example, the neuromodulator dopamine plays key roles in addiction by dynamically activating five G protein-coupled dopamine receptors, which have diverse functions across the brain and periphery, engage numerous downstream signaling proteins, and are associated with varying clinical potential and risk. Thus, the next frontier in addiction research is to uncover the functional role and therapeutic value of specific populations of neural signaling proteins. The goal of this proposal is to develop and apply a highly precise platform technology called Tag-Guided Drug to better understand the functional role of selected populations of neural signaling proteins in addiction. Tag-Guided Drug combines the doseability and reversibility of conventional drugs with the molecular, spatial, and cellular specificity of genetic targeting. We developed a Tag-Guided Drug for dopamine D2 receptor, a putative target for treatment of addiction. We will use the D2R Tag-Guided Drug to better understand the functional role of D2 receptor in a mouse model of cocaine addiction and, in parallel, develop a pipeline for generating Tag-Guided Drugs for other clinically relevant neural signaling proteins, including various G protein-coupled receptors (GPCRs) and intracellular signaling proteins. Overall, Tag-Guided Drug is highly innovative and has major implications for neuroscience, addiction, and biological sciences as a whole.

NIH Research Projects · FY 2025 · 2025-09

Project Summary This proposal aims to address the rate of hypocalcemia following thyroidectomy in the pediatric population using near infrared autofluorescence (NIRAF) of parathyroid glands. Thyroid cancer is one of the most common cancers affecting adolescents and young adults and permanent hypoparathyroidism is the most frequently reported complication following thyroidectomy. Post-operative hypoparathyroidism (PoSH), resulting from damage to the parathyroid glands or their vasculature, gives rise to hypocalcemia in 30-50% of cases transiently and up to 7% permanently. We have developed an approach based on NIRAF exhibited by the parathyroid glands and demonstrated clinical utility by showing that 97% of parathyroid glands have greater autofluorescence than surrounding tissues. The lab-built system used in these studies has since been commercialized as the FDA cleared PTeye® marketed by Medtronic. However, additional work has shown the autofluorescence from other neck tissues are more variable in the pediatric population, causing a higher false positive rate. Here, we propose a rigorous evaluation of the autofluorescence of pediatric neck tissues to aid in the specific translation of this technology to pediatric neck surgeries by tailoring the metrics used for this new patient population. To achieve this, we will characterize the spectral properties of parathyroid gland tissue in children (Aim 1) at five of the nation’s high-volume centers for pediatric thyroidectomies. The variation of NIRAF over time in the pediatric population will then be interrogated using parathyroid gland organoids (Aim 2) to better understand the underpinnings of the fluorescence signal. Finally, the findings from Aims 1 and 2 will be used to modify the PTeye® before deploying it in the clinic to characterize the short- and long-term outcomes of pediatric thyroidectomy among high-volume centers (Aim 3). Because this will be the first multi-center prospective study for pediatric thyroidectomies, Aim 3 will also serve to standardize the perioperative care and clinical outcome definitions, as current practice is extrapolated from adult procedures without pediatric-specific clinical standards.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Epilepsy is a debilitating neurological disorder that affects 50 million people worldwide. Focal epilepsy is the most common form. For one third of patients, medications are insufficient to manage their seizures. Surgery can be curative, but highly depends on the clinical team’s ability to localize seizure origin to a specific volume of tissue deemed the seizure onset zone (SOZ). Even after receiving an invasive workup, where stereotactic electroencephalography (SEEG) leads are implanted intracranially to record seizure activity, 50% of patients continue to have seizures after surgery. This low rate of seizure freedom suggests that we may not be localizing the SOZ entirely and a need to examine the SOZ in relation to broader brain activity. Epilepsy has increasingly been studied as a network disease, which entails examining the physical and dynamic interactions between regions and how these relationships may be abnormal. Through studying the period between seizures (interictal period), our group as well as others observed directed inward connections from areas surrounding the SOZ that appear to decrease the SOZ’s activity. This led to the Interictal Suppression Hypothesis (ISH) which proposes that regions surrounding the SOZ are inhibiting seizure generation. However, it is unclear if seizure generation is related to a change in this inward connectivity. This proposal attempts to address this knowledge gap by examining networks as they evolve from the period between seizures to seizure generation. I specifically hypothesize that seizure generation coincides with a failure of interictal suppression, and that seizure severity is correlated with the degree suppression fails (Aim 1). I will use SEEG recordings from patients in Vanderbilt’s epilepsy monitoring unit to construct networks across four periods: interictal, pre-ictal (before seizure), ictal (seizure onset), and post-ictal (after seizure termination). Then, I will relate changes in SOZ connectivity to seizure spread, duration and clinical severity. In addition to studying network dynamics, I will examine whether a specific region in the brain is directing this activity into the SOZ or if this is a diffuse phenomenon. Given its relevance in seizure propagation, one such region may be the thalamus. I propose to use single pulse stimulation to relate thalamic activity to inward connectivity of the SOZ. I specifically hypothesize that the thalamus will be the largest source of inward connectivity to the SOZ, and that when stimulating the thalamus, SOZ activity will decrease (Aim 2). This proposed fellowship will provide training in a collaborative research atmosphere with expert mentors. Research training will be conducted in an environment that combines an academic medical center with a level 4 epilepsy center, world class research institute, and engineering all on one campus. Studying how epilepsy networks evolve near seizure generation may improve surgical resection by including areas that drive network changes or may improve neuromodulation by targeting areas for stimulation that can maintain the seizure free period.

NIH Research Projects · FY 2025 · 2025-09

Recent reports (NAEP, 2022, 2024) reveal that over 60% of 4th graders are performing at or below the basic level in reading and math; however, successful interventions for struggling upper elementary school learners thus far have proven elusive. Given the importance of these academic skills, understanding more about the mechanisms underlying academic success/failure, and how to ameliorate them, is a key public health issue. It is well established that early reading and math growth are each associated with distinct cognitive skills (phonological awareness for reading and symbolic magnitude processing for math), but also substantially overlap, as seen by: (1) the co morbidity between reading and math difficulties; (2) overlap in genetic variance for reading and math; and (3) the fact that several similar cognitive processes, including executive functions (EFs), are important cognitive correlates of reading and math. Neurobiological evidence also reveals that while fMRI tasks elicit skill-specific areas [reading: left occipito-temporal; math: intraparietal sulcus], both reading and math activate EF regions. Despite these relations, there is little understanding of the neural mechanisms by which EF-academic linkages develop, and how EF-supported neural networks may relate to intervention response, especially in upper elementary learners. Current work suggests that while domain general EF supports initial academic growth, as children develop, domain specific EFs emerge within the context of learning new skills. The fundamental theoretical premise is that while domain general EF may initially facilitate learning; to continue to capitalize on EF for positive academic outcomes, EF must become specialized for the task at hand. As such, we posit that specialization of EF systems (i.e., reading specific EF and math specific EF) must emerge to support positive academic growth in upper elementary school learners. The overarching goal of this MERIT Extension is to examine the neurocognitive correlates of the specialization of the EF system and examine its relationship to academic outcomes in upper elementary school. Aim 1 tests the hypothesis that EF specialization (i.e., reading specific EF and math specific EF) in 2"d/3'd grades mediates the relationship between early domain general EF (kindergarten/1 st grade) and later academic outcomes (4th/5th grade). Aim 2 examines how neural systems engage in the context of an intervention, providing a granular probing of neurocognitive changes as they occur. Aim 2's highly novel approach uses fNIRS (a portable neuroimaging method that captures brain activity similar to fMRI), which allows for a window into brain changes that are occurring during instruction. Capturing neural changes during intervention enables more precise tracking of linkages between EF and reading networks. Overall, understanding domain general EF and domain specific EF across two timescales - year-by- year, kindergarten through 5th grade, as well as moment-by-moment, during instruction, will provide key mechanistic insights as to how EF impacts academics. Understanding these processes may allow for greater specificity of interventional targets to be developed for struggling learners.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Mitral regurgitation (MR) is one of the most prevalent heart valve diseases. If left untreated, patients will experience left ventricle (LV) structural and functional alterations. These include chronic increases in wall stress and changes in cellular and extracellular matrix response that leads to progressive LV hypertrophy and fibrosis, leading to atrial fibrillation (AFib), heart failure, and death. The only effective, long-term treatment for MR remains valve repair or replacement. Minimally invasive mitral valve (MV) repair and percutaneous MV replacement are becoming stronger alternatives to open-chest, MV replacement surgery; however, they are not indicated for all patients, may result in MR recurrence, or have limited durability. Thus, there is a pressing need to develop a therapeutic pharmacological alternative to surgery. Furthermore, there is a need for MV-specific therapies that also address MR-mediated LV dysfunction. Serotonin 2B receptor (5-HT2B) signaling impacts both MV and LV remodeling; however, the interdependence between the mitral valve interstitial cell (MVIC) and cardiac fibroblast (CF) populations remains unknown. Given our ability to selectively remove 5-HT2B from MVICs and/or CFs, we possess the tools to decouple, for the first time, 5-HT2B-mediated MV dysfunction from LV remodeling both in murine models, as well as in human-derived MVICs and CFs. Additionally, our recent development of novel 5- HT2B antagonists that are unable to cross the blood-brain-barrier provides the first treatment option for targeting this pathway for human disease. These studies will result in clarification on the causal role of 5-HT2B in MV disease, while also examining the down-stream role of the receptor in MV-mediated LV dysfunction. We believe that due to the dual citizenship of the 5-HT2B receptor on the MVICs and CFs, which is unique to these cell types vs other valve and heart cells, this strategy can provide a ‘two-hit’ therapy for MV-LV disease, which encompasses nearly all patients with MR.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY AND ABSTRACT Cocaine use disorder (CUD) is a significant public health crisis with no FDA-approved pharmacotherapies. Routes of administration that deliver cocaine to the brain most rapidly, such as inhalation and intravenous (IV) injection, have a greater likelihood of abuse and dependence compared to slower routes like intranasal use. Indeed, even at the same equivalent dose, inhalation of crack cocaine is associated with greater risk for addiction than insufflation of powder cocaine. Thus, the speed of cocaine administration is a key factor that determines its addiction potential. The goal of this proposal is to define how faster infusion of the same dose of cocaine results in increased drug taking and seeking. The nucleus accumbens (NAc) is a critical hub within the brain’s reward circuitry for encoding drug-cue associations. This region is composed of two non-overlapping populations of medium spiny neurons (MSNs) based on their expression of D1 or D2 type dopamine receptors. While D2 MSNs are inhibited by cocaine, D1 MSNs are activated by cocaine and cocaine-predicting cues, undergo robust drug-induced plasticity, and causally drive drug-seeking. Thus, cocaine and cocaine-associated cues selectively recruit specific subsets of NAc neurons (i.e. neuronal ensembles) to mediate addiction-like behaviors. However, it is unknown whether the speed of cocaine delivery alters neural ensemble responses to cocaine and its predictive cues, as well as its role in drug-seeking. There are two key questions that guide this research proposal: 1) Does the speed of cocaine administration influence ensemble activity and drug-cue associations? 2) Does the speed of cocaine administration influence how associated cues drive drug-seeking? I hypothesize that fast cocaine delivery enhances drug-cue associations by more robustly activating D1 MSNs in the NAc, increasing drug-cue ensemble stability and driving drug-seeking. In Aim 1 of this proposal, we will use in vivo cellular resolution calcium imaging to record neural responses to fast and slow cocaine infusions to determine how cocaine infusion speed alters the activity of cocaine ensembles. In Aim 2, we will use calcium imaging to track the same cells over time to determine how cocaine infusion speed alters the development and stability of drug-cue ensembles. Finally, in Aim 3, we will optically stimulate cue-ensembles associated with either fast or slow cocaine infusion to assess their role on the reinstatement of drug-seeking. The training plan in this fellowship will build upon my background in systems neuroscience by providing rigorous training in in vivo cellular resolution calcium imaging, behavioral models of addiction, and viral and genetic approaches for cell-type specific manipulation. Altogether, this project will answer a fundamental question in the addiction field, while also providing exceptional training in my development as an independent physician-scientist.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Social anxiety disorder (SAD) is one of the most prevalent psychiatric conditions worldwide, with a lifetime prevalence of 12.1%. SAD is associated with immense societal burden, including poorer educational and occupational outcomes and reduced quality of life. A sizeable subset of SAD patients (~1/6) do not respond to evidence-based treatments, and even more (17-60%) experience relapse following effective treatment. Accordingly, there is a pressing need to identify novel mechanisms that may be effectively targeted in treatment to improve patient outcomes. Biases in the attentional system may hold promise for future translational work. Attentional bias (AB) describes the preferential allocation of attentional resources to certain types of stimuli over others. In SAD, an AB to external, social-evaluative threats (i.e., angry/disgusted faces) has been reliably observed in the laboratory. However, interventions targeting this bias do not meaningfully reduce SAD symptoms, suggesting that ABs to external threats may represent a disease correlate, not cause. A more meaningful form of AB in SAD may be the extent to which individuals attend internally vs. externally in social situations. Indeed, excessive internally focused attention (i.e., on one’s anxiety-laden thoughts, emotions, and interoceptive sensations) is reliably linked to SAD severity and may contribute to disorder maintenance by increasing perceptions of threat and thus triggering anxious responding across multiple levels. However, researchers have not yet identified if, how, and for whom excessive internally focused attention plays a causal role in SAD maintenance, which is essential to know to inform optimized interventions. The proposed research will utilize an ecological momentary assessment-delivered experimental manipulation to compare the role of internally vs. externally focused attention in the maintenance of SAD. Outcomes will be explored longitudinally across self-report, behavioral, and cognitive levels of analysis, and mechanisms (i.e., threat detection, state anxiety) and moderators (i.e., attentional control) of the effects will be tested. The overarching goal of this project is to identify patterns of attention that play a causal role in the maintenance of SAD to inform novel treatment targets. Specific training goals include conducting experimental psychopathology research from an RDoC-informed framework, acquiring a deeper knowledge of the theory, assessment, and modeling of cognitive systems, applying advanced quantitative methods, and developing professional skills needed for a successful career in clinical science. By integrating theory and methods from multiple areas of basic and clinical science, the PI will acquire a strong foundation for building an impactful program of translational research that investigates the role of cognitive systems in the maintenance of anxiety disorders.

NIH Research Projects · FY 2025 · 2025-09

PROJECT ABSTRACT This project is specific to bioethics research and focuses on the ethical use of surgical robot-enabled data recording. Surgery is on the verge of a paradigm shift towards autonomous robot-assisted surgeries (RAS). Increasingly, RAS is incorporating artificial intelligence (AI) algorithms to automate parts of surgery, allowing computer algorithms to make critical decisions during surgery and directly affecting patient care. AI has the potential to improve patient care but vast amounts of surgical data are required to develop AI algorithms. While video and audio recordings have long been used for sharing surgical skills and education, RAS increases the invasiveness of recordings by also capturing the surgeon’s handling of surgical instruments. The more invasive nature of the recording, combined with the increased need for surgical data driven by AI developments in healthcare, necessitates further consideration of the ethics of surgical data use. The potential for AI-enabled RAS to improve patient care through learning from surgical data recordings raises potential ethical issues in privacy, ownership, and liability. Through recording surgeon’s handling of instruments, companies are starting to automatically evaluate the surgeon’s performance and make comparisons to other surgeons. This increased level of scrutiny potentially invades surgeons’ privacy and affects their willingness to undertake difficult procedures. Additionally, recordings of surgeries may be used to develop autonomous robots that can one day directly compete with surgeons. Companies may make money off the surgical technology developed through recordings of surgeons’ skills. Currently, surgical skills are not generally protectable by patents, leaving surgeons vulnerable to imitation by AI. Lastly, the pervasive use of surgical recordings may increase liability for hospitals. The objective of this study is to examine ethical issues in RAS-enabled surgical recordings. We will examine stakeholders’ perceptions of ethical issues involved in recording and using recorded surgical data, particularly with regard to privacy, ownership, and liability. We will run conference workshops to engage with the community and brainstorm ways technology and guidelines can support the ethical use of recorded surgical data. The specific aims are to: 1) Assess stakeholders’ ethical concerns about privacy, ownership, and liability of recorded surgical data. 2) Engage engineers and surgeons to identify technology designs for the ethical use of surgical data. The impact of the proposed study will be an improved understanding of the ethical concerns regarding privacy, ownership, and liability of recorded surgical data. While conducting our parent R21, we discovered novel ethical concerns about data recording. This bioethics supplement will complement our parent R21 (which focuses on ethical issues concerning informed consent for surgical robots) by addressing broader concerns about surgical data. Our findings will inform guidelines to support the ethical use of recorded surgical data.

NIH Research Projects · FY 2025 · 2025-09

Project Summary: Aging is the prime risk factor for many human diseases including diabetes, cardiovascular disorders, neurological dysfunctions, and cancers. One of the pillars of aging is mitochondrial function, which declines as organisms and cells age. However, the mechanisms contributing to mitochondrial dysfunction in aging cells are not completely understood. Sphingolipid depletion increases longevity in multiple aging models, but the mechanistic basis is not well understood. My preliminary data reveals that decreasing sphingolipid levels preserves mitochondrial morphology and function in aging cells. This raises important questions about the relationship between sphingolipid metabolism and mitochondrial maintenance, particularly in the context of aging or stress. To address these questions, I propose two research aims that examine the relationship between sphingolipid metabolism and mitochondrial biology using two different aging models. The first aim seeks to determine the mechanism of mitochondrial swelling in an aging model of the yeast Saccharomyces cerevisiae. This aim will examine the hypothesis that swelling is caused by accumulation of sphingolipids in aging mitochondrial membranes. Additionally, this aim will map sphingolipid trafficking itineraries in the cell, testing the hypothesis that sphingolipid transport across organelle contact sites contributes to mitochondrial swelling and dysfunction aging cells. This research will contribute new insights at the interface of lipid metabolism and inter-organelle communication. My second research aim will investigate the relationship between sphingolipid metabolism and mitochondrial stress responses using the C. elegans aging model. My preliminary data indicates that sphingolipid depletion in C. elegans suppresses mitochondrial stress responses, and in this aim I will address the mechanistic basis of this suppression. Additionally, I will develop new tools to achieve inducible, tissue-specific sphingolipid depletion in C. elegans. Using these new tools, I will determine how tissue-specific sphingolipid depletion affects longevity. This project will contribute new insights into the relationships between aging, mitochondrial health, and sphingolipid metabolism. In the long run, these studies have the potential to inform new strategies for preserving mitochondria in aging cells to promote longevity and health span.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Glucose control of islet hormone secretion is perturbed in patients with type-2 diabetes (T2D), which contributes to hyperglycemia. It is generally accepted that islet insulin and glucagon secretion occur in response to elevated intracellular Ca2+. However, how islet Ca2+ extrusion modulates hormone secretion and is altered in T2D remain largely unknown. Data from our lab finds that the plasma membrane calcium-transporting ATPase 1 (PMCA1) serves to set basal - and -cell cytoplasmic Ca2+ levels and reduce secretagogue-stimulated Ca2+ influx. Whereas the sodium/calcium exchanger (NCX1) limits - and-cell Ca2+ oscillation amplitude and is activated during arginine stimulation. Further data show that -cell specific ablation of PMCA1 drastically improves glucose tolerance. Finally, our preliminary data provide the first evidence that diabetic conditions inhibit NCX1 activation in -cells, which likely alters Ca2+ handling. Based on these exciting data, the objective of this proposal is to elucidate how PMCA1 and NCX1 modulate islet hormone secretion and health under physiological and diabetic conditions. This project will test the central hypothesis that islet PMCA1 and NCX1 mediated Ca2+ extrusion lowers basal and secretagogue-stimulated cytoplasmic Ca2+, which limits hormone secretion. We further propose that stress-induced inhibition of PMCA1 and inactivation of NCX1 increase islet cell Ca2+ entry and hormone secretion in diabetes. The rationale that underlies this project is that understanding how PMCA1 and NCX1 control islet Ca2+ handling and hormone secretion will expose novel therapeutic strategies for restoring islet hormone secretion in T2D. This project will be accomplished with the following two specific aims: 1) Elucidate the mechanisms governing PMCA1 and NCX1 control of β-cell Ca2+ extrusion and insulin secretion; and 2) Determine how PMCA1 and NCX1 regulate -cell Ca2+ handling and glucagon secretion. Under the first aim, transgenic mice with -cell ablation of PMCA1 and NCX1 as well as human pseudoislets with ShRNA knockdown of -cell PMCA1 and NCX1 will be utilized to assess their roles during secretagogue and inhibitor control of Ca2+ handling and insulin secretion. Aim1 will also determine how -cell PMCA1 and NCX1 function are altered under diabetic conditions and the resulting impacts on insulin secretion, -cell health, and glucose homeostasis. Under the second aim, the roles of PMCA1 and NCX1 on -cell function will be determined in mice with -cell specific ablation of PMCA1 and NCX1 and in human pseudoislets containing -cells with knockdown of PMCA1 and NCX1. Furthermore, Aim2 will determine how alterations in-cell Ca2+ extrusion due to reduced PMCA1 and NCX1 activity under diabetogenic conditions contribute to -cell dysfunction. This project is significant because it is expected to illuminate mechanisms that control -cell and -cell Ca2+ extrusion and how alterations of their function contribute to disrupted islet hormone secretion in T2D. Moreover, this project plans to identify potential signals that can be used to modulate Ca2+ extrusion to help normalize hormone secretion, reduce islet dysfunction, improve islet health, and restore euglycemia in T2D.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract The goal of this new program is to train, educate, and mentor the next generation of biologists, engineers, physiologists, and biochemists in the intradisciplinary field of musculoskeletal research, with a focus on bone biology, biomechanics, and regeneration. Multiple diseases along with aging impede the ability of the skeleton to protect organs, facilitate movement, contribute to mineral homeostasis, and sustain healthy bone marrow. Degeneration of bone and impaired fracture healing can greatly impact a person’s quality of life. Given the diverse structure, function, and tissue types that comprise the musculoskeletal system, an integrated and clinically-informed approach to training is required to keep bone and joints healthy. For example, identifying new ways to prevent fractures requires an understanding of tissue anatomy, molecular biology, pharmacology, genetics, vascular biology, material science, biochemistry, and engineering mechanics. Moreover, a translational training environment is essential to develop musculoskeletal research scientists that will solve the complex scope of clinical problems affecting the health of the skeleton. Our proposed training program, organized through the Vanderbilt Center for Bone Biology, will support the education, mentorship, and research of 3 predoctoral graduate students and 2 post-doctoral fellows for 2 years. Individualized mentorship will be led by faculty across multiple departments: Biomedical Engineering; Chemical & Biomolecular Engineering; Dermatology; Medicine; Orthopaedic Surgery; Pediatrics; and Radiology & Radiological Sciences. Mentors also hold primary and secondary appointments in multiple departments that have graduate programs such as Biochemistry; Cell & Developmental Biology; Pathology, Microbiology, & Immunology; Molecular Physiology & Biophysics; and Pharmacology. Our mix of clinical and research faculty will facilitate opportunities to observe physicians seeing patients in their clinics and hands-on training in bone-specific techniques. Program activities will include seminars by invited speakers, faculty lectures on the musculoskeletal system, annual career development seminars, work- in-progress presentations, student-led journal club, and opportunities to participate in our annual musculoskeletal research symposium. Going beyond the scope of predoctoral student’s didactic coursework in their graduate program, our program provides a focused curriculum on the basics of bone biology, osteoimmunology, fracture repair, skeletal development, bone mechanics, imaging, and clinical diagnosis and management of osteoporosis and osteoarthritis. Professional skills needed for success will be further developed through professional- association conferences where trainees can present their research to other scientists and network with peers and potential employers. Structured progress evaluations will further enhance the students’ success in the program. Encouraging life-long learning and scientific integrity as key to a successful career, the program will provide an inclusive environment for trainees to investigate ideas with integrity and rigor and to have ample opportunities for perfecting communication skills, developing resilience, and acquiring leadership tools.

NSF Awards · FY 2025 · 2025-08

Whether an organism is a plant, insect, or human, its immune system must contend with exposure to parasites many times in its life. Immune responses cost energy, cause damage to self, and can interfere with development. Thus, young organisms may benefit, in terms of health and fitness, from a different level of immunity than older organisms. Metamorphic animals like insects have an advantage over humans and other continuously developing animals because they can remodel their bodies – and immune systems – as they age from juveniles to adults. This project uses experimental, genomics, and computational approaches in the flour beetle Tribolium castaneum to test the hypothesis that metamorphosis makes it easier to evolve different immune responses in different life stages, but only if the immune response does not impact development. This project will shed light on a fundamental question in immunology: why is there so much variation between individuals of different ages in how sick they get from infection? At the same time, it will help to explain why some species have evolved metamorphosis while others have not. The project will train several graduate and undergraduate students in computational and genomic techniques and provide educational outreach opportunities to understand how evolution affects agriculturally important insects. To test the hypothesis that metamorphosis enables selection to act relatively independently on the genetic basis of immune system regulation in different life stages unless the immune response is under developmental constraint, the researchers will undertake three objectives: 1) experimental evolution of stage-specific resistance against parasites targeted by immune pathways that vary in their effect on development in an emerging model insect (the flour beetle Tribolium castaneum), 2) quantification of natural variation in immune responses across life stages and populations to disentangle the contributions of development and local adaptation to immune system variation, and 3) development of computational models of stage-structured infection and immune responses to identify the types of costs that are most likely to lead to immune responses that differ across stages. 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.

NSF Awards · FY 2025 · 2025-08

Neurodiversity is an emerging paradigm through which neurological differences, traditionally viewed only in terms of disability -- autism spectrum disorders, attention deficit hyperactivity disorder, dyslexia -- are instead viewed as human variations having associated impairments but also unique strengths highly relevant to STEM. Yet this group, now representing at least 20% of the US population, does not sufficiently participate in the STEM workforce: recent work suggests that only 11% of STEM undergraduates are neurodiverse, and a 2021 NSF report suggests that only 4.4% of all STEM PhD recipients are neurodiverse. Growing research evidence suggests enhanced abilities and skills in neurodiverse learners highly relevant to the engineering workforce. Examples include enhanced divergent thinking in ADHD, success in competitive colleges for autistic students, and enhanced cognitive and socio-emotional resilience, visuo-spatial ability, and emotional reactivity with corresponding neural differences in dyslexia. This project will address the opportunity to more fully enable this underutilized workforce by standing up a new Center called The Autism Self-advocacy Center for Equity and Neurodiversity in Engineering (A-SCENE). The project’s vision is to model a fully interconnected system of programs, activities, and supports to ensure that neurodiverse students can access and succeed in engineering careers, from the undergraduate experience, to graduate training and professional development, to meaningful engagement in the STEM workforce. The Center will pilot and innovate its signature programs among the initial partner universities (Vanderbilt University, Fisk University, University of Connecticut, and Northeastern University), develop an Engineering Neurodiversity Playbook for adoption of the A-SCENE model by any Engineering school, and then systematically expand through a long-term sustainable Affiliate Universities program, with the goal to eventually reach all engineering schools in the nation. The A-SCENE Phase II effort builds on the unique strengths of the core university partners, bringing together extant efforts including Vanderbilt’s Frist Center for Autism & Innovation, the Fisk-Vanderbilt 3+2 program in engineering, Fisk’s Institute for Neurodiversity & Intersectionality, UConn’s Neurodiversity Teaching Institute, Northeastern’s signature Co-op program, and the national College Autism Network, itself representing more than 125 college and university members. Arizona State and University of Illinois join as A-SCENE’s inaugural affiliate partners, extending our geographical reach and diversity of students. A-SCENE will reach a large community of neurodiverse individuals at the partner institutions as well as much more broadly through dissemination of the model and playbook nationally. During this Phase II effort, A-SCENE will establish mechanisms for long-term continuity and growth of A-SCENE nationally by: (a) curating the Engineering Neurodiversity Playbook, including curricula, guides, rubrics, and other materials as a living online resource; (b) expanding the affiliates program through membership fees to support ongoing growth of the A-SCENE network; (c) creation of a national student organization -- the Society of Neurodiverse Engineers -- with local chapters and national activities supported through dues; (d) exploring a fee structure for access to trainings for student-support professionals and access to employer education services; and (e) exploring a licensing fee structure for use of A-SCENE’s internship- and job-matching tool. We will continually engage additional affiliate partner institutions, which will further amplify the direct impact of this effort. At the largest scale, engineering undergraduate and graduate students nationwide now number more than 700,000, of whom ~77,000 are expected to be neurodiverse. To be sure, these estimates are projections beyond this Phase II effort, but they suggest that the potential for broad impact on the neurodiverse population in engineering is large. Finally, dissemination of the A-SCENE Engineering Neurodiversity Playbook through INCLUDES, ABET, and other national networks will broaden the impact further still. 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 2025 · 2025-08

Project summary: Cochlear implants (CIs) are neuroprosthetic devices that are considered standard-of-care treatment for severe-to-profound sensory-based hearing loss. CIs restore hearing by electrically stimulating the auditory nerve with an electrode array that is implanted in the cochlea. While CIs are effective for most recipients, there is wide variability in outcomes. Research by many groups over the last few decades has shown that proper positioning of the electrode array within the cochlea is crucial for optimizing the electro-neural interface to maximize post-implantation speech recognition. Poor placement can lead to poor electrical coverage of the auditory nerve and/or excessive channel stimulation overlap. In this project, an augmented reality CI insertion guidance system will be developed and validated. The proposed system leverages modern artificial intelligence technology and does not require any expensive or exotic equipment. The system will be experimentally tested to confirm it facilitates achieving a more optimal CI electro-neural interface. System development will begin by developing reliable and accurate algorithms for scene mapping to facilitate microscope self-localization and registration of 2D microscope video capture to 3D pre-operative imaging. Methods will be developed for registering anatomy segmentations and pre-procedure plans created using CT or MR to the microscope video directly as well as solve the microscope self-localization and scene mapping problem to update the registration as the scene changes over time. Next, tool pose detection algorithms to enable active electrode placement feedback will be developed. We will develop machine learning approaches for detecting the 3D pose of CI insertion tools to detect how closely the pre-planned electrode array insertion strategy is being followed. This will facilitate providing warning in the AR environment when the insertion is sub- optimal. Finally, we will develop and validate a fully integrated and automated augmented reality interface. This system will enable visualization of co-registered segmentations and plans and feedback on adherence to the plan. Clinical translation of the system will be comprehensively tested in a large temporal bone study. If successful, the system will facilitate placing arrays with a more optimal electro-neural interface, which would ultimately lead to improved CI outcomes.

NIH Research Projects · FY 2025 · 2025-08

Project Summary The importance of achieving a clear margin in head and neck surgery is emphasized by the fact that a positive margin status increases all-cause mortality by 90%. Yet positive margin rates in oral cavity cancers are among the highest of solid malignancies and have not improved in the past two decades. Of the 65,000 cases each year, up to 78% will undergo surgical treatment. Surgical treatment generally involves lump resection of the tumor with a margin. After initial resection, the resected specimen is sent to pathology to analyze margins through frozen section analysis. Due to the importance of clear margins, the current standard of care is to re-resect if there is a close or positive margin. Unfortunately, studies have found surgeons to be 10.3-20.6 mm off in relocating margin and additional cancer is only found in 20-30% of the cases. Patients with initial positive margins re-resected to negative margins have local recurrence rates similar to those of patients with ?nal positive margins. To improve re-resection success, we propose an augmented reality (AR) guidance system with deformation modeling to aid the relocation task. Once the surgeon completes the initial resection, we 3D scan the resected specimen to create a mesh of the tumor. An RGBD camera mounted above the patient will additionally capture a 3D point cloud of the resection bed. Using the resection bed point cloud as the target, the 3D scanned mesh will be deformed to match. The deformation will be driven by our previously proposed linear iterative boundary reconstruction models. Additionally, we will extend the models to account for additional mechanisms that drive deformation in head and neck specimens and develop novel methods to quantify uncertainty in the deformed mesh. This mesh will be uploaded to an AR system so that a projection of the deformed specimen with pathology annotations appears on the resection bed to aid relocation. To ensure clinical translation, we will conduct co- design studies with surgeons and surgical trainees to discover what features they consider important for such a guidance system. The interviews will be coded and feedback will be used to re?ne the AR interface. This proposal will be evaluated based on two phases. In the ?rst, surgeons with little AR guidance system experience will be asked to resect and relocate margins on phantoms that experience no deformation to test how well the AR interface aids relocation. In the second phase, a surgeon with extensive experience with our AR guidance system will perform resection and margin relocation in cadavers that experience deformation. This phase tests how well the deformation model aids relocalization. Together, these two phases represent the upper bound of how well the proposed system can aid margin relocation. The endpoint of this R01 will be 1) a deformation model for head and neck tumor specimens and 2) a validated AR guidance system to guide re-resection. This study will generate the necessary experimental data to power clinical trials in patients to evaluate margin relocation. As our AR guidance system does not require integration with operating room equipment, it could in principle adapted to bene?t other solid malignancies.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The aHER2 antibody-drug conjugate, trastuzumab deruxtecan (T-DXd}, has revolutionized breast cancer treatment, prompting numerous clinical trials investigating immune checkpoint inhibitors (ICls} in combination with T-DXd. However, few studies have explored T-DXd's immunologic effects, and comprehensive preclinical data supporting ICI combinations is lacking. This challenge stems from trastuzumab's inability to bind to rodent HER2. Consequently, many existing models rely on human-derived cell lines or xenografts transplanted into immune-deficient mice, thus discounting T-DXd's immunologic effects. To address this, we have developed a robust, immunocompetent tumor model to study trastuzumab-based therapies by minimally editing the mouse HER2 trastuzumab binding region, which we termed HER2x. The HER2x tumor model binds trastuzumab, is nonimmunogenic, and is sensitive to TDXd treatment. Preliminary experiments utilizing this model suggest that T-DXd induces immunologic memory formation, potentiates responses in immune-competent compared to athymic nude mice, and increases tumor T cell infiltration. Additionally, combining T-DXd with aPD-L 1 (an ICI) showed additive therapeutic benefits in pilot experiments. Taken together, we hypothesize that T-DXd enhances adaptive antitumor immune responses through modulation of the tumor microenvironment and can be further optimized through combination with ICls. To test this hypothesis, Aim 1 will determine if T-DXd augments T cell-mediated antitumor immune responses in HER2+ breast cancer models, and if this is necessary for treatment efficacy. HER2x tumors will be inoculated into immunocompetent, syngeneic mice, which will then receive either T-DXd treatment or a vehicle control. At set timepoints, tumors will be extracted for immune phenotyping via multiparametric flow cytometry, single-cell RNA sequencing, and immunohistochemistry. In vivo T cell depletion studies will then establish the importance of CD4+ and CD8+ T cells for T-DXd efficacy in the HER2x model. Aim 2 will determine if combining T-DXd with aPD-1 or aPD-L 1 provides improved and more durable responses in HER2+ breast cancer. HER2x tumors will be inoculated as before, and mice will receive treatment with T-DXd, trastuzumab, or a vehicle control, in combination with aPD1, aPD-L 1, or an isotype control. Survival and tumor volume will then be tracked until endpoint. All complete responder mice will undergo a tumor rechallenge experiment to establish if combination therapy enhances tumoral immunologic memory formation. Additionally, combination treated tumors will be extracted at set timepoints for immune phenotyping to assess if ICI treatment alters T cell functional phenotypes in T-DXd treated tumors. Completion of this proposal will deliver urgently needed insights into the immunologic mechanisms of T-DXd, with the potential to provide clinically relevant and translational data supporting ICI combinations in patients. Furthermore, the completion of this project will facilitate the development of my technical, critical thinking, and communication skills that will be crucial to my success as independent translational oncology scientist.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Mutations are the ultimate source of genetic variation in all organisms and, coupled with natural selection, shape the natural world and are responsible for the biodiversity we enjoy today. However, mutations are crucial for human health and disease. It is mutations that allow bacteria to become resistant to antibiotics and cancer cells to chemotherapy. However, what cellular processes promote spontaneous mutagenesis, and therefore drive evolution, as well as the role of the environment in this process, remains poorly understood. We have shown that error-prone DNA polymerases promote mutations and the evolution of antibiotic resistance in bacteria. Importantly, this is dependent on a DNA repair pathway called transcription-coupled repair, that depends on transcription, but it is independent of replication. This is in contrast with the most well-known mechanisms of mutagenesis, which depend on replication. Because the chemical makeup of the environment in which different bacteria are found can dramatically affect the sources of DNA damaged that they are exposed to, I hypothesize that it will have a strong influence on this pro-mutagenic process. The goal of this proposal is to describe how bacterial error-prone polymerases promote transcription associated mutagenesis and the evolution of antibiotic resistance, as well as how the environment in which bacteria live affects this process. For the K99-phase of the proposal, I will characterize the molecular mechanism by which these polymerases promote transcription associated mutagenesis (Aim1), and which types of mutations these polymerases make in model bacteria (Aim2). At the same time, I will learn the necessary skills to study this process in different medically relevant bacterial species. With these new skills, during the R00 phase of the proposal I will determine which types of transcription associated mutations most commonly arise in highly divergent bacteria that are found in different environments (Aim2). In addition, I will determine the evolutionary history of these pro-mutagenic polymerases to find out how their environment has shaped the way they have evolved (Aim3). In addition, I will establish the role of error-prone polymerases in driving bacterial evolution, antibiotic resistance, and pathogenicity (Aim3). This research as well as my career development plan will take part at Vanderbilt University, in the laboratory of Dr. Houra Merrikh. Dr. Merrikh has a track record of doing groundbreaking work on the mechanisms of mutagenesis and the evolution of antibiotic resistance. During my time in her lab, I will benefit from her expertise and scientific knowledge. The work pertaining to Aim3 will be done with the assistance of my collaborator Dr. Antonis Rokas of Vanderbilt University, which is an expert in the study of evolution. The novel skills I will learn during my time at Vanderbilt University will help me establish an independent research program. Overall, this K99/R00 proposal will allow me to successfully transition from a mentored scientist into a successful independent researcher, while providing key insights on how the environment affects bacterial evolution and antibiotic resistance.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY/ABSTRACT Despite important advances in the treatment of learning disabilities (LDs), the dominant approach to intervention—direct skills instruction—fails to meet the needs of 25-45% of LD students. This indicates the need to expand the framework for LD intervention science with innovative approaches. This clinical trial (CT) assesses the effects and mechanistic processes of an innovative approach to intervention guided by cognitive-academic mutualism theory, in which cognitive resources support development of academic competencies while academic tasks in turn exercise & strengthen cognitive abilities. The CT’s innovative intervention provides coordinated cognitive training & direct skills instruction with supports for transfer across domains. The academic focus is math: word-problem solving & arithmetic, both critical foundational skills. The cognitive focus is working memory (WM) because WM plays a central role in early math development. Participants are 6–8 years old, a critical age when WM malleability & beneficial effects between emerging skills are rich in opportunity and when school instruction on the targeted math competencies intensifies. Also, delays that remain at the end of 1st grade forecast math LDs. First-grade children selected for math delays and low WM are randomly assigned to: (1) standard-of-care direct skills math treatment + coordinated computerized WM training (the innovation; CO-Tx); (2) the same standard-of- care direct skills math treatment + the same amount of computer game-like instructional activities not involving WM or math (the contrast standard-of-care condition); & (3) control group (the conventional school program & maturation; CON). Treatment occurs 3 times per week for 15 weeks. The primary outcomes are word-problem solving, arithmetic, & WM. Innovative intervention’s added value over standard-of-care direct skills math treatment (without WM training) is tested at posttest & delayed posttest, with 1-year follow-up effects explored. Mechanistic processes are assessed by testing whether bidirectional relations between WM & math are involved in the mediation pathway linking CO-Tx’s effects on delayed posttest math & WM and whether CO-Tx’s bidirectional relations are stronger in CO-Tx than in other conditions. Exploratory subgroup analyses are conducted to provide insight into the robustness of effects. This CT impacts science by deepening understanding about the potential for treatments based on cognitive-academic mutualism theory to enhance learning more than conventional direct skills instruction and deepening understanding about bidirectional relations between WM and early math development. Results may impact clinical practice by providing an innovative approach for treating math difficulties and other forms of LD. This CT is highly relevant & significant because math LDs are associated with long-term debilitating difficulty in school, the workplace, and everyday life and because pressing need exists to expand the framework for treating LDs with innovative approaches.