Duke University

NSF Awards · FY 2025 · 2025-06

The annual Device Research Conference, which is currently in its 83 rd year, is the premier forum for innovative and newly-emerging semiconductor devices. One of the key features of DRC is the balanced participation of students and leading world experts in the field, which provides a unique learning and training opportunity for the student participants. Specifically, in addition to contributed oral talks and posters, the 2025 DRC will offer a half-day technical short course taught by prominent experts, three plenary sessions and 38 invited talks by academic and industry leaders, and an evening rump session at which panelists interact with attendees to debate a technical topic of particular current importance. This year, the rump session will focus on: “Who defines important research directions for the field? Academia, industry or funding agencies?”. The short-course title for this year is “Heterogeneous Integration”, and the tutorial will be “Device Modeling”. In addition, to encourage student engagement, the DRC gives awards every year for the Best Student Paper Award and the Best Student Poster Award. NSF support for the DRC 2025 will provide student participants with the opportunity to gain exposure to new materials and devices, their basic physics, and their engineering applications. Semiconductor devices are key to all modern technology, and continued innovations are needed to achieve high-performance computing, robust high-speed communications, machine learning, image and video processing, as well as energy-efficient and sustainable power generation and control. For continued U.S. leadership in these important fields, it is critical that the next generation of STEM researchers be trained to address emerging needs for electronic, optoelectronic and quantum devices. Federal investments in the semiconductor manufacturing industry through the CHIPS and Science Act of 2022 make the training of device engineers even more imperative so we can provide the skilled workforce that will support expansion of domestic chip production. For dissemination, attendance at the conference and short course is subsidized for all students, and presenting authors can elect to make their abstracts available online through IEEE Xplore. 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 · 2025-06

The broad goal of the Schmid lab is to understand how stress response mechanisms evolved. Archaea are the evolutionary progenitors of eukaryotes according to mounting phylogenomic evidence. Transcriptional regulation is required across life for surveillance and immediate response to stressful conditions. Transcription proteins, including transcription initiation proteins TATA binding protein (TBP) and Transcription Factor B (TFB), and histones, are strongly conserved across eukaryotes and archaea; however, it remains unclear in both domains of life how these proteins function together with other transcription factors (TFs) in transcription regulatory networks (TRNs) to sense and respond to stress. Moreover, how TRNs evolve under selective pressure from abiotic stress remains a major knowledge gap. Archaea dominate in stressful environments, where conditions vary between extremes of temperature, pH, and salinity. They are single-celled microorganisms that lack nuclei and complex posttranscriptional mechanisms. Together these features present an ideal, simplified model for understanding conserved mechanisms of transcriptional regulation in response to stress, and how those mechanisms evolve. Recent research in the Schmid lab discovered specific examples of TRN conservation and rewiring by comparing the architecture and dynamic function of TRNs across related species of hypersaline adapted archaea, or haloarchaea. Together, this research has led us to hypothesize that extreme and variable abiotic stress conditions select for more highly interconnected or complex TRNs, enabling rapid physiological adjustment in response to variable environments. To test this hypothesis, here we will use an integrated experimental and computational systems biology approach pioneered in the Schmid lab to characterize TRN architecture (how TFs interact with their target genes) and function (dynamical gene expression and phenotypic outcomes) across the entire archaeal tree. We will compare these TRNs with those in eukaryotes to determine how TFB/TBP function is conserved, and to detect patterns of TRN conservation vs rewiring across large evolutionary distances. We expect that the research results will yield fundamental insight into transcription mechanisms across domains of life.

NIH Research Projects · FY 2026 · 2025-06

SUMMARY Nutrient-responsive pathways govern gene expression and metabolism to adapt to starvation, and their dysregulation causes cancer, diabetes, and aging. The Baugh lab uses C. elegans to investigate how animals maintain developmental homeostasis despite fluctuations in nutrient availability. C. elegans is a premier animal model to study starvation responses, both acute and long-term. Worms reversibly arrest development in the first larval stage when they hatch without food (L1 arrest). The Baugh lab’s foundational work has shown that L1 arrest is a powerful model for cancer and aging, pathological effects of early life starvation on adults, and multigenerational plasticity. They discovered that insulin/IGF signaling (IIS) and daf-16/FoxO are critical regulators of L1 arrest, that RNA Pol II is poised at growth genes during starvation, that early life starvation causes adults to develop tumors, and inter- and transgenerational effects of starvation. Current work is focused on starvation resistance mechanisms, nutritional control of gene expression, long-term consequences of early life starvation, and maternal effects of diet and IIS on progeny. Despite substantial progress, significant knowledge gaps remain. Though well studied, the role of tumor suppressors daf-18/PTEN and lin-35/Rb in promoting starvation resistance is poorly understood. The IIS/PI3K-independent function of DAF-18 is uncharacterized, and LIN-35 effector mechanisms are unknown. Additional genes that support starvation resistance remain to be identified. The transcriptional response to starvation has been well characterized, but mechanisms responsible for tissue-specific responses have not been identified. The lab implicated IIS, lipid synthesis, Wnt, and Hedgehog-related signaling in development of starvation-induced tumors, but how these pathways interact is unclear. The lab discovered that daf-16 and mpk-1/MAPK regulate vitellogenin lipoprotein oocyte provisioning, but it is unclear how soma-to-germline trafficking of lipids is regulated. The long-term goal of this project is to elucidate the signaling and gene regulatory mechanisms that enable worms to adapt to fluctuations in nutrient availability as a model for understanding regulation of growth and quiescence in humans. The central hypothesis is that a conserved network of tumor suppressors governs the starvation response. The objective of this proposal is to close gaps in our understanding of this network by identifying novel components, regulatory interactions, and effector mechanisms. Goals include identification of targets of DAF-18 protein- phosphatase activity, identification of transcriptional effector mechanisms of DAF-18 and LIN-35, identification of novel regulators of starvation resistance, anatomical resolution of the starvation response, elucidation of regulatory interactions among signaling pathways affecting starvation-induced tumor formation, and molecular mechanisms governing lipoprotein trafficking. The lab will leverage their expertise in rigorous genetic analysis, innovative functional genomics, mechanistic biochemistry, and automated image analysis. Closing these gaps will be significant given conservation of critical disease-relevant function of the potent regulators involved.

NIH Research Projects · FY 2026 · 2025-06

ABSTRACT Postoperative delirium is a frequent complication that follows surgical interventions and impairs recovery of many older adults. Delirium contributes to both acute and long-term complications, including mortality and co- morbidities that further reduce quality of life and increase healthcare costs, including the burden of newly diagnosed Alzheimer’s disease and related dementias (AD/ADRD). Hypertension is a common diagnosis for millions of older adults (65 years of age and older) and is a known risk factor for dementia with well-documented neurological implications, especially stroke. Although recent epidemiological evidence associates hypertension with delirium, the mechanisms whereby chronic hypertension contributes to postoperative delirium and long-term cognitive decline remain poorly understood. Our research demonstrates that blood-brain barrier (BBB) dysfunction and postoperative neuroinflammation are exacerbated in mice with Angiotensin II (AngII)-dependent hypertension. This pathological brain response to surgical stress is accompanied by upregulation of the Ang II type 1 receptor (AT1R) and induction of perivascular macrophages (PVMs) in the hippocampus. The overarching goal of this proposal is to ascertain the causal role of these targets as key contributors to vascular impairments in postoperative delirium and ensuing ADRD onset. Our primary objective is to elucidate the specific contributions of endothelial cells (ECs) and PVMs to surgery-induced neuroinflammation, BBB disruption, and delirium-like behavior in aging and hypertension. Our central hypothesis posits that BBB dysfunction in hypertension primes the neurovascular unit (NVU) by worsening border-associated immune activation and vascular dysfunction, thus exacerbating delirium-like behavior after orthopedic surgery and aging. Our aims will: 1) determine the effects of hypertension on postoperative neuroinflammation and cognitive outcomes with aging, 2) analyze the alterations in ECs and PVMs following hypertension and orthopedic surgery, and 3) identify the role of AT1R signaling in delirium superimposed on hypertension and with a microphysiological NVU platform. Our respective laboratories have established the feasibility for all these models and techniques. Our innovative approach incorporates novel transgenic mouse lines and advanced behavioral assays to longitudinally evaluate cognitive decline in hypertensive mice following surgery and aging. These models are integrated with a microphysiologic NVU platform using an optical transparent silicon membrane (μSiM-NVU) populated with human induced pluripotent stem cells (iPSCs) differentiated into the cell types that constitute the BBB to further identify signaling and key targets at the NVU. The rationale for the proposed research is that successful completion will expand our understanding of vascular risk factors and NVU dysfunction in hypertension and postoperative delirium. This knowledge is significant as it can identify potential therapeutic strategies to prevent delirium and subsequent ADRD in older and vulnerable patients.

NIH Research Projects · FY 2026 · 2025-06

ABSTRACT Brain metastasis leads to cognitive decline and is associated with increased cancer patient morbidity and mortality. The hypoxic microenvironment of brain metastases, as well as the presence of the blood-brain barrier, makes these tumors difficult to treat. Current therapies to treat brain metastases are ineffective and lack durable responses. Therefore, mechanistic understanding of the underpinnings required for brain metastasis promotion is needed for the development of novel therapeutic strategies. Hypoxia Inducible Factor-1 (HIF-1) is the master regulator of the hypoxia response and is upregulated in hypoxic areas, including brain metastases. It was reported that increased HIF-1 signaling correlated with enhanced proliferation of breast cancer metastases in the brain, and breast cancer brain metastases patient specimens exhibited increased HIF-1 expression compared to matched primary breast tumors. We have identified a potential functional interaction of HIF-1 with TAZ, a transcriptional co-activator in the Hippo signaling pathway. Here we propose to evaluate the hypothesis that this interaction regulates expression of a subset of target genes that promote brain metastasis in triple- negative breast cancer (TNBC). Notably, we recently found that the Abelson (ABL) family kinases regulate the expression and activity of HIF-1 in breast cancer cells. We have identified a novel ABL-dependent pathway whereby an E3-ligase targets HIF-1α for degradation in the presence of ABL kinase inhibitors in hypoxia in TNBC. Previous work uncovered ABL kinase mediated regulation of TAZ. Thus, we will evaluate whether ABL- dependent activation of HIF-1 and TAZ in brain metastases leads to enhanced expression of unique transcriptional targets, and whether inhibition of ABL-mediated HIF-1 and TAZ activation impairs brain metastases in TNBC. The proposed research is expected to reveal novel mechanistic insights on the modulation of HIF-1 activity and crosstalk with TAZ downstream of ABL-mediated kinase regulation and elucidate the role of HIF-1 in the promotion of breast cancer brain metastasis.

NIH Research Projects · FY 2025 · 2025-06

This Lung Transplant Clinical Trials Network (LT-CTN) CTOT-CA consortium includes twelve of the high-volume, research-oriented adult and pediatric lung transplant programs in North America. Long-term survival for lung recipients is limited by chronic lung allograft dysfunction (CLAD), the final manifestation of chronic lung rejection. CLAD is not effectively prevented by posttransplant immunosuppression, as over 50% of lung recipients develop CLAD within five years. Evidence suggests upregulation of inflammatory cytokines in the allograft contributes to CLAD through innate immunity and allorecognition-driven adaptive immune responses. We previously showed posttransplant acute rejection (AR), lymphocytic bronchiolitis (LB), organizing pneumonia (OP), or acute lung injury (ALI), increase CLAD risk and are associated with elevations of Types I & II cytokines in the lung fluid. Because these cytokines share signaling through the Janus Kinase (JAK) family, blocking the JAK signaling modulator Rho-associated protein kinase 2 (ROCK2) could be an effective strategy to limit inflammatory cytokine responses and prevent CLAD. Studies in bone marrow recipients with graft vs. host disease showed clinical benefit with the oral selective ROCK2 inhibitor belumosudil, including in patients with the pulmonary manifestation of bronchiolitis obliterans syndrome, the most common presentation of CLAD. Thus, we hypothesize that adding belumosudil to standard posttransplant immunosuppression will reduce inflammatory cytokine signaling, diminish innate and adaptive immune responses, and prevent CLAD. To test this, we will complete the BLOCK-CLAD (Belumosudil to Block CLAD in High-Risk Lung Transplant Recipients: a randomized, multicenter, double-blind placebo-controlled trial) study, randomizing 234 bilateral lung recipients at higher CLAD risk (i.e. evidence of AR, LB, OP, or ALI) to belumosudil or placebo. Enrollment will occur over two years with participants having one to three years of follow-up. We will conduct mechanistic studies to determine how innate and adaptive responses that contribute to CLAD are mitigated by belumosudil. Our investigator team brings longstanding collaboration and a depth of experience, including leading the adult CTOT-20 and -22 and pediatric CTOTC-03, -05, -08, and -11 studies. When completed, BLOCK-CLAD has potential to transform clinical practice, improve lung recipient outcomes, and expand immunosuppression paradigms after solid organ transplantation.

NIH Research Projects · FY 2026 · 2025-05

ABSTRACT Alzheimer's Disease and Related Dementias (ADRD) represent one of the most urgent public health crises in the United States, with over 6 million Americans currently affected, and a growing burden among communities of Asian descent. Despite this, most well-established dementia care programs have been developed and tested predominantly in White populations, limiting their applicability to the many Americans living with ADRD from different cultural backgrounds. Over 80% of persons with ADRD receive care from one or more of their family members worldwide. This proportion is even higher among Asian and Asian American families where the demand for dementia care has increased dramatically, yet institutional and community care services for dementia are limited. Currently, most well-established dementia care programs are intense, multicomponent, resource-demanding, and focus only on the primary caregiver. It is unclear whether these current dementia care programs are appropriate and/or easy to implement among persons with ADRD from other cultural backgrounds, socioeconomic statuses, and/or community settings. In an Asian cultural context, social expectations of caregiving within the home/family (e.g. filial piety), changes in family structures (e.g. urbanization and migration), intergenerational living environments (e.g. multigenerational households), and involvement by non-family members (e.g. domestic helpers) contribute to a wide array of family dynamics in providing care to persons with ADRD. Therefore, identifying major types of family structures is critical for capturing the demand for informal caregiving and other support(s) and services. Without such knowledge, the development and implementation of effective, contextually relevant, and person-centered interventions and policies to support caregivers for persons with ADRD across U.S. communities and beyond will remain elusive. To address this critical gap, we propose to leverage Common Data Elements from 10 national aging studies to (1) identify major types of family structures of dementia caregiving across different contexts, (2) assess individual and context-specific factors associated with the types of family structures among persons with ADRD, and (3) evaluate how the types of family structures are associated with care utilization and overall wellbeing in persons with ADRD. This study will not only define the landscape of family resources to support dementia caregiving across various cultural contexts, but will also develop much needed evidence that policy makers can use to better inform the design, targeting, and types of community-based dementia care services to prevent suboptimal outcomes and to improve well-being for the many Americans from varied cultural backgrounds living with ADRD.

NIH Research Projects · FY 2026 · 2025-05

Project Summary Our first research theme is the accurate and efficient description of bio-molecular interactions, which is at the core of biological modeling, particularly for the understanding of protein structures and the reactions catalyzed by enzymes. Achieving optimal results requires an energy function that balances accuracy with computational efficiency, in both quantum mechanical (QM) methods and the molecular mechanical (MM) force fields. The second theme is to study and reveal the complex reaction mechanisms of key enzymes. Enzymes are biological catalysts that drive biochemical reactions essential for life. Studying reaction mechanisms in enzymes is crucial for obtaining insights into fundamental biological processes, developing inhibitor and drug, aiding in the development of diagnostic tests and prognostic tools for diseases, optimizing biomedical technology, and inferring evolutionary relationships. This proposed MIRA research project focuses on three directions. (A) Developing QM methods based on density functional theory (DFT) to achieve accuracy and efficiency needed for biological systems. DFT is the most widely used QM for biological molecules. Despite its success, DFT can still suffer from large pervasive systematic errors. We will develop the localized orbitals scaling corrections to eliminate these errors. (B) Constructing protein and biomolecular force fields based on multiscale QM and MM and machine learning (ML). Although MM force fields have been successfully applied to many problems, they still frequently fail to capture the correct conformational and energetic features of diverse biomolecules. We will build on the residue-based systematic molecular fragmentation (rSMF) approach developed in the PI lab to develop a general and scalable ML force field for all biomolecules based on QM/MM and rSMF, providing a unified model for not only proteins, but also protein-ligands, RNA-ligands, and other complexes. (C) Investigating reaction mechanisms of 5’-deoxyadenosyl radical formation in radical SAM enzymes. Radical S-adenosylmethionine (SAM) enzymes form one of the largest enzyme superfamilies with more than 700,000 unique sequences. They are abundant in Nature, involving in many medically important pathways. We will characterize the mechanism of SAM cleavage using MoaA radical SAM enzyme as a model system, in collaboration with experimental efforts. The plan research, harnessing the latest QM, QM/MM and ML developments, will advance simulation methods for biological systems and provide valuable insights into enzyme functions.

NIH Research Projects · FY 2026 · 2025-05

In situ reprogramming of scar fibroblasts into cardiomyocytes is therapeutically beneficial. However, functional improvements are relatively modest. The challenges for effective reprogramming are suboptimal timing of delivery, repressive barriers, and poor delivery to fibroblasts. Consequently, we hypothesize reprogramming efficacy will be improved by delivering reprogramming factors into the heart once the infarct has stabilized ablating the function of a repressor complex, and targeting reprogramming factors to cardiac fibroblasts. The hypothesis will be tested by three specific aims. Aim 1 will focus on the mechanism by which a repressor complex comprised of Cbx1, PurB and Sp3 inhibits cardiomyocyte genes. Studies will test the hypothesis that the repressor complex functions by inducing a DNA-loop and blocking access to enhancer elements. DNA-looping will be investigated by deleting or repositioning the repressor complex binding sites through the introduction of variable helical twists in a promoter reporter construct and then measuring luciferase reporter activity. Due to the apparent cooperativity between Cbx1, PurB and Sp3, we will also determine if knockdown of one repressor is sufficient to re-capitulate the effects of combined knockdown. Aim 2 will investigate the hypothesis that targeting the Cbx1-PurB-Sp3 repressor complex will improve miR combo efficacy in a mouse model of cardiac injury. The hypothesis will be tested by injecting fibroblast-selective C166-derived exosomes containing miR combo and a repressor-complex targeting siRNA into the hearts of fibroblast-lineage tracing mice immediately following MI or up to 4 weeks post infarct. The latter time-point will be used to determine if reprogramming can be employed as a salvage therapy once the infarct is completed with development of fibrosis. The effects on reprogramming (lineage tracing), cardiac structure (infarct size, fibrosis, etc.) and cardiac function (echocardiography) will be assessed over time. Aim 3 is tasked with moving reprogramming towards clinical applications via studies in a pre-clinical pig model of cardiac injury. Our preliminary data shows that pig cardiac fibroblasts internalize C166- derived exosomes and that miR combo improved cardiac function in infarcted Yorkshire mini-pigs. Following transient occlusion, C166-derived exosomes loaded with FITC-labelled miRNAs will be delivered into the hearts of Yorkshire mini-pigs and cardiac tissue analyzed for exosome uptake by measuring FITC incorporation in cardiac cells including fibroblasts, cardiomyocytes and endothelial cells. Additional studies will determine the function benefits arising from a therapy combining miR combo and a repressor targeting siRNA. In summary, successful completion of these studies is expected to delineate the role of transcription repressors as a newly discovered barrier to reprogramming. In addition, applying this knowledge in conjunction with fibroblast-selective delivery of miR combo via C166-derived exosomes is expected to enhance the efficacy and therapeutic outcomes of reprogramming fibroblasts to cardiomyocytes. Moreover, translational studies will move our MI- therapy closer to clinical applications.

NIH Research Projects · FY 2026 · 2025-05

ABSTRACT The cerebellum shares rich anatomical connections with prefrontal and limbic areas and participates in processes well beyond motor coordination. Recent evidence on the role of the cerebellum in fear learning and memory, coupled with established findings of posttraumatic stress disorder (PTSD)-associated abnormalities in threat detection and processing, suggest the cerebellum may play a significant role in the pathophysiology of PTSD. Smaller whole cerebellar and cerebellar subregion volumes have been observed in adults and children with PTSD. However, sparse knowledge of cerebellar activation and functional connectivity differences in PTSD need to be addressed with large, rigorous, and reproducible characterizations of the cerebellum in PTSD, and its potential as a treatment target. Widespread connectivity of the cerebellum with stress related regions (e.g. amygdala, hippocampus, periaqueductal gray) make it vulnerable to traumatic stress and disruption by brain-mediated stress responses via cortico-cerebellar circuits. We hypothesize these connections are highly relevant to PTSD neurobiology. Our overarching goal is to study cerebellar subregion connectivity (structural and functional) to cortical regions, subcortical regions, and canonical resting-state networks implicated in PTSD. We will analyze existing neuroimaging and clinical data in > 1,887 samples of PTSD cases and trauma-exposed controls from 25 international cohorts shared with the ENIGMA-PTSD Consortium workgroup. Aim 1 will investigate the influence of PTSD, trauma exposure, and PTSD symptom clusters on the functional connectivity of cerebellar subregions to cortical regions and subcortical regions. Aim 2 will examine the structural covariance and structure-function coupling of cortico-ponto-cerebellar tracts, cortical regions, and subcortical regions with cerebellar subregions. Aim 3 will investigate differential effects of PTSD on task-positive networks (ventral attention, fronto-parietal), task-negative networks (default mode, dorsal attention), the putative balance between task-positive and task-negative networks, and other canonical resting-state networks. Aim 4 will explore cerebellar subregion activation and connectivity in response to threat stimuli in PTSD and trauma exposure. The proposed research may pay a central role in developing neuromodulatory therapeutics for PTSD. Cortico-cerebellar paired associative stimulation may be deployed in the future with a paradigm to enhance feedback and feedforward cortico-cerebellar connections involved in threat processing, particularly threat stimuli that evoke a fight or flight response.

NIH Research Projects · FY 2026 · 2025-05

Morbidity and mortality in alcohol-related liver diseases (ALD) are caused by severe alcohol-induced steatohepatitis (SAH) and cirrhosis (AC). Effective therapies are lacking because the mechanisms driving the pathogenesis and progression of SAH and AC are unclear. This research program has evaluated the general hypothesis that bad outcomes of alcohol-induced liver injury result from deregulated repair mechanisms that cause defective regeneration of mature hepatocytes. Our prior results indicate that effective liver regeneration requires reactivating fetal programs to nurture the outgrowth of liver progenitors but then silencing these programs, so the liver matures appropriately. Thus, we will continue to evaluate the hypothesis that ALD progresses because mechanisms controlling when fetal programs are switched ON and OFF in adult liver cells are dysregulated. We have evidence that liver failure in human SAH results from the over-activation of fetal programs. Conversely, our pre-clinical data suggest that cirrhosis evolves when adult programs are not suppressed sufficiently for injured livers to regenerate. RNA Binding Proteins (RBPs) dynamically control the stability, translation, and splicing of mRNAs encoded by liver genes. Thus, we propose that RBPs critically control adult-fetal “switching” in hepatocytes during ALD. To identify the repertoire of RNA binding proteins, RNA splice variants, and liver genes that change in response to alcohol-induced liver injury, we coupled high- resolution sequencing of liver RNA with single-cell transcriptomics and chromatin accessibility analyses. ESRP2 was identified as one of the most down-regulated hepatocyte RBPs in human SAH. ESRP2 regulates the splicing of ~20% of hepatocyte RNAs, generating splice variants that encode functional differences in proteins that control hepatocyte proliferation and differentiation. We have reported that ESRP2 is critically important for switching on the adult program in developing livers and that over-expressing ESRP2 blocks adult liver regeneration. Our new data show that human SAH livers are enriched with fetal splice variants of ESRP2 targets that alter the activity and cellular localization of their encoded proteins. We reported that TNF and IL1 (critical cytokines in ALD pathogenesis) regulate both ESRP2 expression and adult-to-fetal “switching” in hepatocytes. Our ongoing studies indicate that manipulating ESRP2 exacerbates liver damage in mouse models of steatohepatitis, further supporting the concept that ESRP2 misregulation is an important driver of deregulated repair mechanisms in ALD. Iterative analyses of human liver samples and mouse models of liver injury and repair will continue during the next funding cycle. Based on present data, we will prioritize studies to determine how ESRP2-regulated RNA splicing events control hepatocyte responses to alcohol-induced injury, delineate how these adapted hepatocytes reconfigure other liver cell communities to dictate ALD outcomes, and define mechanisms that regulate ESRP2 expression, thereby revealing novel therapeutic targets to improve recovery from ALD.

NSF Awards · FY 2025 · 2025-05

Non-technical Abstract: In the time of rapidly expanding interest and investment in Quantum Information Science and Engineering (QISE), relevant education and workforce development efforts are becoming critical. This three-year project is designed to accelerate progress across the quantum education community by amplifying its efforts through dissemination, cohesion, and collaboration. The project will also allow expansion of the Key Concepts for K-12 education, so that the community can work towards integrating QISE into early education. Activities include a website that serves as a hub for the wider QISE education ecosystem, and a plan for a cohesive set of workshops to further the development of age-appropriate K-12 QISE education resources. Transdisciplinary and convergent connections across the QISE education ecosystem spanning K-12, academia, government, industry, professional societies, and informal education organizations are a central element of this effort. QISE draws from the fields with some of the lowest percentages of underrepresented minority and female students, and this program involves mechanisms to increase participation of underrepresented groups in QISE. Technical Abstract: QISE education and the associated research is distinct from quantum mechanics, mathematics, or computer science, but it is not its own field. This activity bootstraps a community of educators, education researchers, and QIS professionals to further develop QISE education, seed new efforts and magnify research in this critical area. Core research and technological progress in QISE depends on supporting this community. Moreover, planned activities enable the education community to take concrete collaborative steps towards making changes to curricula and implementing tools that increase awareness, intuition, and literacy in quantum information science at the K-12 level and ultimately across all ages and learning environments. Planned activities and outputs are designed to be inclusive, and to build connections with underrepresented groups in the fields of science, technology, engineering and mathematics. Broadening access to QISE for students of different backgrounds, and increased female and minority representation at the college level are also the goals of this work. An evaluator will assess the project activities and deliverables using methods such as surveys, focus groups, and data analytics collected from web logs. Given the emphasis on facilitating connections across QIS education ecosystem, evaluation protocols will be developed based on a framework for assessing the attributes of collaborative communities. This project is partially supported by NSF's Discovery Research PreK-12 (DRK-12) program, in the Directorate for Education & Human Resources and Directorate for Mathematical and Physical Sciences (MPS) through the Office of Multidisciplinary Activities (OMA), Division of Materials Research (DMR) and Division of Physics. DRK-12 seeks to significantly enhance the learning and teaching of science, technology, engineering and mathematics (STEM) by preK-12 students and teachers through research and development of innovative resources, models and tools. Projects in the DRK-12 program build on fundamental research in STEM education and prior research and development efforts that provide theoretical and empirical justification for proposed projects. 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 · 2025-05

Summary The ventral tegmental area (VTA) is a midbrain region that has long been implicated in the learning and expression of motivated behavior. It contains dopamine (DA) neurons that give rise to the mesolimbic dopamine pathway, as well as GABAergic (GABA) projection neurons that target multiple midbrain and brainstem regions. According to the reward prediction error (RPE) hypothesis, phasic activity of VTA DA neurons encode a reward prediction error, whereas GABA neurons encode reward prediction, which is used to compute reward prediction error. However, recent work has begun to challenge this hypothesis, by showing precise encoding of action parameters by VTA DA and GABA neurons. It remains unclear how the role of VTA in performance may be reconciled with a role in learning and reinforcement. The overall aim of this proposal is to elucidate the function of the VTA circuits using a highly integrative approach that combines multiple levels of analysis, from single neurons to behavior. We will use bidirectional optogenetics, in vivo electrophysiology and photometry, and quantitative behavioral measures with unprecedented temporal and spatial resolution, to elucidate the contribution of the VTA circuit to the learning and performance of motivated behaviors. This proposal will test the hypothesis that the VTA GABA projection neurons provide continuous descending commands for steering of the head and body, and that the output of the DA neurons is used to adjust the gain in the limbic basal ganglia responsible for generating such commands critical for approach and retreat in all motivated behaviors. We will record and perturb neural activity from VTA DA and GABA neurons using a number of behavioral tasks in head-fixed as well as freely moving mice. Using the latest DA sensors, we will also record DA signaling in multiple striatal regions that receive VTA projections. Finally, we will develop a computational model of the VTA circuit, focusing on interactions between VTA DA and GABA neurons and their collective contributions to behavioral output. Results from proposed experiments can lead to a new and unified model of adaptive performance and learning in motivated behaviors.

NIH Research Projects · FY 2026 · 2025-05

Project Abstract To survive in dynamic environments, animals utilize continuous sensory information to drive precise and coordinated motor behavior. For instance, to catch a flying ball, one must reach with a targeted, discrete arm movement. Therefore, the neural networks processing visual information must transform these continuous motion cues into distinct motor commands to achieve locomotion with appropriate speed, vigor, and duration. So far, there has been no single-cell resolution and mechanistic characterization of these circuits in vertebrates due to the overwhelming size of the mammalian brain. In this proposal, I will leverage the optically and genetically accessible larval zebrafish (Danio rerio) for cellular level dissection of the visuomotor circuit underlying a visually guided behavior, the optomotor response (OMR). During the OMR, zebrafish stabilize their body’s position by compensating perceived optic flow via discrete locomotion events (i.e. bouts), consisting of undulating tail movements for short periods followed by passive glide phases. Previous behavioral and neural imaging studies have characterized motion-processing neural circuits across the brain, including the retinorecipient pretectum (Pt). Recently, we have implemented these circuits into quantitative models and a physics-based neuromechanical simulation, simZFish, which allows for simulated OMR behavior experiments with biologically derived neural circuits. Yet, these virtual whole-brain OMR circuit models lack clarity in the functional circuit architecture and mechanisms that transform continuous visual motion encoded by the Pt into discrete movement. Here, I hypothesize that specific motion-selective Pt neurons drive the activation of a recurrent inhibitory bout- generating circuit, composed of specific midbrain spinal projection neurons, excitatory hindbrain neurons, and hindbrain inhibitory neurons. To determine the functional neural circuit that transforms visual motion into motor commands, I will use in vivo volumetric two-photon imaging with precise 3D holographic optogenetic photostimulation to map cellular functional connections across brain regions between motion responsive Pt neurons and the midbrain cells that initiate bouts (Aim 1). To determine how continuous visual motion is converted into discrete locomotor events, I will investigate how the midbrain cells recruit specific excitatory and inhibitory hindbrain neurons using the same all-optical techniques with simultaneous tail tracking (Aim 2). Results from both aims will update the simZFish neural circuit and then tested in virtual experiments to validate these findings. Using integrative all-optical, behavioral, and neuromechanical approaches, this proposal aims to provide insights into how single neurons transform sensory information into motor commands and general principles of vertebrate locomotion control. Ultimately, my long-term goal is to comprehensively understand how neurons compute information across brain regions to generate movement for future applications to develop physiologically accurate prosthetics and treat motor neurodegenerative diseases. \

NIH Research Projects · FY 2026 · 2025-05

Project Abstract/Summary Sepsis is among the leading causes of death in the intensive care unit, and therapies that combat the dysregulated host response underlying its high morbidity and mortality remain elusive and urgently needed. Animal studies indicate that the gut microbiota plays a critical role in host immune responses, and modulation of microbiota structure or function may be an effective strategy in the treatment of sepsis. However, development of similar therapies for clinical practice first requires a better understanding of the relationships between the gut microbiota and immune status in septic patients. Due to the increased intestinal permeability associated with sepsis, delineating these host-microbe interactions also requires the consideration of gut- derived microbial products in the blood, and their potentially distinct influences on immune responses. Emerging evidence using modern sequencing techniques demonstrates that microbial products (including lipopolysaccharide) from gut microbes are not universally pro-inflammatory, but rather, transmit species- specific signals to immune cell toll-like receptors (TLRs) that differentially influence nuclear factor-κB activation and cytokine responses. Changes in gut microbial community structure and collateral effects on the composition of blood microbial signatures thus may contribute to the degree of systemic immune activation in sepsis. However, interactions between gut and blood microbial signatures and immune responses have never been simultaneously explored in septic patients. This proposal aims to unravel these relationships, using a meta-systems approach to integrate gut microbial community profiling, metabolomics, measures of intestinal permeability, and blood microbial signatures with immune phenotypes and clinical endpoints in a prospective longitudinal cohort study of ICU patients with sepsis. These investigations will reveal how changes in the microbiota in sepsis – compared to critical illness alone – influence blood microbial signatures and burden, and if specific gut and blood microbial signatures relate to, or are predictive of, immune activation/exhaustion and end-organ dysfunction. Additionally, biochemical, sequencing, and peripheral immune cell assays will be used to investigate if distinct blood microbial signatures identified in septic patients differentially modulate innate immune cell TLR activation and cytokine production. The findings from this study will enhance our understanding of microbiota-immune interactions and have the potential to reveal novel therapeutic approaches that are urgently needed for this lethal disease.

NSF Awards · FY 2025 · 2025-05

This project expands opportunities for students to enroll in doctoral programs and pursue social science as a profession in academic and non-academic careers. The project immerses undergraduates in the summer of their junior year in a five-week intensive program that includes graduate level coursework, as well as the design, analysis, writing, and presentation of original research papers. The program simulates the graduate school experience and focuses on scientific analysis by introducing the students to research methods, statistics, and the research process. Those students whose empirical papers are judged to be of high quality are invited to present their work in a poster session at the annual meeting of a professional association. The ultimate goal of the Ralph Bunche Summer Institute is workforce development, specifically to increase participation of undergraduate students in graduate programs and then as faculty in colleges and universities and as researchers in the private and public sectors. The project provides a five-week intensive program for undergraduate students that prepares them to pursue a doctoral degree in social science with the goal of increasing their preparation for and awareness of opportunities for them in academia as professors and researchers and in the private sector as practitioners. The program includes graduate level coursework, training in statistical/quantitative methods, and completion of an original research project. Outcomes from previous years indicate that the RBSI has succeeded in preparing students for graduate programs in several social science fields. The program has also been successful in increasing substantially the number of students with masters degrees, many of whom have gone into government service. 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 · 2025-05

ABSTRACT A major goal in neuroscience is to analyze neural circuit structure and function in diverse brain regions and species with cell type resolution. Achieving this goal requires novel technologies and reagent resources that grant cell type access yet are scalable and generalizable across brain regions and species. Transcriptional regulation of gene expression is a fundamental and universal mechanism underlying cell type specification across species and life spans. Most current approaches to gain access to cell types attempt to recapitulate RNA expression patterns through DNA engineering of transcriptional regulatory elements (e.g. enhancers). However, the generality and scalability of the enhancer approach, especially to other non-model vertebrate species, remain to be established. We recently invented an orthogonal RNA and translation-based method that represents a new paradigm in cell type technology. CellREADR/RADARS is built upon the universal RNA editing system within all metazoan cells mediated by the enzyme adenosine deaminase acting on RNA (ADAR). CellREADR is deployed as a single modular RNA molecule that detects a specific cellular RNA through RNA-RNA base pairing and then switches on the translation of effector proteins to monitor and manipulate the cell. Notably, CellREADR can be delivered efficiently to brain tissues via viral vectors. As such, CellREADR is potentially highly specific, easy to use, exceptionally scalable and programmable, and applicable to all vertebrates. Fully realizing the enormous potential of CellREADR requires a scalable and generalizable platform for systematically screening and validating a large number of RNA sensors for all major cell types across brain regions and vertebrate species. Here we have assembled an exemplary team of molecular geneticists, systems and evolutionary neurobiologists, and a physicist to establish a spatial transcriptomics-based pipeline that is scalable and generalizable for high-throughput screening of RNA sensor libraries in the brains of different vertebrate taxa. We will first apply this pipeline to identify hundreds of cell type RNA sensors across marmoset, mouse, songbird, and salamander brain. We will focus on cell types of the cerebral cortex/pallium, basal ganglia, and thalamus, as these structures give rise to the cortico- basal ganglia-thalamic circuit loops that are highly conserved across vertebrates and fundamental to sensory, motor, cognitive, and emotional functions. We will then validate the specificity, efficiency, and functionality of these RNA sensors. Finally, we will register these sensor libraries with current cell type atlases in each species and catalog them with validation information in a format that facilitates dissemination through the BRAIN Armamentarium network and other publicly accessible portals. Our project is poised to transform vertebrate neuroscience through cell type and circuit resolution comparative analysis and will lay a path to cell type-targeted gene therapy and circuit modulation in neuropsychiatric diseases. 1

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY/ABSTRACT. Approximately 10 to 15% of all cancers utilize the alternative lengthening of telomeres (ALT) mechanism to maintain telomere length and achieve replicative immortality. ALT occurs frequently in high-grade gliomas (HGGs), including IDH-mutant astrocytomas, pediatric HGGs with H3G34R mutations, and a subset of adult primary GBMs. The overarching goal of this F32 Fellowship Award is to investigate the role of SMARCAL1, an annealing helicase that catalyzes replication fork reversal, in promoting glioma cell proliferation and suppressing tumor-intrinsic inflammation. HGGs are notoriously immunologically cold with large suppressive myeloid compartments. Current therapies have struggled to generate an immune response. Our preliminary data in pre-clinical glioma models shows that therapeutic targeting of SMARCAL1 represents a path to tumor- cell specific DNA damage and inflammation, and depletion of SMARCAL1 increases replication stress, DNA damage, and aberrant DNA and RNA species. This project will investigate the intrinsic and extrinsic inflammatory response following SMARCAL1 depletion in ALT+ HGG cell lines and orthotopic syngeneic murine glioma models. SMARCAL1 will be depleted in human ALT+ HGGs and syngeneic murine ALT+ cell lines utilizing RNAi lentiviral particles containing two distinct doxycycline-inducible SMARCAL1-targeting shRNAs. In vitro studies will involve investigation of pattern recognition receptor (PRR) signaling within tumor cells and the resulting effects on the secretome, measured using western blot and LegendPlex. The specific mechanism of PRR derived inflammation will be elucidated using CRISPR/Cas9 gRNA knockdown studies and visualized using IF-FISH with confocal microscopy. The effect of inflammation on phagocytic myeloid cells will be monitored using living cell imaging and flow cytometry. In vivo studies will investigate the inflammatory response in orthotopic murine glioma models in C57Bl/6 mice with syngeneic tumors. These studies will identify alterations to the inflammatory profile of ALT+ tumors within tissue context and provide information on the role of the immune system following SMARCAL1 depletion using both in vivo and ex vivo models. Alterations in the inflammatory response and T cell mediated cytotoxic killing will be investigated using flow cytometry and transcriptomics. Both mentors are experts in the field with well-respected publication records in the fields of HGG, ALT, and SMARCAL1 and will provide the appropriate mentorship as Dr. Erman transitions her immunology expertise from nephrology to oncology, as well as facilitating her mentorship of more junior members. The resources and facilities at Duke University are exemplary and all studies will be performed using the most modern techniques with the guidance of experienced and respected collaborators. The proposed studies include techniques Dr. Erman has extensive experience with including flow cytometry and transcriptomics yet allowing her to apply them to a new field, and areas for growth including murine glioma models, cell culture, and IF-FISH with confocal microscopy.

NIH Research Projects · FY 2026 · 2025-05

ABSTRACT: Macrophages are vital components of a diverse and extensive set of physiological processes, and rely on precise response to both internal and external cues to perform their functions. G-protein signaling comprises a significant proportion of these functional cues, and thus is a significant and consequential mechanism of macrophage regulation. Regulators of G-protein signaling (RGS) proteins are a family of related proteins that exert control over G-protein pathways by accelerating the termination of signaling cascades. RGS12 is the largest member of the RGS family and possesses a number of protein-protein interaction domains in addition to this G-protein regulation capability. The goal of this proposal is to investigate how RGS12 influences macrophage function in the context of a leukocyte-rich structure known as a granuloma. In response to persistent inflammatory stimuli including mycobacterial infection, macrophages aggregate into a granuloma structure, and a subset of these cells undergo a transformation into epithelioid macrophages, which are critical to the integrity of the granuloma structure. Using the zebrafish-Mycobacterium marinum model and available human tuberculosis (TB) patient cohort datasets, we have found that the zebrafish ortholog rgs12b is enriched in the epithelioid macrophage population and that RGS12 is associated with increased TB severity, while preliminary data suggests that loss of rgs12b disrupts macrophage epithelioid transformation and granuloma bacterial containment. Thus, we hypothesize that rgs12b is an important regulator of macrophage function and identity, and will utilize the zebrafish-M. marinum model to investigate the mechanism of this interaction in the context of a mycobacterial granuloma. Completion of the proposed work will represent a significant contribution to our understanding of how macrophage behavior and G-protein signal regulation can alter function. The findings will be relevant to the development of host-direct therapies targeting the granuloma structure, and could also extend to a number of blood and lung-related disorders in which RGS protein irregularities have been implicated.

NSF Awards · FY 2025 · 2025-05

T cells are a type of white blood cell that plays an important role in the functioning of the immune system. Therapies based on T cells (CAR T-cell therapy) are proving to be effective for certain cancers. T cells are isolated from a patient’s blood and modified to express a binding protein (CAR) that allows the T-cell to more effectively attach to tumor cells. Once modified, the CAR T-cells are grown to create millions of them, and then introduced into the patient, where they bind to cancer cells and kill them. The weak link in this process is the growth step. As the cells grow in number, they create inexact copies of the original cell, so ultimately there is a broad distribution of effectiveness in the resulting CAR T-cells. This reduces the effectiveness of the treatment. This project will attempt to track the development of these growing populations and determine what causes this variability. In parallel, the PI will be developing hands-on lessons and computational tutorials on light microscopy for high school and college-level communities. This should enhance STEM education and broaden the understanding of single-cell biological engineering. This project aims to decode how single-cell phenotypic heterogeneity arises and can be precisely controlled by linking dynamic cellular behaviors to deep molecular phenotyping. Currently, a major limitation is the inability to observe how a cell’s molecular phenotype relates to the multimodal signals and dynamic paths it takes through time and space. To address this challenge, the research leverages three cutting-edge technologies: (1) spatial proteomic multiplexed imaging; (2) in vitro cell tracking; and (3) engineered biomaterial artificial antigen-presenting cells (aAPCs) that deliver controlled stimulatory signals to T cells. The scope of the project is centered on three main objectives. First, it will image and computationally extract dynamic cell interactions to link these events directly to downstream T cell phenotypes. Second, it will establish a barcoded, dynamic, multi-input T cell stimulation platform and decode the complete stimulation histories of individual cells as they acquire their final phenotypes. Third, it will use these integrated datasets—encompassing dynamic behavior, molecular signatures, and multiplexed stimulation conditions—to learn and predict how T cell phenotypes emerge from complex, time-varying inputs. To accomplish these goals, the project employs existing and newly developed computational workflows, including segmentation, unsupervised clustering, machine learning, and data-driven multiscale modeling. By constructing a powerful, decodable perturbation screening platform, the research will uncover how distinct combinations and sequences of stimulation events shape T cell fate. 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 · 2025-05

NONTECHNICAL SUMMARY This CAREER award will support research and education activities that advance the understanding of MXenes, an emerging class of atomically thin materials. These materials possess unique combinations of properties: they conduct electricity exceptionally well, interact strongly with light to enable energy conversion, and can be flexed or bent without breaking. These extraordinary characteristics position MXenes as important materials for advancing electronic devices and robotic systems. However, current manufacturing methods produce MXenes with imperfect surfaces, which limits their performance. The research will employ advanced fabrication techniques, artificial intelligence, and innovative engineering approaches to reveal the true capabilities of these materials. The research will focus on three main objectives: 1) developing new methods to create pristine MXenes with clean, controlled surfaces, 2) using artificial intelligence to quickly analyze and understand these materials, and 3) enabling new types of electronic devices and soft robots that take advantage of MXenes' intrinsic properties. By combining this research with educational activities including summer camps for K-12 students, research experiences for undergraduate students, and an open-access course with virtual laboratory experiences, the project creates new scientific knowledge while strongly contributing to workforce development in advanced materials and manufacturing. TECHNICAL SUMMARY The research will advance the fundamental understanding of MXene materials by addressing key challenges in their synthesis, characterization, and property measurement. The scientific problem centers on creating and studying pristine MXenes - a goal that has remained elusive due to limitations in current fabrication and analysis methods. To overcome these challenges, the project will develop atomic-precise fabrication methods, including plasma-assisted atomic layer etching and chemical vapor deposition, to create pristine MXenes with controlled surface chemistry and large crystalline domains. For efficient materials development, machine learning algorithms integrated with large language models will enable rapid and precise analysis of material structure and properties. These advanced synthesis and characterization capabilities will allow systematic investigation of previously unexplored characteristics of pristine MXenes, including electron transport and light-matter interactions. Through comprehensive study of these well-controlled materials, this research will establish benchmark measurements of MXenes' intrinsic properties and will provide critical insights into how surface chemistry influences their electronic and optical behaviors, advancing the scientific understanding needed for next-generation electronics and robotics. The education and outreach activities will focu on creating a pipeline of talent in advanced materials and manufacturing. The project will implement three integrated programs: a K-12 summer camp module featuring hands-on activities with soft robotics, a research program providing summer research opportunities for underrepresented undergraduate students, and an open-access course featuring an innovative virtual cleanroom experience. These activities will incorporate research findings from the MXene project and will expose students to cutting-edge concepts in materials science and nanofabrication. 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 · 2025-05

Project Summary A fundamental goal of sensory neuroscience is to understand how external signals from the environment are detected and translated into neural signals that underlie perception and enable discrimination of different stimuli. In the mammalian olfactory system, odorant detection and discrimination are mediated by hundreds of distinct odorant receptors (ORs) tuned to detect small, volatile molecules with diverse physicochemical properties. To understand the neural basis of olfactory sensation it is necessary to determine the nature of OR sensitivity and selectivity across olfactory chemical space, as well as how OR – odorant interactions drive neural activity. The proposed project addresses these goals by investigating OR selectivity and function at multiple levels for three ORs in the mouse olfactory system. The project builds on a well-established collaborative pipeline between the two co-Investigators that allows for predictions arising from structure-function studies and in vitro assays to be tested in vivo for the same ORs. The project is organized around two major Aims. Aim 1 will investigate the structural determinants of OR activation and corresponding neural signaling in awake, freely breathing mice. We will focus on three ORs – one Class I and two Class II ORs – where high-potency in vivo ligands and glomerular projection targets have already been identified and use OR-IRES- mKate2 gene knock-in mouse lines (already generated) crossed with lines expressing the latest- generation optical reporters (GCaMP8m) expressed in either olfactory sensory neurons or mitral/tufted cells. We will compare in vitro activation profiles and in vivo response features for each OR and test hypotheses for how OR activation translates to in vivo neural activity patterns at each level. Aim 2 will investigate the structural basis and in vivo efficacy of OR antagonism, which is hypothesized to shape the encoding and perception of odorant mixtures but is poorly understood. We will test a novel model of the structural basis for antagonism of an identified Class I OR using in vitro functional assays, then define the efficacy and specificity of OR antagonism in shaping odorant-evoked neural activity in the awake mouse. Completion of these Aims will provide new foundations for linking the understanding of olfactory sensing mechanisms from the level of ORs to the brain, pave the way for rational design of OR antagonists, and ultimately achieve a generalizable understanding of the relationship between OR structure, ligand selectivity, and OR-driven neural activity in vivo.

NIH Research Projects · FY 2025 · 2025-05

ABSTRACT Controlled deposition of materials is central to realizing a wide variety of biomedically relevant devices, from immunoassays to microfluidics. Well-established printing techniques such as inkjet and aerosol jet have opened new possibilities for scaling down material consumption while boosting performance of devices; however, these printers are limited to resolutions > 10 microns with restrictions on printable ink properties that often preclude utility in many biomolecule printing applications. The Hummink NAZCA printer is a first-of-its-kind capillary flow printer that offers < 1 µm resolution and compatibility with inks spanning a broad range of viscosities. Operation of the printer is simple: A small volume of ink is loaded into a glass micropipette, which is brought into close proximity with a substrate such that deposition proceeds via capillary forces. The system borrows its core operation control from atomic force microscopy (AFM), making it possible to offer dual functionality as a deposition and imaging tool. Over the last six months, Duke University has been the first institution in the United States to test the NAZCA via a rental agreement with Hummink and already the impact on numerous NIH-funded projects has been significant. We have realized the first fully printed submicron electronic biosensing transistors, demonstrated enhanced biomarker detection with printed nanoparticles for surface-enhanced Raman spectroscopy, and shown an order of magnitude reduction in costly biomolecular (e.g., antibody) ink usage for immunoassay printing. Hence, our team of 4 Major and 5 Minor Users seeks this S10 Shared Instrumentation Grant to support the acquisition of the NAZCA to continue supporting the already impacted projects and enable numerous other NIH-relevant work. Seven NIH-funded R01 projects will immediately be impacted by the advantages the NAZCA tool provides for high-resolution printing. Long-term objectives for the NAZCA are to provide a novel, shared-use instrument for low-volume, direct deposition of materials and to facilitate new research directions in spaces such as DNA origami, biomedical wearable sensors, and nanofiber formation for nerve defect repair.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Male germ cells (MGCs) are precursors to spermatogonial stem cells (SSCs), a stem cell population that both self-renews and differentiates, supplying spermatozoa for the entirety of a male’s reproductive lifespan. Therefore, any genomic perturbation in MGCs caused by inaccurate DNA damage repair can be heritable. Just prior to birth, MGCs undergo a relatively long period of cellular quiescence (G0). This period is required for SSC development and is developmentally conserved between mice and humans. During this G0 phase, MGCs experience hyper-transcription and changes in epigenetic modifications, two cellular activities that directly cause DNA damage in somatic cells. However, little is known about the DNA damage that accumulates in MGCs during this G0 arrest or how it is repaired to maintain fidelity of the germline genome. The most potent form of DNA damage is double strand breaks (DSBs). DSBs are often repaired by one of two pathways, non-homologous end joining (NHEJ) or homologous recombination (HR). NHEJ is an efficient, yet error-prone repair mechanism that is used in the G0/G1 stages of the cell cycle. In contrast, HR, which requires a homologous template, is a more complex, yet accurate repair mechanism that is used in S and G2 stages of the cell cycle. In G0 MGCs, maintaining the integrity of the genome during DSB repair is of utmost importance. However, the mechanism in which G0 MGCs repair DSBs is unknown. The overall objective of this K99/R00 proposal is to determine how G0 MGCs respond to and molecularly repair DSBs and to elucidate the importance of G0 MGC DSB repair in SSC development. The central hypothesis, which is based on preliminary data, is that G0 MGCs employ a modified-HR mechanism that incorporates NHEJ proteins, using the homologous chromosome as a template to repair DSBs and ensuring SSC development. In Aim 1 (K99 phase), single cell transcriptomics, immunofluorescence, and genetic models will be used to define the pathway that MGCs employ to repair DSBs. In Aim 2 (K99/R00 phase), a novel, in vivo CRISPR-Cas9 based assay will be generated and used to elucidate the molecular mechanism of DSB repair. In Aim 3 (R00 phase), genetic models, single cell transcriptomics, and single cell genomics will determine the implications of DSB repair defects in G0 MGCs on SSC development. Data and skills obtained from the K99 portion of this proposal will provide the basis for a strong and innovative independent research program, which will be expanded upon using data obtained from the R00 phase. Completion of these Aims will require training in complex bioinformatic analyses and mouse genetics, and the enclosed development plan describes a two-year blueprint designed to strengthen these skills. The research and development plans will be implemented at Duke University in the laboratory of Dr. Blanche Capel. Overall, the enclosed K99/R00 proposal can successfully transition a mentored scientist into a creative and skilled independent researcher and significantly advance knowledge for the improvement of reproductive health.

NIH Research Projects · FY 2026 · 2025-05

Project Summary/Abstract An alarming number of Gram-negative nosocomial pathogens have acquired resistance to nearly all currently available antibiotics, making it very difficult to treat patients effectively. Although a handful of new antimicrobial agents have been approved by the FDA recently, they have mostly targeted drug-resistant Gram-positive pathogens. Thus, new antibiotics targeting unexploited pathways are desperately needed to stem the tide of multidrug-resistant Gram-negative bacteria that are becoming a major threat to the public health. The goal of this proposal is to develop small molecule inhibitors of LpxH, an essential enzyme in the lipid A biosynthetic pathway, as novel antibiotics for the treatment of Gram-negative bacterial infections caused by multidrug- resistant Enterobacterales, such as the extended-spectrum -lactamase (ESBL)-producing Enterobacterales and carbapenem-resistant Enterobacterales (CREs), that pose serious threats to the public health. Preliminary data have demonstrated our expertise in developing and optimizing small molecule inhibitors of LpxH based on structural insights and ligand dynamics information and have established the in vivo efficacy of a promising new LpxH inhibitor in rescuing mice with lethal Klebsiella pneumoniae infection. Leveraging our accumulated knowledge and demonstrable success in LpxH inhibitor development, we propose to design and synthesize potent LpxH inhibitors with optimal drug-like properties. At the completion of the project, we anticipate having developed a lead LpxH inhibitor with potent antibiotic activity against multidrug-resistant Enterobacterales (such as E. coli and K. pneumoniae) and having demonstrated its safety and efficacy in the murine sepsis model. The successful execution of the proposed studies will establish the therapeutic potential of LpxH-targeting antibiotics and set the stage for accelerated clinical development.