Duke University

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY / ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a highly fatal disease characterized by irreversible destruction of lung tissue and a median survival well below 5 years. The pathologic effector cells in IPF are collagen-secreting fibroblasts driven by transforming growth factor beta (TGF-β). Despite the promise of TGF-β inhibition as a treatment for pulmonary fibrosis, global blockade has been associated with severe side effects, necessitating the identification of strategic therapeutic targets within this pathway. Harnessing the candidate's formal training in biochemistry and innovative expertise in protein post-translational modifications, proteomics, and machine learning, a previously unknown site of lipid modification (S-palmitoylation) on the TGF-β receptor (TGFβR1) has been discovered that appears to regulate its activity. Additionally, evidence of global S-palmitoyl perturbation in IPF has been identified. Based on preliminary data, the candidate hypothesizes that S- palmitoylation of the TGFβR1 receptor represents a reversible pro-fibrotic regulatory mechanism, whose enzymatic regulators may represent novel anti-fibrotic targets. The proposal’s three aims interrogate the roles of S-palmitoylation at three distinct levels: molecular, cellular, and regulatory. Aim 1 utilizes cultured fibroblasts to probe the molecular implications of S-palmitoylation on ligand-induced TGFβR1 phosphorylation and immediate effectors such as Smads, MAP and Src kinase. Aim 2 uses adeno-associated viral (AAV)-based fibroblast expression of TGFβR1 to examine the role(s) of S-palmitoylation within two distinct fibrotic mouse models. Finally, Aim 3 utilizes AAV-based CRISPR deletion to investigate the fibrotic contributions of two enzymatic S-palmitoyl regulators – palmitoyl transferase Dhhc20 and depalmitoylase Abhd17a – that are selectively induced in pathologic fibroblasts and may represent novel antifibrotic targets. These aims allow for the candidate's skill development in cell biology and animal models, while simultaneously supporting a career development plan that fosters expertise in AAV tools, quantitative microscopy, flow cytometry, mouse handling, and advanced bioinformatics. The proposed aims and training plan will delineate the role(s) of S-palmitoylation in IPF and potentially generate a novel therapeutic angle to target pathologic fibroblast signaling and reduce fibrosis. The mentorship team, led by Dr. Purushothama Rao Tata, includes experts in lung biology, fibrosis, TGF-β signaling, and proteomics, ensuring comprehensive training and guidance throughout the award period. This K08 award will pave the road toward the candidate's overarching career goal of anti-fibrotic discovery by focusing on fibrosis-oriented post-translational protein modifications, ultimately aiming to improve outcomes for patients with IPF and other fibrotic lung diseases.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY This CTSA-affiliated Institutional Career Development K12 Program from Duke builds on an earlier Duke CTSA-affiliated career development program (KL2). The foundational KL2 program supported 28 scholars from varied background. We now propose a new K12 program in which we maintain the KL2 themes (recruiting scholars from all background , team science skills, and skills in translational research) and add training in population research, translational science principles, use of artificial intelligence (AI), and mentoring-training, and preparation for next-step funding. The objectives are: Objective 1: Provide junior faculty scholars with research resources and fundamental transdisciplinary research knowledge and skills. Research-intensive early-stage faculty from Duke and NCCU will receive three years of 75% effort support (50% for proceduralists), research funds, mentoring, career development activities, and training in translational science, team science, and principles of AI. Objective 2: Promote development of a translational research workforce. The proposed K12 will employ successful strategies developed in the foundational KL2 to recruit scholars from all demographics and research focus from both Duke and NCCU. We will conduct targeted outreach, provide all applicants with resources to prepare strong applications through a tailored application preparation program, and implement a transparent, and trustworthy review process. Objective 3: Prepare junior faculty scholars to employ principles and strategies to promote trustworthiness in all aspects of their research. K12 scholars will participate in a population health curriculum provided collaboratively by the CTSA’s Workforce Development (WD) Module, Community and Stakeholder Engagement Research Module, and Duke’s Clinical and Translational Science Institute (CTSI) Center for population health. The curriculum will provide training to equip all scholars, regardless of research focus, to employ unbiased research processes that maximize benefits and minimize harm for all populations. Objective 4: Promote success with next level funding. Of the 25 graduates of the foundational KL2 to date, all have academic faculty appointments and funded effort on research grants, and 15 (60%) are Principal Investigator on a K, R, or comparable award. Building on this success, in the proposed K12, we will create and implement “REKAPPNext”, a program that will provide K12 scholars with concept review, a workshop series that coaches scholars on each component of the next-step application, and pre-submission internal review. Impact: The proposed K12, coupled with strong institutional commitment, an accomplished and committed leadership team, and extensive research infrastructure and administrative support, will contribute to a skillful and successful translational research workforce of the future.

NSF Awards · FY 2025 · 2025-08

High energy collisions between atomic nuclei are known to produce a novel state of matter, called a quark-gluon plasma and containing unbound constituents, quarks and gluons, that has unusual properties. Existing descriptions of the formation and decay of this state are based on statistical concepts that ignore essential aspects of quantum physics, such as quantum entanglement and microscopic preservation of information. This project will develop descriptions of these processes that exactly respect the laws of quantum physics using a two-pronged approach: (i) The formation of a thermal gluon plasma is studied by exact numerical simulations of gluon dynamics starting from a highly excited quantum state and following it up to the formation of a thermal gluon plasma. (ii) The decay process, in which the quark-gluon plasma decays into many individual particles, is modeled extending ideas from string theory to systems of relevance to nuclear physics and enabling a study of quantum entanglement between emitted particles. The methods and insights developed in this project have broad relevance for the quantum description of dynamical processes in isolated quantum systems, utilizing heavy ion collisions as near-ideal prototype to the mutual benefit of nuclear physics and quantum information science. Dynamical processes involving quarks and gluons at strong coupling are beyond the reach of perturbation theory and Euclidean lattice gauge theory. An important phenomenon of this type is the process of thermalization, which is pervasive in cosmology and high-energy nuclear and particle interactions but conceptually at odds with the microscopic reversibility ensured by the unitarity of quantum evolution. Another process that is usually described by statistical, rather than quantum mechanical techniques is multi-fragmentation as it occurs, e.g., during the deconfinement-confinement transition of a quark-gluon plasma. This proposal follows three interrelated tracks: (a) Delineation of the limits of feasibility of exact real-time lattice calculations with digital computers in the context of the simplest non-abelian gauge theory realized in nature, SU(2). (b) Identification of observable deviations from full thermal equilibrium due to quantum entanglement in exactly solvable low-dimensional models of strongly coupled non-abelian gauge theories using techniques derived from string theory. (c) Exploration of the capabilities of available quantum computers to study the thermalization and fragmentation processes that are accessible to digital computation within certain system size limits. The results obtained with digital computers serve as benchmarks for simulations on quantum computers and help determine the threshold for quantum supremacy. 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

This project introduces novel nanobodies, or VHHs, as cost-effective, reproducible and tunable alternatives to traditional growth factors in cell culture media. Cell culture is fundamental to modern biotechnology, supporting applications from regenerative medicine to cultured meat production, yet current methods often rely on expensive and inconsistent animal-derived growth factors. VHHs, which are small antibody fragments, can be precisely designed to activate cell growth receptors, mimicking natural proteins at a significantly lower cost. Leveraging a novel microbial production system, we can drastically improve growth factor prototyping, reduce manufacturing costs and eliminate batch-to-batch variability common with conventional growth factors. Project outcomes will lead to advances in cell culture methods with broad impacts on human health, sustainable food production, and U.S. biomanufacturing competitiveness. This project aims to engineer novel VHH-peptide fusions as next-generation growth factor alternatives for synthetic cell culture media. Our core innovation involves creating bispecific molecules that combine a receptor-binding VHH with activating peptides. Specifically in this work we will target growth factor alternatives which activate the FGF receptor (FGFR) and the epidermal growth factor receptor (EGFR). These VHHs will be produced using a two-stage bacterial expression system in E. coli, which enables soluble expression, proper disulfide bond formation, and simplified purification, significantly reducing production costs (projected from $15,000/g to $100-500/g). Our approach is systematic, beginning with the design and validation of FGF receptor-activating VHH fusions using cell-based reporter assays and surface plasmon resonance to assess binding kinetics and activation. Subsequently, we will leverage Design of Experiments methodology to optimize complete synthetic media formulations for pluripotent stem cells and bovine satellite cells, ensuring robust proliferation and maintenance of cellular identity. A multi-omics strategy, encompassing RNA-seq transcriptomics, proteomics, phosphoproteomics, and targeted metabolomics, will provide a systems-level characterization of cellular responses to the VHH-fusions, comparing them to natural growth factors across multiple temporal points to capture signaling dynamics and validate functional equivalence. The platform will then be expanded to engineer EGFR-activating VHH-fusions for mesenchymal stem cell culture. This research will generate comprehensive molecular signatures and optimized media formulations, addressing critical challenges in cost, reproducibility, and scalability of cell culture. The integrated academic-industrial collaboration with Roke Biotechnologies provides a clear commercialization pathway, enhancing U.S. biomanufacturing competitiveness. This project is being jointly supported by the Division of Molecular and Cellular Biosciences at NSF and the BioMADE Manufacturing Innovation Institute. 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

Amputation is a devastating but preventable complication of diabetes (DM) and peripheral artery disease (PAD); it serves as a marker for severe cardiovascular disease and for gaps in quality of care. Although amputation risk is highest in communities with higher levels of traditional risk factors, such as DM, PAD, cardiovascular disease, and tobacco use, it is also disproportionately higher in communities impacted by high economic hardship and chronic external stressors. Disparities in amputation rates, thus, serve as a marker for issues related to health care access, quality of health care, and nonmedical factors, such as food security, transportation, and housing stability. There is a critical gap in research on effective amputation prevention interventions in communities experiencing amputation disparities. Through my K23 project we found that a community-engaged, implementation science-driven intervention to decrease DM/PAD limb complications in rural West Virginia (WV) was both feasible and acceptable. The preliminary work for the K23 required high granularity geographic analysis of the state of WV to identify amputation “hot spots” to focus our study. This was coupled with focus groups in a sequential explanatory mixed methods approach to gain a better understanding of the risk factors specific to people with amputation in the state. This preliminary data was essential to gaining community support and partnerships for the K23. The objective of this R03 project is to take the first steps to expand the WV project to a larger scale in North Carolina (NC), a state with a much larger population that is also impacted by high rates of amputation and rural and urban health disparities. To achieve this objective, we will perform a mixed methods study in NC to identify geographic “hot spots” for amputation across the state and determine pertinent risk factors for people with amputations. The Aims of this project are to: 1) Determine contemporary rates and risk factors for DM/PAD-related amputations in NC and identify geographic areas with disproportionately higher rates of amputation. This will be performed using the state inpatient HCUP dataset through descriptive and inferential statistics and advanced Bayesian spatial analyses; 2) Identify the barriers faced by patients and their providers that lead to amputation. Informed by geospatial findings, we will use focus groups to gain an understanding of the contextual, cultural, systemic and environmental factors that increase or mitigate risk factors for amputations; 3) Translate and disseminate findings to communities disproportionately impacted by amputation. We will develop and implement a comprehensive translation and dissemination plan using community engagement best practices. Upon completion of the Aims of this R03, I will have the data to scale my K23 findings to a large quasi-experimental intervention effectiveness study and transition to independent funding, which will help me to achieve my long-term goal, which is to reduce amputation disparities through the implementation of feasible, acceptable and effective community-engaged interventions.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Access points to evidence-based HIV prevention services like pre-exposure prophylaxis (PrEP) are limited in the South, the epicenter of the US HIV epidemic. Given their ubiquity in communities across the country, pharmacists and pharmacies are uniquely positioned to increase access to PrEP. Unfortunately, pharmacists lack the skills needed to provide PrEP at their community-facing points of care, a major barrier to leveraging the pharmacy profession towards ending the Southern HIV epidemic. To address this barrier, comprehensive instruction of pharmacists in HIV prevention as part of their professional training is a compelling approach to systematically closing the knowledge deficit that hinders Southern pharmacists from incorporating PrEP into their clinical practice. Furthermore, equipping pharmacists in training with the skillset to create and develop innovative approaches to pharmacy-based PrEP delivery remains an important gap in efforts to maximize pharmacy’s contribution to mitigating the region’s HIV epidemic. To date, a comprehensive pharmacy-school based curriculum in HIV prevention has never been developed. Our proposed project, Pharmacists for Prevention (P4P): Harnessing the role of pharmacists in ending the HIV epidemic through collaboration with pharmacy schools will leverage our prior work in pharmacist-focused instruction in HIV prevention by adapting, implementing, and evaluating a comprehensive curriculum that includes HIV epidemiology, HIV prevention, and implementation science content across six, pharmacy schools in the South. All partner schools are located either in Ending the HIV Epidemic (EHE) priority jurisdictions or in areas with high HIV prevalence (> 20 incident cases per 100,0000). Specifically, in Aim 1, we will partner with our six sites to assess the feasibility of incorporating instruction on HIV prevention into their existing curricula. Aim 2, guided by the ADAPT-ITT framework, will feature a systematic adaptation of an online pharmacist-focused HIV prevention curriculum (developed previously by our group) into each school’s curricular sequence. Lastly in Aim 3, we will implement the program over two years with the potential to reach 1,200 pharmacy students and conduct a comprehensive, mixed-methods evaluation on the short-term, mid-term, and long-term impact of the program. We will specifically assess students’ knowledge and willingness to integrate HIV prevention services into their clinical practice (primary outcome). Comparative evaluations will be conducted on an inter-cohort (vs. prior pharmacy school class) and intra-cohort basis (pre-post evaluation). We will also examine long-term outcomes such as self-reported PrEP prescriptions/referrals in the first year of clinical practice and number of students who select a career in research, public health, or HIV/infectious diseases. The successful completion of this project will provide an evidence base for an HIV prevention curriculum sequence that can be scaled across pharmacy schools in the South and beyond.

NIH Research Projects · FY 2025 · 2025-08

Abstract The cerebellum is a compelling model for studying how cellular activity can shape animal behavior, one of the key goals of neuroscience research. Molecular, circuit, and behavioral studies have tested cerebellar function at these respective levels; however, due to technical limitations for measuring synaptic responses in vivo, it has been challenging to connect synaptic plasticity mechanisms with cerebellum-dependent motor learning. This proposal is designed to test the role of synaptic plasticity onto cerebellar Purkinje cells in motor learning, using cerebellar-dependent delay eyelid conditioning behavior to assess plasticity mechanisms at the parallel fiber- Purkinje cell synapse, as well as the molecular signaling cascades involved in the expression of this form of plasticity. Thus, these experiments will directly test the hypothesis that long-term synaptic depression of parallel fiber inputs onto Purkinje cells is involved in cerebellar motor learning. I will use a powerful combination of established optogenetic and in vitro electrophysiology techniques to measure synaptic plasticity in tissue from animals trained on the delay eyelid conditioning task. Additionally, I will test a novel biosensor, SPOTlight, for its potential to identify Purkinje cells that have undergone postsynaptic long-term depression. Overall, this research will test a learning mechanism at the molecular, circuit, and behavioral levels to address a foundational question of how cerebellar function enables learning.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Cryptococcus neoformans is the most common and deadly fungal pathogen of the central nervous system in HIV/AIDS patients worldwide, causing hundreds of thousands of cryptococcal meningitis (CM) cases each year. With the profound loss of CD4+ immune cells and weakened blood-brain barrier, C. neoformans spreads efficiently from the lung to the brain and is difficult to treat. Clinicians lack the critical diagnostic information to identify highly pathogenic yeast isolates and successfully treat their patients because the factors that influence CM disease severity in humans are largely unknown – and no new antifungal agents have been developed in over 25 years. Preliminary data show clearly that C. neoformans isolates differ in their pathogenicity, and isolates from clinical – but not environmental – settings are associated with high CM disease severity in animal models. We will address the critical need to determine the underlying mechanisms responsible for C. neoformans pathogenicity, by defining and characterizing the evolving population of diverse isolates in both environmental and clinical settings. Our comprehensive platform of phenotyping, comparative genomics, and genome-wide association studies will enable genotype-to-phenotype analyses, focusing on virulence traits: (1) a collection/repository of 3000+ global C. neoformans isolates with sequenced genomes; (2) a high-throughput robotic system for large-scale phenotypic analyses; (3) phenotypic arraying for in vivo relevant phenotypes that can be linked to genomic data and specific clinical outcomes; (4) robust animal models (i.e. zebrafish for screening large numbers of yeast isolates; murine for brain and lung disease assessment through yeast census and immune responses; and rabbit for CNS disease validation); (5) a genetics system that facilitates multiple analyses and genetic crosses for future QTL-based studies, as well as robust genetic and molecular biology methodologies to dial down on targeted genes of interest; (6) metadata on clinical de-identified human data, as well as on isolates for yeast burden during infection and impact on mortality; and (7) defined in vivo yeast transcriptomics from isolates from human CSF to link in vitro and in vivo animal studies with human disease. Aim 1 will determine the genetic variants associated with virulence by systematic, comparative analyses of clinical and environmental isolates. This will answer the question of what turns an environmental strain that does not cause disease into a clinical strain. Aim 2 will identify and validate genetic variants associated with aggressive clinical isolates that enhance human infection. This will address the question of what causes increased aggressiveness in a clinical strain. These components will identify genes critical for C. neoformans production of aggressive disease and for in vivo survival/fitness in animal models and humans. enable us to link important disease traits with specific genomic features, in order to predict strain virulence based on genotype. Our data should lead to development of new therapeutic strategies that reduce disease severity and improve outcomes in HIV/AIDS patients. Finally, this study will create a substantial infrastructure addition to a library of well- characterized wild-type strains for use by the entire cryptococcal community for future pathobiology work.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Clostridioides difficile is a leading cause of healthcare-associated infection with >450,000 cases yearly in the United States. Infection prevention strategies have had limited success at curtailing C. difficile infection rates. Making matters more difficult, individuals can also carry C. difficile asymptomatically. While carriage is both highly prevalent and associated with increased risk of subsequent disease, only a minority of carriers actually progress to disease. The factors responsible for preventing or promoting progression from carriage to disease remain largely unclear. By combining recent improvements in clinical testing algorithms, statistical modeling, and bioinformatics, we aim to undertake a more innovative and comprehensive approach to modeling C. difficile infection. The advent of two-step testing helps to distinguish carriage from disease. Time-to-event models permit accurate and efficient handling of longitudinal outcomes. Finally, advances in bioinformatics facilitate additional insight into the roles of the metagenome and metabolome. Using this multi-modal approach, we seek to improve the current understanding of progression from C. difficile carriage to disease through the following aims: 1) Identify metagenomic/metabolomic risk factors present at time of carriage that are associated with later progression to C. difficile disease; 2) Assess for changes in the metagenome/metabolome temporally associated with progression from carriage to C. difficile disease. 3) Identify C. difficile strain attributes (particularly those related to toxin regulation) associated with risk of progression from carriage to disease; An improved understanding of the factors that prevent or promote progression to disease could inform novel targets for C. difficile prevention and better direct potential therapies to those at highest risk. My short-term goal is to develop a skillset for the analysis of metagenomic and metabolomic data. My long-term goal is to become adept at incorporating metagenomic and metabolomic data into prospective studies of C. difficile acquisition and progression to disease. This proposal is designed to cultivate my development as a future leader in incorporating metagenomic/metabolomic data into studies of infectious disease transmission and prevention.

NIH Research Projects · FY 2025 · 2025-08

Survivors of gynecologic, anorectal, and urologic cancers often complete pelvic radiation therapy, resulting in many survivors (38-80%) developing shortening or narrowing of the vagina (i.e., vaginal stenosis). Vaginal stenosis may cause patients to avoid or be unable to complete pelvic exams for cancer surveillance due to pain or vaginal obstruction. Vaginal stenosis may also cause painful sexual intercourse. Dilator therapy is the primary treatment for preventing and treating vaginal stenosis. However, engagement with dilator therapy is poor. There are modifiable biopsychosocial barriers to dilator therapy engagement (symptom burden [e.g., pain, vaginal dryness], emotional distress, dilator knowledge), but few interventions have addressed modifiable barriers and improved engagement with dilator therapy. If engagement remains poor, survivors are at risk for missing critical cancer surveillance, emotional distress, impaired sexual and relational functioning, and poor quality of life. Grounded in the NIH stage model, this study aims to develop, refine, and pilot test a novel behavioral intervention, informed by the Health Belief Model, to enhance engagement with dilator therapy among female cancer survivors who underwent pelvic radiation. In Phase I, individual qualitative interviews with patients in the target sample (N=20) and medical providers (N=10) will be used to inform intervention development. It is anticipated that the intervention will employ strategies from cognitive behavioral therapy and acceptance and commitment therapy. In Phase II, the intervention will be refined through user testing interviews (N=12). In Phase III, feasibility and acceptability of the intervention will be examined, as well as patterns of change in primary (frequency and duration of dilator use) and secondary (symptom burden, emotional distress, and dilator therapy knowledge) outcomes of interest, through a pilot randomized controlled trial. Participants (N=88) will be randomized to the intervention or enhanced usual care and complete 4 primary assessments (baseline and 3, 6, and 9 months post-baseline) plus a brief monthly survey evaluating dilator use. In line with the NCI’s priority area of cancer survivorship, the overall goal of the award is Dr. Stalls’ becoming an independent clinical scientist with expertise in developing, evaluating, and disseminating behavioral interventions to improve sexual health among cancer survivors. To do so requires a unique combination of knowledge and skills: 1) Sexual Health among Cancer Survivors, 2) Sexual Health Research and Advanced Qualitative and Quantitative Research Methods, 3) Randomized Controlled Trials Design and Conduct, and 4) Leadership and Professional Development. Dr. Stalls will accomplish these career development goals through training with expert mentors, collaborators, and consultants as well as capitalizing on the resources and training opportunities at Duke University and Duke Cancer Institute. Completion of this award would strengthen the cancer research workforce, a direct mission and priority area of the NCI; Dr. Stalls’ developed expertise would help address a national gap in clinician scientists working at the intersection of behavioral oncology and sexual health.

NIH Research Projects · FY 2025 · 2025-08

In the scenario of a nuclear accident or radiological attack, the survivors of acute radiation syndrome (ARS) may be at risk of developing Delayed Effects of Acute Radiation Exposure (DEARE), which can lead to severe morbidity and death due to injury of multiple organs such as the heart. Although it has been demonstrated that exposure to ionizing radiation significantly increases the risk of cardiac dysfunction, there is no FDA-approved biomarker that can accurately predict the risk of heart disease among individuals who have been exposed to heterogeneous doses of ionizing radiation from nuclear terrorism. Thus, the overall goal of this U01 grant proposal is to develop an early biomarker that can identify victims of radiological attacks who are at high risk of developing heart disease following radiation exposure and would benefit from early therapeutic intervention. Our published data demonstrate that fibroblasts isolated from the fibrotic heart express N-cadherin on the cell surface in the precursor form as pro-N-cadherin (PNC). In our recent publication, we demonstrate that serum PNC is an early marker of subclinical heart failure in the general population. In addition, our preliminary data show that PNC+ cells are substantially enriched in the heart of various animal models of cardiac injury including cardiac transplant rejection and ionizing radiation. We hypothesize that radiation damage to the heart promotes tissue remodeling and aberrant cell-surface PNC localization in cardiac fibroblasts. Thus, serum PNC will be a promising biomarker to predict the risk of heart disease after radiation exposure among survivors of ARS. We will test this hypothesis by using serum samples from non-human primates that survived ARS and cancer patients treated with radiation therapy for breast cancer, esophageal cancer, or lung cancer. In addition, we will conduct mechanistic studies in vivo and in vitro to define the population of cardiac fibroblasts expressing PNC+ and mechanisms of aberrant cell-surface PNC localization in the irradiated heart of mice. We anticipate that by completing the proposed experiments, we will generate critical data to support the further development of serum PNC as an early biomarker for predicting the risk of heart disease among individuals affected by accidental radiation exposure through the FDA animal rule.

NIH Research Projects · FY 2025 · 2025-08

Lower respiratory tract infection (LRTI) is the leading infectious cause of death globally. Despite its prevalence, the exact etiology of LRTI is unknown in the vast majority of cases. Even when identified, bacteria or viruses in nasopharyngeal (NP) or sputum samples may be colonizers in the upper tract rather than the cause of infection in the lower tract. Unclear LRTI etiology results in the overprescription of antibacterials, which in turn drives the global crisis in antibacterial resistance. Antibacterial overprescription and resistance are greater in low- or middle-income countries (LMICs), where basic diagnostic capacity is limited. Host-based diagnostics, which assess the host immune response to infection, have recently emerged as a complementary method to pathogen-based diagnostics for identifying the class of respiratory infection. Our team has developed host- based gene expression classifiers using peripheral blood samples to differentiate viral versus bacterial respiratory infection. The goal of the current application is to develop an integrated diagnostic that uses a single, non-invasive NP sample to detect both pathogen and host response to identify LRTI etiology. The following specific aims will be conducted at a collaborative research site in Sri Lanka: 1) Develop a novel NP- based gene expression classifier to identify viral versus non-viral LRTI, and 2) Design and validate an integrated pathogen and host gene expression test to identify viral versus non-viral LRTI using a quantitative real-time polymerase chain reaction (qRT-PCR) assay. For aim 1, we will use previously collected NP samples from clinically adjudicated viral and non-viral LRTI patients in Sri Lanka and conduct low-input RNA sequencing. Machine-learning approaches will identify host gene expression classifiers that discriminate viral versus non-viral LRTI. For aim 2, the genes identified in the NP-based classifier, as well as nucleic acid targets for two respiratory viruses that are frequently implicated in true infection as well as asymptomatic colonization (SARS-COV-2 and human rhinovirus [HRV]), will be migrated onto TaqMan Low-Density Array (TLDA) cards. A prospective cohort of patients will be enrolled in Sri Lanka, and etiological testing and clinical adjudications will be performed as the reference standard to identify viral (including SARS-CoV-2 and HRV) and non-viral LRTI. Using an optimally retrained and parsimonious viral versus non-viral classifier, we will perform a feasibility analysis of incorporating pathogen detection and host-response classifier. Among samples with TLDA-based pathogen detection for SARS-CoV-2 or HRV, performance of the host- response classifier to distinguish viral versus non-viral LRTI will be assessed. Successful completion of these aims will result in the development of a novel diagnostic that integrates host and pathogen detection using a single, non-invasive NP sample to identify the etiology of LRTI. Translation of this assay to a rapid platform will help shift the current diagnostic paradigm for LRTI.

NIH Research Projects · FY 2026 · 2025-08

ABSTRACT Malignant gliomas remain lethal with available therapies, including immune checkpoint blockade. Tumor cells and glioma-associated microglia/macrophages (GAMMs) collectively activate inflammatory responses in the tumor microenvironment (TME), leading to immune suppression, therapy resistance, tumor progression, and relapse. Hence, targeting the protumorigenic TME inflammation is an attractive approach against gliomas. TME inflammation can be induced by inflammasomes, cytosolic innate immune protein complexes that induce cytokine secretion. The NLRP3 inflammasome is expressed in multiple immune cells, and we have identified a population of NLRP3+IL- + proinflammatory macrophages in gliomas. Intriguingly, we found that (1) NLRP3+IL- + GAMMs are increased in both normal and glioma-bearing females, (2) NLRP3-responsive inflammatory genes are enriched in the mesenchymal glioblastoma subtype, (3) high NLRP3 levels are associated with a poor prognosis in female mesenchymal glioblastoma patients, and (4) inflammasome and inflammatory proteins are higher in gliomas from female mice. Our data is consistent with the known inflammatory propensity of females and the presence of key immune regulatory genes on the X chromosome. To determine whether NLRP3 inhibition would overcome inflammation-induced immune suppression and potentiate antitumor immune therapies, we treated male and female glioma-bearing mice with an EGFR targeting antibody toxin conjugate (ATC) and either pharmacological inhibition or genetic deletion of NLRP3. ATC + NLRP3 inhibition/deletion significantly prolonged survival in female but not male mice. In addition, estrogen receptor signaling inhibition decreased NLRP3 and Caspase-1 levels in gliomas during ATC or radiation therapy, indicating a role for sex hormones in NLRP3 regulation. Hence, we hypothesize that NLRP3-induced inflammatory responses promote immune suppression and dampen therapy-induced antitumor responses, specifically in females. Herein, we will 1) Determine whether NLRP3+IL- + GAMMs are primary regulators of sex-dependent ATC therapy response, 2) Determine whether sex hormones vs. sex chromosomes regulate NLRP3 and sex-dependent ATC antitumor response, and 3) Determine whether NLRP3 signaling regulates antitumor responses to radiotherapy in a sex- dependent manner. 1

NIH Research Projects · FY 2025 · 2025-08

Despite the known benefits of regular physical activity (PA), adherence to recommended PA guidelines remains alarmingly low, with marked variation observed across the population. PA behavior is influenced by genetic, behavioral, environmental, and social factors. In particular, the built environment—where people are born, live, learn, work, play, worship, and age—has become an increasingly important focus for interventions aimed at promoting healthy PA behaviors. However, understanding the role of the built environment in shaping PA behaviors has been limited due to incomprehensive measures of PA and the infeasibility of randomized controlled trials. Our project aims to address this gap by leveraging the large, longitudinal wearable device data from the All of Us Research Program (AoURP). We propose a novel approach to represent PA behaviors and a machine learning framework to uncover the mechanisms through which the built environment factors influence PA and, by extension, health outcomes. We will utilize minute-level intraday step data from the AoURP to generate PA behavior profiles—a data-driven representation for quantifying daily patterns of PA. This high-frequency data from wearable devices offers detailed insights into each individual’s daily interactions with the built environment, offering greater temporal specificity than conventional summary metrics, such as average daily steps or minutes of moderate-to-vigorous activity. We hypothesize that PA will be strongly associated with a variety of factors, including the built environment, and that these associations will be more pronounced using PA behavior profiles than traditional summary measures. We also aim to study the indirect effects of the built environment on health outcomes through a machine learning framework that incorporates counterfactual analysis. Through this framework, we will examine how hypothetical modifications in the built environment could "flip" health outcomes by altering an individual's PA behavior. In addition, stratified post-hoc analyses will be conducted to explore the differential impacts of environmental changes across various subpopulations. This proposed project will advance our scientific understanding of population-level health outcomes through the development of a new approach for representing PA behaviors from wearable device data. By proposing a novel framework for counterfactual analysis, the project will demonstrate how observational data can be used to understand the underlying etiologic factors and mechanisms that contribute to variation in health outcomes.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT One in five US adolescents have obesity, making pediatric obesity a significant public health problem. Safe and effective treatment options exist for adolescents with obesity including motivational interviewing, intensive health behavior and lifestyle therapy, pharmacotherapy, and metabolic and bariatric surgery. Recently, several anti- obesity medications (AOMs) have been approved for use in adolescents, showing great promise for reducing obesity. However, to date, these AOMs have only been studied in tightly controlled clinical trials. While clinical trials have high internal validity and provide evidence for efficacy of pharmacological approaches, they are limited in their external validity and real-world generalizability. This has lead to gaps in our understanding of adolescent AOM use including knowledge of the reach of AOMs in youth, effectiveness within real-world clinical settings, and possible unintended consequences of AOM use. It is imperative that these gaps are addressed to ensure that adolescents receive safe and effective clinical care. Therefore, the objective of this project is to collect real- world evidence that can be used to inform clinical practice, improve health outcomes, and ensure patient safety among adolescents using AOMs. The proposed project will recruit a cohort of adolescents using AOMs (12-17y; n=200) from two pediatric obesity treatment clinics. In Aim 1, we will characterize the population of youth using AOMs by examining demographic characteristics from the electronic health record of cohort youth compared to those who are eligible, but never prescribed AOMs. In Aims 2 & 3, cohort participants will be followed for 18- months, completing four study visits that will include measure of body composition, diet, physical activity, mental health and quality of life. A subset of patients will complete DXA scans to further assess changes in body composition and semi-structured interviews to yield richer contextual information. Data will also be obtained from the electronic health record and assessments of adherence throughout the duration of cohort participation. In Aim 2, effectiveness of AOMs will be evaluated by examining change in relative BMI among cohort youth compared to the youth not utilizing AOMs from Aim 1 using propensity weighting approaches. Additional analyses will examine the relationship between changes in diet, physical activity and study outcomes as well describe adherence to AOM treatment protocols including medication switching and discontinuation. In Aim 3, we will consider the unintended consequences of AOM use including longitudinal changes in mental health, development of disordered eating behavior, and changes in DXA measured body composition and bone mineral density. Overall, this project will provide valuable clinical evidence around AOM use in adolescents by addressing key gaps in our knowledge of access, effectiveness and factors that influence effectiveness, and potential unintended consequences. Successful completion of this project will inform clinical recommendations around adolescent AOM use and has broader implications for implementation of AOMs among specialized obesity treatment centers and general pediatric clinics.

NIH Research Projects · FY 2025 · 2025-08

Recent work suggests that infection with the B-lymphotropic herpesvirus, Epstein-Barr virus (EBV), is a key early event in the etiology of multiple sclerosis (MS). However, the molecular basis for how EBV promotes MS is currently unknown. EBV infects most human in the first decade of life and by adulthood, nearly 95% are latently infected. Given this very high prevalence of EBV in the general population, it is unclear why only 1:300 people in the US are afflicted with MS. Despite the well-studied, yet heterogeneous, genetic risk factors associated with MS, this apparent disconnect might be explained by a mechanism whereby EBV infects a particular B cell subset that accumulates in individuals at high genetic risk for MS. The expansion of such a pathogenic, potentially autoreactive and pro-inflammatory B cell subset has been described, yet little is known about the mechanism of how EBV plays a role in the expansion or activity of these cells. It is our ultimate goal to define the role of EBV in MS pathogenesis. In this proposal, we aim to characterize the temporal and spatial expression of EBV and EBV-regulated genes within a unique B cell subset. It is our central hypothesis that EBV persists in atypical memory B cells which display markers consistent with CNS trafficking ability and pro-inflammatory cytokine production. We have formulated our central hypothesis based on extensive preliminary data characterizing an EBV de novo infection signature in T-bet+/CXCR3+ B cells and observing this EBV-associated signature in clinically isolated syndrome (CIS) and MS patient samples. However, the capture of EBV-specific transcripts are outstanding in these clinical samples, which is a critical need to determine the putative role of EBV in MS pathogenesis. The rationale for this proposed research is that defining the role of EBV and its effects in B cells of CIS/MS patients will provide important insight into MS pathogenesis as well as new diagnostic and prognostic indicators of disease. Our laboratories are well positioned to pursue these studies as they have complementary expertise in EBV and MS biology and immunology as well as access to and experience with cutting edge single cell resolution techniques for studying viral and host gene expression in clinical samples. We plan to test our hypothesis and complete the objectives outlined in this proposal through the following two specific aims: 1) Validate and extend an EBV-associated peripheral atypical B cell gene expression signature in CIS/MS patients and 2) In situ transcriptomic analysis of ABC and EBV status in MS CNS tissue. The proposed study constitutes a comprehensive approach to precisely define the peripheral and CNS-resident cells that harbor EBV in patients with MS. In conjunction with our prior work, the data generated herein will yield invaluable insight into EBV- mediated loss of immune tolerance associated with CNS pathology. Completion of this project will directly guide future mechanistic studies of EBV involvement in neuroimmune dysregulation and inform clinically actionable biomarkers and therapeutic targets for the treatment and management of MS, thereby providing a springboard for a more expansive proposal.

NIH Research Projects · FY 2025 · 2025-08

Project Summary The Sequencing and Genomics Technologies (SGT) Core Facility at Duke University provides end-to-end leading edge next generation sequencing (NGS) services. The SGT has collaborated with hundreds of Duke and external NIH-funded investigators from 235 institutions across multiple countries. Over the last twenty years, the SGT has prepared over 150,000 samples, performed more than 13,000 sequencing runs, and produced more than 5.4 petabases of data. During that time, the actual sequencing has dropped dramatically in price, but genomics experiments remain expensive due to the costs of processing samples into libraries that are compatible with sequencing platforms. Recently liquid handling robotic technology has advanced to support fully automated NGS libraries production using fractional reagent volumes to decrease library production costs. The SGT has not yet realized these technological advancements. For the SGT to continue to serve the need of its ever-increasing number of users, outdated NGS library preparation workflows must be augmented by a next-generation enclosed turn-key liquid handler, the SPT Labtech firefly+. The SGT has an urgent and compelling need to replace existing manual and large reaction volume automated production pipelines to meet investigator deadlines. Manual NGS library production precludes scaling workflows to address the current and future needs of the SGT while also being prone to operator error and inducing repetitive-motion injuries. The current automation in the SGT is not capable of handling low volume liquid processing. To support the increasing number and scale of studies over a wide variety of biomedical fields, the SGT must adopt miniaturized reaction pipelines that use substantially less reagent volume without compromising library quality. The firefly+ has been purposefully designed to support miniaturized reaction pipelines. Acquisition of the firefly+ will both enable the SGT to realize the immense labor, time, and reagents savings afforded by advances in liquid automation and attract new users studying low abundance samples. The strengths of this proposal include: (1) An efficient and effective centralized facility serves an extraordinarily diverse and productive investigator user base; (2) The extensive experience of the SGT; (3) The extensive infrastructure and expertise available to bring the requested instrumentation online and oversee its continuous use. Duke University has made a significant investment in capital and institutional talent to build a world-class genomic service center that has proven highly successful. The requested instrumentation will leverage the infrastructure to ensure its high value and broad impact on NIH-funded biomedical and basic research within and beyond the Duke community.

NIH Research Projects · FY 2025 · 2025-08

This supplement will follow the approved Abstract under the ECHO CC U2COD023375-08. Child health is determined by multiple environmental forces; however, surprisingly little is known about the interactions of these forces. In addition, despite an emerging consensus that numerous gene-environment interactions determine child health, much remains unknown about how genetic and environmental factors combine to promote or prevent adverse outcomes. This Environmental influences on Child Health Outcomes (ECHO) Coordinating Center (CC) proposal seeks to further strengthen the broad children’s health research community to increase the body of knowledge about these complicated effects by fostering collaboration among internal and external stakeholders and supporting the research of the ECHO Program to enhance the health of children for generations to come. The Duke Clinical Research Institute (DCRI) is uniquely positioned to serve as the ECHO CC after successfully serving as the ECHO CC for the last seven years. In addition, DCRI manages >30 active network and administrative coordinating centers and has emerged as a leader in pediatric research. Unique features of the proposed ECHO CC include: 1) extensive experience and track record of the leadership team in the support of the initial ECHO Program and conduct of multiple pediatric studies; 2) pediatric operational expertise of the DCRI; and 3) existing, robust administrative infrastructure necessary to effectively and efficiently manage responsibilities for coordinating the ambitious efforts of the ECHO Program. The team is led by Drs. P. Brian Smith and Linda Adair. The specific aims for the ECHO CC are to: 1) provide organizational infrastructure to coordinate and oversee ECHO Program’s research activities; 2) support ECHO Cohort Committees and communication among all ECHO Program Components and stakeholders; 3) manage the ECHO OIF and foster training of early investigators through a comprehensive research environment. The ECHO CC will establish and oversee the required infrastructure to coordinate the multiple levels of membership in the ECHO Program. This infrastructure will focus on methods of learning valuable information about environmental exposures through aggregation of massive amounts of data from ECHO Cohort Study Sites. The ECHO CC will make scientific efforts faster and more efficient while protecting human subjects. This infrastructure is possible because of the expertise of DCRI, which not only has extensive experience in coordinating pediatric studies but also has the essential platforms ready.

NIH Research Projects · FY 2025 · 2025-08

Abstract C-terminus of HSC70 Interacting Protein (CHIP) is a neuroprotective protein that is beneficial in many different neurodegenerative diseases. More recently mutations in CHIP have been identified as the cause of two neurodegenerative diseases. Recessive mutations in CHIP cause Spinocerebellar ataxia autosomal recessive type 16 (SCAR16), while dominant mutations cause Spinocerebellar ataxia type 48 (SCA48). While SCAR16 is a very rare disease, SCA48 is a more common form of ataxia. Many mutations that cause SCA48 exist in the tetratricopeptide repeat domain of CHIP and map to a single interface between the first and second TPR repeat of CHIP. That led us to investigate the importance of this domain. Our findings indicate that mutations in this domain cause SCA48 by inducing a structural change that partially unfolds the TPR domain of CHIP. Importantly this unfolding event can be reversed by addition of excess ligand suggesting that mutations that cause SCA48 do not terminally unfold the TPR domain of CHIP. Importantly these results also suggest that one could identify small molecules that stabilize this domain and thus may be therapeutic for patients with SCA48. Here we propose to optimize and miniaturize a series of assays. These assays will then be utilized to screen for small molecules that restore the proper fold and function to the TPR domain of CHIP. Compounds from the screen will then be evaluated with secondary and tertiary assays to identify hits. These hits will then be tested in cell culture models of SCA48 to see if they reverse disease phenotypes. Together the work proposed in this application will put us on the road to developing small molecules that may one day be therapeutically useful.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitor (ICI)-based therapy revolutionized cancer treatment; however, prostate cancer (PCa) is known to be generally immune-cold and refractory to ICI in non-selective patients. A lack of cytotoxic T lymphocyte (CTL) infiltration and the enrichment of myeloid-derived suppressor cells (MDSCs) contribute to immune evasion in PCa. Exact mechanisms that shape PCa’s tumor immune microenvironment (TIME) remain poorly understood. Recent studies point to critical involvement of epigenetic regulators. ~8% of the human genome are endogenous retrotransposons (ERVs), which are normally silenced by epigenetic mechanisms, notably, histone H3 lysine 9 trimethylation (H3K9me3). We recently identify TNRC18, an under-studied epigenetic factor, to be a new H3K9me3 reader that mediates ERV silencing. TNRC18 directly binds H3K9me3 via a C-terminal BAH domain and uses its N-terminal segment for recruiting corepressor such as HDAC. In the TCGA PCa patient dataset, we observe a significant negative correlation between TNRC18 expression and anti-tumor immune response, which indicates TNRC18 epigenetically modulates immunity. Our preliminary results collected from both human and mouse PCa cell models now show that TNRC18 knockout (KO) or loss- of-function (LOF) mutation activates ERVs and immune activation-related genes (such as CXCL10), which induces viral mimicry and immune activation. Combined scRNA-seq and flow cytometry-based analyses of immune cells in a murine PCa model further show that TNRC18 loss causes dramatic changes of TIME, notably, decrease of MDSCs and increase of CTLs; and in the same mouse PCa model, TNRC18 inactivation significantly sensitizes PCa to anti-PD1 treatment. Our hypotheses are that (i) in PCa, TNRC18 epigenetically silences the immune activation-related transcripts and immunogenic ERVs to promote immune evasion and that, (ii) conversely, TNRC18 LOF induces an ‘inflamed’ TIME, enabling the ICI-based therapy. To test these innovative hypotheses, we propose to use representative preclinic models to elucidate TNRC18’s tumor- intrinsic functions in regulating transcriptome and immunogenicity of PCa (aim 1); here, we use genome-wide profiling to dissect involvement of TNRC18 and associated Sin3/HDAC complex for epigenomic modulation and for silencing of immune activation pathways. We will also assess the TNRC18 LOF-induced viral mimicry effects on inducing interferon response and suppressing PCa growth. On a separate line of research (aim 2), we will define tumor-extrinsic effects of TNRC18 LOF on inducing an immuno-‘hot’ TIME, re-sensitizing PCa to ICIs; here, we will also examine the chemokine signaling pathways that mediate recruitment/infiltration of CTLs and MDSCs to PCa. The completion of the proposed research will not only gain novel mechanistic insights into epigenetic regulation of PCa’s immuno-‘cold’ characteristics but importantly will provide new therapeutic strategies that may be translated to the clinic in the future. The potential impact of the project is high.

NSF Awards · FY 2025 · 2025-08

Making electrochemical materials more stable is a significant challenge. These materials are used in many energy technologies such as batteries and fuel cells. Tiny imperfections in the material — called defects — can cause the material to wear down faster. However, new experiments show that some very small, nanoscale defects might actually help make the materials more stable. It is important to understand which kinds of defects are helpful and which ones are harmful, depending on the material and the conditions it is used in. This knowledge can help scientists design materials that are both more active and longer-lasting. Also, for electrochemical technologies to be used on a larger scale, it's better to use materials that do not rely on rare or expensive elements. This research project will investigate how tiny structural differences in materials can affect how well they work and how long they last. The goal is to use this understanding to improve the performance and stability of electrodes. The project will combine the efforts of two research teams with complementary expertise, where experiments will provide unique insights into interfacial structural dynamics. The project will use liquid-phase transmission electron microscopy with near-atomic spatial resolution and high temporal resolution. By employing transmission electron microscopy, the researchers will be able to observe how different crystallographic facets of metal-oxide nanoparticles dissolve in situ and estimate dissolution rates associated with a variety of structural heterogeneities. The imaging results will be supported by electrochemical measurements and quantum-mechanical DFT simulations of thermodynamic, kinetic, and electronic-structure properties. Results will enable a more systematic design of improved catalysts for emerging electrochemical technologies, leading to reduced utilization of critical materials. The project will involve high school, undergraduate, and graduate students in Nebraska and North Carolina, who will acquire broad education in materials characterization, electrochemistry, data science, electronic-structure, and free-energy calculations. 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

Biological cells need to sense their own shape and size for a variety of their functions, such as deciding when to divide and how to fit in narrow spaces. Studies over the past decade have shown that the filament-forming protein septin can sense the cell membrane’s shape and curvature by preferentially binding and assembling to areas of cell membrane curvature. This is surprising, since septin protein is only several billionths of a meter in length but can sense broad curvature over 100 times that length. This would be akin to using your foot to measure the curvature of a sphere the width of a football field. Recent studies by this team show that septin curvature sensing is determined through septin polymerization and assembly on the membrane, rather than by single molecules of septin. However, little is known about the interplay between the molecular makeup of these septin bundles, filament formation and the whole-cell scale organization of septins on the membrane, and how the assembly process relates to membrane curvature. This project will study this question in three scales of septin assembly, namely the scale of a few septin moelcules bound together, larger septin filaments, and the whole-cell scale. In order to tell the story of this research to the broader public, the team will design and conduct activities around the theme of “Self-Organization in Biology'' for middle school and high school students and their teachers. Lastly, integral to this research plan is the training of multidisciplinary undergraduate and graduate student scientists to work at the interface of physics, mathematics, and biology. Cellular surfaces often adopt shallow micron-scale curvatures, such as in fungal branches and cytokinetic furrows, whereas the proteins that sense these shapes are only several nanometers in size. This project will determine how cells sense geometry on the micron-scale with nano-scale proteins. The researchers have discovered that septin, a highly conserved filament-forming cytoskeletal protein, is localized to areas of micron-scale curvature on the membrane, and that septin curvature sensing is determined through its multistep, multiscale assembly on membranes. Yet, the relationships between septin’s molecular structure, its packing and organization, and curvature sensing ability remain poorly understood. This project will develop a multiscale mechanical model of septin assembly and curvature sensing in three aims, that correspond to three scales of septin assembly. In Aim 1 (molecular scale), the researchers will determine the effect of septin molecular structure on the binding, unbinding, and polymerization rates of a single oligomer. Aim 2 (filament scale) focuses on determining how this molecular-scale information influences filament-scale structure and transport. Aim 3 (system scale) focuses on analyzing the processes that determine the system-scale assembly - the density, packing, and layering of septin filaments. In order to measure and model these couplings, the researchers will combine multiple simulation and experimental tools across scales, including atomistic and coarse-grain particle simulations and kinetic modeling, with experimentally derived parameters from single-molecule imaging, confocal microscopy, and scanning electron microscopy. This project is funded by the Cellular Dynamics and Function Program of the Division of Molecular and Cellular Biology. 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

Many problems in material science, chemistry and nuclear physics whose solutions promise to transform society and our view of the universe, are quantum in nature. Confronted with complex quantum phenomena, classical computers quickly run out of steam. By utilizing quantum mechanics, quantum computers promise to tackle the development of high-temperature superconductors, improve chemical catalysis, and explain the structure of compact stars and nuclei. While quantum computers based on trapped atomic ions feature leading low error rates, to perform complex calculations, we need to accurately control many more ions than is currently possible. The ColleqtIon project will support my effort scale up trapped-ion systems by manipulating and connecting trapped ions using light. The ColleqtIon project will leverage my experience in quantum science and the resources of my research group to improve undergraduate education through hands-on experience and curriculum development. My outreach effort to colleges in North Carolina will help recruit a train a broad quantum workforce, while a partnership with industry on optical alignment techniques will help develop commercial applications. The first goal of ColleqtIon will be to pin in place barium ions using a standing light wave, manipulate these ions using lasers, and use them for quantum simulations of condensed-matter and high-energy physics. In the second thrust, I plan to connect groups of ions on the same trap chip using photons stored in an optical resonator. This photonic approach may scale to hundreds of ions, improving the scale and connectivity of ion-based quantum computers. 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

ABSTRACT: Young adults with juvenile systemic lupus erythematosus (JSLE) and dermatomyositis (JDM) have greater risk of cardiovascular disease (CVD) than the general population. Increased CVD risk in JSLE/JDM starts in childhood. Suboptimal cardiovascular health (CVH), defined by the American Heart Association (AHA) as protective factors against CVD, is common in adolescents and young adults with JSLE/JDM (AYA-JSLE/JDM), with >95% non-ideal CVH behaviors (i.e. physical activity, diet, sleep). Psychological stress further increases long-term CVD risk via associations with worse CVH behaviors and elevated inflammation. Roughly 50% of JSLE/JDM patients report moderate-to-severe stress even when disease activity is low, yet most do not receive formal treatment due to treatment access barriers. Given the prevalence of unmitigated stress and CVD risk, there is a critical need to develop accessible JSLE/JDM-tailored interventions for stress reduction and CVH behavior promotion. The overall research objective of this proposal is to use a culturally sensitive intervention adaptation framework (Formative Method for Adapting Psychotherapy [FMAP]) to engage AYA- JSLE/JDM as partners in developing, piloting, and refining an online, self-administered intervention for stress reduction and CVH behavior promotion in AYA-JSLE/JDM, i.e. Teams Engaged in Accessible Mental Health Interventions for Lupus Erythematosus and Dermatomyositis Stress (TEAM-LEADS) intervention. Dr. Ardalan’s long-term career goal is to develop interventions to improve mental and physical health outcomes in JSLE/JDM and other rheumatic diseases. His mentoring team has expertise in clinical trials, CVD, and stress (Dr. Schanberg), pediatric mental health and remote pediatric behavioral interventions (Dr. Connelly), trial design and biostatistics (Dr. Hornik), and the application of health behavior change theory and partner engagement methods for behavioral intervention adaptation (Dr. Gierisch), facilitating Dr. Ardalan’s acquisition of skills in partner-engaged research methods, pediatric mental health and health behavior change, contemporary clinical trial design, and remotely delivered behavioral interventions. The following aims are proposed: Aim 1) Partner with AYA-JSLE/JDM patients, parents, and health care providers to develop TEAM-LEADS via co-design sessions; Aim 2) Determine feasibility, acceptability, adherence, and impact on stress and CVH behaviors of the initial TEAM-LEADS intervention for AYA-JSLE/JDM in an open-label, single-arm successive cohort design pilot trial; Aim 3) Refine the TEAM-LEADS intervention by addressing facilitators and barriers identified by AYA-JSLE/JDM pilot trial participants in exit interviews. Completion of these aims and training goals will lead to an R01 application to conduct a larger efficacy trial of TEAM-LEADS. Future research directions include determination of optimal combinations and sequences of TEAM-LEADS components via novel trial designs and adaptation of TEAM-LEADS for other chronic pediatric and adult conditions.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT The overarching goal of this application is to define and investigate host factors required for influenza virus replication. Despite current interventions, influenza viruses are responsible for a significant portion of upper respiratory infections globally. This has prompted exploration of how these viruses interact with host cells to facilitate their replication. We conducted a series of genome-wide CRISPR screens with nine genetically divergent influenza viral strains to explore shared host-dependency factors. We identified one such host factor, TTC14, an uncharacterized RNA binding protein completely required for the replication of all influenza virus strains. The studies proposed in this application will provide important insights into the role this protein plays in regulating RNA processing and how its absence impacts influenza virus infection. The goals of this application are premised on the central hypothesis that TTC14 binds to transcripts and coordinates RNA splicing, leading to proper downstream protein translation. In Aim 1, I will investigate the molecular mechanism of TTC14-regulated mRNA splicing in the absence of and during influenza infection. In Aim 2, I will characterize how the loss of TTC14 expression impacts influenza virus replication in primary human airway cells and how this alters host immune responses against viral infection. Notably, this research will illuminate a novel regulatory mechanism of RNA splicing and reveal a new interface between influenza virus and host machinery that many strains manipulate to aid their replication. Given the extensive expertise of my lab in studying host factors involved in viral replication, I am uniquely positioned to perform these studies, which will provide new paradigms in characterizing the complex host-viral interactions of influenza viruses.