Duke University

NIH Research Projects · FY 2025 · 2024-08

The tobacco industry has been rapidly introducing products with novel designs and constituents, in response to regulatory interventions, to maintain nicotine dependence in people who quit smoking and to attract new consumers. Oral nicotine pouches (ONPs) are a rapidly growing new smokeless tobacco product category introduced to the US market in 2019 by several tobacco companies. ONP’s contain a white powder, claimed to be tobacco-free, consisting of filler, nicotine and a wide variety of flavors. More recently, “non-menthol” cigarettes were introduced in California and Massachusetts, two states that banned menthol cigarettes, targeting former menthol smokers. Currently, only limited data are available about the chemical composition of these products, and their behavioral and addictive effects, especially in adolescents initiating product use. In this proposal, we hypothesize that: (i) product design and formulation of these novel products enables efficient and fast release of nicotine and flavors; (ii) flavors released from nicotine pouches are especially attractive to adolescents and promote nicotine intake; and (iii) additives released from “non-menthol” cigarettes facilitate smoke inhalation and increase nicotine inhalation. These hypotheses are based on our published work and preliminary data demonstrating that ONPs contain significant amounts of synthetic high- intensity sweeteners, that some ONPs contain a less irritating form of nicotine, and that “non-menthol” cigarettes contain synthetic cooling agents replacing menthol. The following Specific Aims will be pursued: Aim 1: Analyze the chemical composition of nicotine pouch products and “non-menthol” cigarettes for flavors, sweeteners and tobacco-derived or tobacco-free racemic nicotine. Aim 2: Examine the behavioral effects of sweeteners and nicotine forms on initiation of consumption of oral nicotine pouch extracts in mice. Aim 3: Quantify the effects of synthetic cooling agents in “non-menthol” cigarettes on the sensory respiratory irritation response in mice.

NIH Research Projects · FY 2025 · 2024-08

Abstract Exercise training is linked to beneficial effects on maladaptive immune aging. In patients with rheumatoid arthritis (RA), exercise training is a disease modulating therapy and may improve premature biological aging inherent in RA, however, the mechanisms by which exercise benefits immune health is poorly understood. Improved knowledge of the specific types of exercise and the mechanisms by which exercise reduces disease activity in RA will enhance clinical care for older adults with chronic inflammatory conditions. Further, this work has potential to generalize to improving immune function in older adults without inflammatory conditions. My career goal is to lead a comprehensive exercise rheumatology translational research program to study the effects of exercise on disease-promoting immune-aging pathways and personalized lifestyle prescriptions for older patients with rheumatic disease. I plan to gain the training and experience to become a leader in exercise rheumatology studying lifestyle interventions for improving immune aging in chronic inflammatory diseases. In particular, I will complete three objectives to address the key gaps in my career development training: 1) develop geroscience-specific competency in clinical aging research assessments; 2) acquire skills in translational aging science statistical analysis; and 3) cultivate clinical-translational aging research leadership skills. Further, I will achieve my career development plan with expert guidance of my mentors and collaborators at the Duke Molecular Physiology Institute and Duke Aging Center. In the proposed study, I will investigate whether exercise training-induced benefits to RA are linked to improvements in T cell function, T cell mitochondrial oxidative metabolism, and markers of T cell aging. In Aim #1 and Aim #2, I will utilize data from a NIH-funded randomized, controlled trial to determine if compared to lifestyle counseling, a remotely supervised caloric restriction and exercise training (CRET) program leads to greater improvement in RA regulatory T cell function and metabolism (Aim #1) and T cell aging (Aim #2). In Aim #3, I will perform an independent pilot study to inform future investigations on the best exercise doses and intensities to improve RA immune aging. To this end, I will determine if a remotely supervised high-intensity aerobic exercise training intervention is safe, acceptable, and feasible. Results from my Aim #3 pilot study will inform my planned R01 randomized controlled trial proposal comparing remotely supervised moderate- versus high-intensity aerobic exercise training on RA immunoregulatory function and immune aging. With successful completion of this K23 project, I will bridge the gap to achieving my career goal of becoming a leader in aging science and physical activity interventions for older patients with RA and chronic inflammatory diseases.

NSF Awards · FY 2024 · 2024-08

This project builds on observations in the Neuse Estuary (North Carolina) that have been collected previously and expands upon them through 3-d modeling with a widely used model called ROMS (short for Regional Ocean Modeling System). Unique features of the Neuse Estuary include a close to 90 degree bend and a micro-tidal environment, with wind forcing thus thought to be dominant over tides. Wind effects on estuaries are understudied because usually tides are more prevalent and cause most of the mixing. In this case, the proposed model experiments will investigate how wind forcing at different angles relative to the two connecting estuary legs as well as the duration and intervals of the wind events affect circulation and salinity distributions in a model set-up that resembles the Neuse Estuary. The results from this work will inform communities around the Neuse Estuary how to better interpret water quality time series, knowing more about the circulation features that affect residence and flushing times of the estuary. The results will also help enhance prediction and management of water quality in the Neuse Estuary. More specifically, the project will investigate how the circulation and salinity distribution in estuaries with curved sections respond to wind events using simulations on idealized and real estuary domains. Of primary interest is how interaction between estuary legs parallel and perpendicular to the wind, and lateral circulation and mixing in the connecting curved region, impact the strengths of horizontal and vertical salinity gradients and the distance that high salinity water extends upstream. Also of interest is how wind event duration and interval between wind events relative to timescales associated with wind mixing, wind-driven currents, and the baroclinic response, control the circulation and salinity distribution. To address these questions, simulations on idealized estuary domains using ROMS will be conducted. Three sets of simulations will be performed in which parameters are varied systematically: 1) constant wind at varying angles to a straight estuarine channel; 2) constant wind on an estuary with perpendicular legs connected by a curved region, varying wind speed, direction, freshwater inflow, and radius of curvature; and 3) finite length wind events, varying event duration and separation. Finally, simulations on a realistic Neuse Estuary domain will be conducted to examine how theory developed from idealized simulations can be applied to a real wind-dominated estuary. This work will advance understanding of wind effects on estuary dynamics by extending it to more general estuarine geometries that have bends and more realistic situations in which wind varies with time. 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 · 2024-08

In delirium and Alzheimer’s disease (AD), which increase the risk for each other, patients suffer deficits in executive functions, including attentional control. There is a critical gap in our understanding of the mecha- nisms by which attentional control capacity may promote cognitive resilience in both delirium and dementia. Even under normal conditions neural resources for navigating the world around us are fundamentally limited (ie, we can’t attend to everything in our environment), yet attentional control allows the brain to effectively allocate neural resources to accomplish cognitive tasks. During stressors that limit neural resources further, eg neuro- inflammation after surgery or AD-related neurodegeneration, attentional control can compensate for neuronal injury to preserve cognitive function by marshaling remaining neural resources. Given the potential protective benefits of robust attentional control, this proposal introduces attentional resilience—ie the ability to retain robust attentional control despite physiological stressors—and evaluates its potential underlying neural mecha- nisms using the stressor of scheduled surgery in cognitively healthy older adults as a “natural experiment.” Our overall objective is to better understand the neural mechanisms underlying attentional resilience, which enable individuals to more effectively allocate neural resources to remain attentive to their surrounding environ- ment despite neuronal injury and/or neuro-inflammation. Our central hypothesis is that neural mechanisms underlying robust attentional control before surgery facilitate attentional resilience after surgery. Our aims eval- uate neural activity patterns that have been linked to robust attentional control. Given the well-established link between electroencephalogram (EEG) alpha (7-13 Hz) power and attentional control, Aim 1 focuses on the ability of attentional control processes to enable attentiveness by attenuating alpha power. In Aim 2, we explore alpha- driven enhancement of sensory processing, an attentional control mechanism that amplifies neural responses to relevant sensory stimuli. These attentional control processes facilitate externally directed attention, and we will evaluate how their mechanisms relate to attentional resilience. Building on this, Aim 3 explores neural circuit contributors to these attentional control processes as possible mechanisms underlying attentional resilience. Because robust neural circuits depend on healthy neuronal substrates largely free from AD-related pathology, we will evaluate the effect of tau pathology on attentional resilience mediated by coordination of the dorsal at- tention network and the default mode network, two complementary neural circuits critical for attentional control. In sum, this project will advance understanding of why some older adults maintain strong attentional perfor- mance after surgery while others do not. In particular, this work will reveal key neural-systems-level mechanisms that support attentional control capacity and link low-level neuronal damage to diminished high-level cognitive performance. Finally, this work supports the long-term goal of identifying potentially modifiable neural targets for delirium and dementia interventions.

NIH Research Projects · FY 2025 · 2024-08

It has become increasingly clear that environmental exposures, the genome, gut microbiome, diet, and lifestyle all affect an individual’s metabolic state contributing to brain health and disease, including Alzheimer’s disease (AD) and AD-related dementia (ADRDs). Our AD Metabolomics Consortium (ADMC), in collaboration with the AD Neuroimaging Initiative (ADNI), is applying state-of-the-art metabolomics and lipidomics technologies combined with genomic and imaging data to map metabolic failures across the spectrum and trajectory of AD- ADRDs. The ADMC is part of the Accelerating Medicines Partnership for AD (AMP-AD), a flagship precompetitive partnership that brings government, industry, and nonprofit organizations together to transform the current model for developing new AD diagnostics and treatments. Our work confirmed that peripheral metabolic changes, influenced by the exposome, inform about cognitive and brain imaging changes and ATN markers for disease, highlighting peripheral and central changes are connected in part, through the metabolome. The Alzheimer Gut Microbiome Project (AGMP) that we launched in partnership with ten AD Research Centers (ADRC) and large diet and lifestyle interventions (POINTER, MIND, BEAT-AD) aims to define the influences of the gut microbiome, diet, and gut-brain axis in AD. This research infrastructure is building the first AD molecular atlas that captures exposome influences on AD-associated metabolomic profiles. Five metabolomic centers of excellence are completing a ring trial to identify environmental chemical exposures, dietary components, and drug signatures that when linked to gut microbiome and metabolomic data will define exposome profiles associated with AD/ADRDs. In this U01, we leverage a large NIA-funded collaborative infrastructure, connections to 10 ADRCs, and access to unique community-based longitudinal cohort studies and biobanks (FHS, ROSMAP, Rotterdam, UK Biobank) to: (i) expand coverage of the chemical exposome in blood and brain, and (ii) link identified signatures to brain aging, incident dementia, and AD. Human data generated in this project will inform and be informed by results from complementary preclinical exposome studies in AD mouse models (AG-24-023) and cell-based systems (AG-24-241). A long-standing partnership with Sage Bionetworks allows for rapid sharing of exposome data collected under this application through the AD Knowledge Portal. We will leverage data generated under the AMP-AD, AGMP, and this U01 to enable data harmonization with existing data generated in the AMP-AD and AGMP with the goal of integrating of complex exposure data across multiple cohorts. This project provides an unparalleled opportunity to create a deeper understanding of how the exposome interacts with genetics, gut microbiome, and metabolome to modulate AD pathogenesis, potentially leading to novel therapeutic approaches and preventative measures for AD that address ethnic, socioeconomic, and geographic diversity. Our European and USA partners connect us with large exposome initiatives including in the Netherlands and “The Human Health Exposure Analysis Resource” (HHEAR) network.

NSF Awards · FY 2024 · 2024-08

Drawn by the beauty and recreational opportunities of beaches, communities and economies have sprung up along many coastlines in the last half century. However, coastal environments tend to change more rapidly than other landscapes, posing challenges to maintaining development. Shorelines change position, often moving landward (eroding) over years and decades, bringing the shoreline and storm impacts ever closer to homes and infrastructure originally constructed at a safe distance. The storm impacts that threaten communities range from short term beach erosion to flooding from storm surge—all driven by wind and waves and amplified by increasing rates of sea-level rise. This project will transform the understanding of what causes shorelines to move in such complicated ways, and it will create an opportunity to forecast changes in shoreline erosion and storm hazards in coming decades (and century). The forecasting opportunity arises because winds over an ocean basin produce waves, and because changes in typical patterns of winds in the future can be forecast using global climate models. This project features further development and application of sophisticated techniques for translating forecast future weather over an entire ocean basin into the winds and waves affecting specific shorelines in coming decades. The wind and wave forecasts will, in turn, feed into computer models representing how waves and storm surge move sand around, leading to forecasts of patterns of shoreline erosion ‘hot spots’ as well as storm hazards. This project will bring together experts in shoreline change from around the world to test what is most important in producing shoreline change over days, years, and decades, by comparing model results with observations and with each other. The results of this model intercomparison will be shared broadly and translated into educational materials through the Community Surface Dynamics Modeling System and the Museum of Life and Science. In the coming decades coastlines will move even more rapidly than in the past. Along with the effects of sea-level rise, changing storm behaviors—whether related to decadal-scale climate oscillations or to longer-term trends—cause magnitudes and locations of coastal erosion ‘hot spots’ to shift, compounding threats to coastal communities. This project will revolutionize the scientific community’s ability to understand and forecast coastline change patterns, over timescales ranging from a year to a century. The project starts with the development of new, efficient approaches to downscaling Global Climate Model output to produce forecasts of the waves and winds affecting particular coastlines. This pioneering work will address the Carolina coastline as an initial case study. The downscaled wave data will then drive coupled models addressing coastline shape and position, in response to storm/wave climate shifts, sea-level rise, and inlet dynamics. Model hindcasts will be confronted with historical observations to test the new model and the importance of large-scale coastline dynamics in long-term shoreline change. The downscaled wave, wind, and water-level data will also form the centerpiece of a workshop and community model-intercomparison effort that will bring together contrasting coastline-change models, with the common goal of hindcasting and forecasting changes, comparing the results with each other and with observations, and thereby accelerating coastal science. This project is jointly funded by the Marine Geology and Geophysics program in the Division of Ocean Sciences and the Geomorphology and Land-use Dynamics program in the Division of Earth Sciences. 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 2024 · 2024-08

Scientific computing touches all modern technology from the design of batteries and photovoltaics to understanding properties of nanomaterials and pharmaceuticals. Quantum computers promise to speed up a broad range of scientific computations, but current quantum computers lack the scale or precision to outperform standard computers. The Quantum Advantage Class Trapped Ion (QACTI) project is designing and constructing an ion trap quantum computer to demonstrate a scientific computation beyond the capabilities of a standard computer. The QACTI project is a collaboration between scientists, computer scientists, and engineers working towards the common goal of achieving scientific quantum advantage. Prototype devices and methods are being tested to determine the best path forward. The collaborative effort combines advanced engineering solutions for trapped atomic ions with forward-looking integrated control technologies that allow for exploration and optimization of quantum algorithms by domain specialists. The project is also building a quantum workforce with a focus on training undergraduate students. The effort in the Pilot phase of the program focuses on working with the broader community to clarify promising directions in both hardware and applications. The project involves the co-design of an ion trap quantum computer tailored to the most promising scientific applications. Research directions include the exploration of new quantum algorithms for scientific computing, the development of an open-source and flexible control system, and the scalable implementation of parallel operations on multiple ion chains. The research program concentrates on four intertwined activities to develop the quantum computer. First, the project formulates the specific ion trap hardware architecture for the device, driven by aggressive performance metrics needed to execute the desired application space. Second, the project innovates on the component technologies of the QACTI system, such as optical control systems including integrated optical devices and ion trap and vacuum packaging solutions. Third, the project identifies a particular class of quantum algorithms to be pursued, likely involving a hybrid compute model that takes full advantage of standard computers. Fourth, the project creates improved software expressions that map high level applications to native architectural elements such as gate protocols, connectivity, and qubit modularity. The project is creating and implementing a workforce development program to train future researchers in quantum information science and engineering. This project advances the objectives of Quantum Information Science and Engineering at NSF in response to the National Quantum Initiative Act for the continued leadership of the United States in QIS and its technology applications. 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 2024 · 2024-08

Despite its societal benefits, generative AI also raises many societal and legal concerns. For instance, it may be abused to generate harmful content and boost disinformation campaigns. Watermark-based detection of AI-generated content is a key technology to address these societal and legal concerns. Several companies--such as Google, OpenAI, Stability AI, and Microsoft--have deployed such techniques to watermark their AI-generated content. Despite the growing deployment and adoption of watermarking techniques, there remains an education gap among various stakeholders--such as students, government policymakers, the current workforce, and the imminent generation of workers--regarding the theoretical foundations, technical implementations, and practical applications of these watermark techniques. The objective of this project is to bridge this education gap in watermarking AI-generated content. This project will develop a systematic lab-based curriculum that offers a diverse range of laboratory exercises for hands-on experience and practical skills acquisition of watermarking AI-generated content. The project will also develop and release an Open-Watermark-Platform with integrated labs to enable hands-on learning on watermarking. The lab-based curriculum and other education materials developed in this project will train the next generation of workforce to meet the urgent needs of watermarking AI-generated content and enable continual learning for the current workforce and policymakers. This project is supported by the Secure and Trustworthy Cyberspace (SaTC) program, which funds proposals that address cybersecurity and privacy, and in this case, cybersecurity education. The SaTC program aligns with the Federal Cybersecurity Research and Development Strategic Plan and the National Privacy Research Strategy to protect and preserve the growing social and economic benefits of cyber systems while ensuring security and privacy. 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 2024 · 2024-08

Partial differential equations (PDEs) are a ubiquitous modeling and analysis tool in both pure and applied mathematics and are used in biology, chemistry, quantum mechanics, and many other areas. In the recent few years, the synergy between PDEs and machine learning has dramatically strengthened. On one hand, machine learning methods, specifically neural networks, have been shown to be very useful for improving the process of solving PDEs---at both the level of representing the solutions of individual PDEs, and by capturing the mapping from a PDE to a solution. On the other hand, with the advent of diffusion models as the dominant approach to generative AI, stable, efficient and parallelizable solvers for PDEs are ever more important for training large-scale AI systems. This project will build mathematical foundations for several key questions pertaining to both the use of machine learning for PDE solving, and the use of PDEs as a tool for generative modeling. It will explore issues around the representational power of different neural architectures, their inductive biases, their statistical complexity, and their numerical stability. It will also aim to further elucidate the relative tradeoffs of different PDE-based generative models. The investigators will leverage their joint expertise in mathematical foundations of PDEs and generative modeling, as well as numerical aspects of optimization to fruitfully mine the rich overlap between PDEs and machine learning. 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 · 2024-08

Millions of older adults receive care in intensive care units (ICUs) annually. However, the quality and accessibility of ICU-based palliative care is highly variable across hospitals and clinicians, due in part to specialists’ limited workforce and geographic inconsistency. Furthermore, there are few evidence-based interventions designed to help ICU clinicians provide primary palliative care themselves. To address these gaps, we developed an innovative mobile app-based primary palliative care intervention called ICUconnect. ICUconnect facilitates families’ and patients’ self-report of actual palliative care needs across all core domains of palliative care quality, provides ICU clinicians with a scalable digital infrastructure for coordinating consistent and personalized needs-targeted care, and provides a variety of informational supports relevant to each user’s role. In a recent single-center cluster RCT with 111 patient-family member dyads (U54 MD012530), ICUconnect significantly improved unmet needs and goal concordance of care compared to usual care control. What is now needed is a multicenter RCT to test the intervention’s efficacy and simultaneously ascertain potential challenges to broader implementation. Therefore, we propose to test ICUconnect vs. usual care control among 350 patient-family member dyads with elevated baseline levels of unmet palliative care need in a 4-site network (Duke, Medical University of South Carolina, University of Alabama at Birmingham, Columbia). The specific aims are to: (1) Test the efficacy of ICUconnect vs. usual care control in improving palliative care needs and other person-centered outcomes including psychological distress, (2) Determine participant characteristics associated with a greater treatment response using a heterogeneity of treatment effects approach, and (3) Ensure off-the-shelf intervention readiness for implementation using a mixed-methods integration of qualitative analysis of semi-structured trial participant interviews and quantitative RE-AIM implementation framework-informed trial data. This project is likely to make a strong clinical impact because it fills notable gaps in the rigor of prior research, targets populations often omitted from past palliative care trials, and tests an innovative intervention that could be immediately used in any healthcare setting at population scale, is easily adaptable to any language, leverages strong preliminary data, and includes new concepts in care delivery and outcomes measurement. The likelihood of success is high because of the team’s expertise in clinical trials, critical care, palliative care, geriatrics, and health technology.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY/ABSTRACT This K23 application outlines a career development plan that will advance Dr. Michael Devinney on his pathway to becoming an extramurally funded, independent critical care physician-scientist. His long-term career goal is to discover underlying mechanisms that contribute to delirium and its sequelae such as post-ICU cognitive impairment and Alzheimer's Disease and related Dementias (ADRD). Delirium is a syndrome of disrupted attention and consciousness that occurs in ~20% of the >19 million older surgery patients and ~50% of the >5 million intensive care unit (ICU) patients in America every year. Delirium is also associated with increased risk for long-term cognitive impairment and ADRD, yet there are no FDA- approved drugs to prevent delirium, due to a major gap in our understanding of the mechanisms that drive delirium. One possible mechanism that may underpin delirium (and subsequent post-ICU long-term cognitive impairment) is neuroinflammation. Surgical trauma and critical illness induce systemic complement activation and blood-brain barrier dysfunction, which could cause activated complement factors to enter the brain. These activated complement proteins then can cause synaptic tagging for phagocytosis, which can disrupt the neural connectivity necessary for human cognition. Indeed, complement-dependent synapse loss leads to memory deficits in mouse ADRD models, and patients with ADRD have increased cerebrospinal fluid (CSF) C3 levels. However, few, if any, studies have investigated the role of CSF complement activation in delirium and post-ICU long-term cognitive impairment. In this proposal, Dr. Devinney will determine the role of CSF complement activation in postoperative delirium, ICU delirium, and post-ICU long-term cognitive impairment. To do so, he will leverage a unique perioperative CSF biorepository, and also recruit a prospective cohort of 120 older ICU patients that will undergo CSF sampling, delirium assessments, and 6-month post-discharge cognitive testing and dementia assessments. CSF complement activation will be measured with immunoassays, and unbiased proteomics will be used to characterize CSF complement levels and to discover other novel pathways involved in these disorders. CSF ADRD biomarkers will also be measured in both cohorts. Dr. Devinney has co-designed a career development plan and a research proposal with his cross-disciplinary mentorship team to accomplish the following short-term objectives: 1) Obtain expertise in the molecular role of complement in synaptic dysfunction and ADRD 2) Develop a thorough understanding of the practical and ethical considerations of ICU research, 3) Acquire the skills needed to lead larger studies of older ICU patients, and 4) Gain expertise in the staging of ADRD. These objectives will be accomplished through formal training, workshops, experiential learning, and focused mentorship. Thus, this K23 award will allow Dr. Devinney to acquire the outlined research skills, knowledge, and experience to continue his pathway towards independence.

NIH Research Projects · FY 2024 · 2024-08

ABSTRACT Black and Latinx people in the United States (US) suffer disproportionately high levels of substance use and mental health disorders. Further, racial and ethnic minoritized groups have decreased access to behavioral health treatment services than white people. Emergent literature has zeroed in on how structural factors can impact various health outcomes. In this application, our main objective is to understand the connection between behavioral health outcomes, structural racism, and an urgent and escalating contemporary issue: natural disasters. Therefore, in response to RFA-DA-23-013 we propose our project, “The Contribution of Structural Racism to the Effects of Natural Disaster on Behavioral Health Outcomes (SALENDO)” study. The objective of this study is to clarify the overlapping effects of structural racism, natural disaster exposure and risk, and behavioral health. Our specific aims are: 1) Evaluate temporal and geographic correlations of structural racism, utilizing indices at the concentration of extremes (ICE) measures, natural disaster susceptibility, and rates behavioral health-related emergency department visits/inpatient hospitalizations/overdoses by county in Texas (TX) and Louisiana (LA); 2) Examine how Hurricane Harvey shaped behavioral healthcare utilization and overdose fatalities and the role that structural racism played in these consequences; and 3) Interpret and actionize data in collaboration with impacted communities.

NIH Research Projects · FY 2025 · 2024-08

Parkinson's disease (PD) is an intractable disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra, resulting in tremor, rigidity, bradykinesia, and postural instability. By the time a clinical diagnosis is confirmed, a considerable proportion of dopaminergic neurons have degenerated. Gastrointestinal (GI) dysfunction may be an early manifestation of the disease and the gut may be an unexplored diagnostic and/or therapeutic target. In response, the Gut Brain Parkinson's Disease Consortium (GBPDC) will build an annotated repository of biospecimens to allow for the identification, development and validation of innovative early-phase GI-based diagnostic tools and biomarkers for PD. To support the creation of this valuable resource, we will develop a Coordinating and Data Management Center (CDMC) that addresses the resource sharing, data science and analytical challenges unique to this consortium. Our team brings immediate expertise in key areas of biorepository management, data science and analysis, combined with an operational structure and guiding principles of the Duke Clinical Research Institute (DCRI). Our vision is to employ a team science approach to establish an innovative, efficient, flexible, and metric driven CDMC designed to support the establishment of the GBPDC biorepository and accelerate development of innovative early-phase GI- based diagnostic tools and biomarkers for PD. To achieve our vision, we will establish a program framework of three Cores: Research and Resources, Data Management, and Biorepository to execute the three main CDMC functions outlined in our aims: 1) provide program leadership and expertise; assistance in study and protocol design; and study implementation, monitoring, and management for GBPDC awardees; 2) support the creation and maintenance of a harmonized GBPDC data and research ecosystem; facilitate compliant and seamless data sharing and dissemination; 3) provide scientific and laboratory expertise and leadership to coordinate the receipt, processing, storage, and distribution of biospecimens. The Cores will be supported by the Web-based Activities and Dissemination Program Core that will ensure a rich research communication plan to facilitate the sharing of resources with the internal consortium and broader scientific communities. Our proposed CDMC will establish the required functions to efficiently support the establishment of the GBPDC program with a focus on expanded reach, efficiency, and accelerated data analysis and result dissemination. This program is possible because of the unparalleled breadth of complementary services and expertise offered by our collaborative team.

NSF Awards · FY 2024 · 2024-08

Predicting how species will be impacted by ongoing and future changes to their environment is critical. Species responses to these changes will determine how well ecosystems function and the ability of the Earth to continue providing food and other resources. Most such predictions focus on changes where a species can occur, but not changes in the numbers of a species, which can be more important for ecology. One major difficulty is that the environment can differ a lot from year to year, which makes it harder to predict how species will be impacted by gradual changes over a long period of time. Also, individuals of widespread species are often adapted to do best in their local environments, which means that the same species in different areas can have different environmental requirements. This project uses transplant experiments and long-term monitoring of wild populations to overcome these challenges, and tests how two common plant species are impacted by environmental change from New Mexico to arctic Alaska. The researchers also team up with educators to create middle and high school curriculum to teach students how to think critically and use real data to investigate ecological and environmental questions. This research relies on a comprehensive dataset spanning 15-28 years documenting demographic trends in two widespread, long-lived tundra plant species (Silene acaulis and Polygonum viviparum) in 29 populations across western North America. By continuing to monitor these wild populations, the researchers will develop a functional definition of rare climate events and assess their demographic impacts. The project also uses common garden transplants and controlled thermal performance experiments to assess local adaptation to climate and the demographic mechanisms driving it. This project will follow the performance of transplants for a total of 9 years, allowing researchers to test the importance of environmental extremes and cumulative abiotic effects on the magnitude and spatial scale of local adaptation. The researchers will integrate demographic and experimental datasets to develop environmentally-explicit and density-dependent demographic models to make range-wide predictions of distribution and local abundance, considering environmental variability and local adaptation. Notably, predictive models will be validated by testing their ability to “present-cast” current patterns of abundance and occurrence in new locales across the species’ latitudinal ranges before forecasting responses to projected climate change. The project’s goals are to both better predict how these particular species will respond to changes in their environment and to develop and test methods for making predictions that can be used for many other species. 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 · 2024-08

Abstract Propionic acidemia (PA) is a rare metabolic disease due to PCCA or PCCB mutations. PA could develop various complications even with dietary restriction. While gene therapy holds promise, it remains hampered by challenges. Hence, there is a pressing need to develop novel, effective, and systemic therapy for PA. PCC deficiency leads to propionyl-CoA accumulation, depleting free CoA and inhibiting acetyl-CoA synthesis. This reduces the C2/C3 ratio from 11 to 0.08 in PA mouse model. Elevated propionyl-CoA disrupts acetyl-CoA- involved pathways, impeding energy metabolism (propionyl-CoA, methylcitrate), causing hyperammonemia (propionylglutamate), and affecting histone acetylation and gene transcription. Restoring the acetyl-CoA level, particularly the C2/C3 ratio, is crucial to prevent metabolic alterations and subsequent propionyl-CoA-driven pathology. Our preliminary data demonstrate the therapeutic efficiency of acetate supplementation, which improves the C2/C3 ratio and further overall survival of Pcca-/-(A138T) mice. Triacetin, an FDA-approved food additive, is a glycerol and acetic acid triester that undergoes rapid metabolism into glycerol and acetate upon absorption. This makes it a secure and effective means of supplementing acetate. Therefore, we hypothesize that balancing the acetyl-CoA/propionyl-CoA ratio via triacetin supplementation offers therapeutic potential for PA, bolstering acetyl-CoA synthesis and competitively impeding propionate metabolism. To test our hypothesis, we have formulated the following two specific aims. Aim 1. To evaluate the efficacy of triacetin in rectifying metabolic abnormalities, cellular phenotypes and functions in human PA cells and its pharmacokinetics and pharmacodynamics (PK/PD) in vitro. We will utilize human PA fibroblasts and PA hepatocyte (PCCAA138T-HepG2) to examine whether triacetin can mitigate propionyl-CoA metabolism, cellular phenotypes and function in vitro. PK/PD of triacetin will be examined to establish correlations between its efficacy and these parameters. Aim 2. To assess the metabolic effects, therapeutic efficacy, and PK/PD of triacetin in Pcca-/-(A138T) mice in vivo. To thoroughly validate the therapeutic effectiveness of triacetin, we will conduct an in vivo study involving PK/PD analysis in Pcca-/-(A138T) mice. We will assess the metabolic impact of triacetin supplementation by examining parameters such as the C2/C3 ratio and the levels of propionylcarnitine, methylcitrate, and ammonium in the plasma and various tissues of Pcca-/-(A138T) mice. Additionally, we will perform tissue histological evaluations and monitor overall survival to gain valuable insights into the therapeutic potential of triacetin.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY/ABSTRACT With a prevalence of 10 cases per million, immune thrombotic thrombocytopenic purpura (iTTP) is classified as a rare disease. Yet, it has significant human and economic impacts – untreated mortality rates of 90%; disproportionate effects on women and minorities; and per-patient costs > $1 million. Adding to these impacts, patients with iTTP report that their most significant health-related quality of life impact is cognitive function. Yet, despite promising therapeutic candidates (anfibatide and TAK-755) in early phase clinical trials, cognitive function impacts cannot be accurately measured because a comprehensive assessment of aspects of cognitive function influenced by iTTP has not been conducted. Though used in iTTP clinical trials, available cognitive measures lack sufficient validity evidence. Thus, no validity evidence is insufficient for clinical outcome assessments (COAs) of cognitive function for the context of use of iTTP clinical trials. Without validity evidence for COAs, iTTP clinical trials cannot align with FDA recommendations for patient-focused drug development: They cannot incorporate outcomes that are important to patients. Even worse, patients’ cognitive function response to new therapies cannot be appropriately assessed. Thus, patients cannot be referred for treatments that improve cognitive function outcomes. Thus, the absence of validity evidence for COAs of cognitive function is a critical barrier to iTTP clinical trial readiness. To facilitate clinical trial readiness in outcomes that are important to patients, there is an urgent need to develop a measurement strategy for iTTP-associated cognitive impairment. The objective of the study is to develop a consensus-driven measurement strategy of cognitive function for iTTP clinical trials. To this end, the study will both determine iTTP impacts on cognitive function and develop a cognitive function measurement strategy. To this end, the study will use a sequential mixed methods approach. First, using qualitative interviews of 24 patient-caregiver dyads, the study will develop an iTTP-induced cognitive impairment draft conceptual model. Second, using both a literature review and a multistakeholder advisory panel, a consensus-based approach will be used to select cognitive function COAs that have sufficient evidence for being fit-for purpose. The study will benefit from robust recruitment at 3 participating sites within the National Patient-Centered Clinical Research Network – PCORNnet®. The study team has expertise in iTTP, neurogenic disorders, and COA measurement strategy. A boon to iTTP clinical trial readiness, successful completion of this study will support the use of cognitive function COAs that are psychometrically rigorous. Furthermore, because they will be made available in the public domain, the conceptual and measurement models from this study will be used to further iTTP clinical trials: They can be accessed by both industry and regulatory agencies. This research is significant because it addresses cognitive function – the aspect of iTTP survivorship most important to patients. Because it will develop a consensus-driven measurement strategy of cognitive function, this research is also innovative. Responsive to PAR-23-159, this research meets the National Center for Advancing Translational Sciences (NCATS) priority of facilitating clinical trial readiness for rare diseases, disorders, and syndromes.

NIH Research Projects · FY 2025 · 2024-08

Project Summary/Abstract Increasing evidence suggests that activated neutrophils play a critical role in promoting vaso-occlusion and morbidity in sickle cell disease (SCD). Multiple factors are thought to contribute to neutrophil activation in SCD, including products of red cell (RBC) hemolysis and cellular interactions between neutrophils and the endothelium or platelets. Once neutrophils are activated, stimulus-dependent effects on neutrophil phenotype and functional capacity have been reported, resulting in dysfunctional neutrophils which propagate inflammation. Unlike prior studies in SCD which largely suggest that neutrophil activation occurs via indirect mediators, our preliminary data support the hypothesis that sickle RBCs (SS RBCs) directly activate neutrophils, resulting in enhanced adhesiveness and increased degranulation responses. We show that these 2 effector functions are further enhanced when SS RBC phosphatidylserine (PS) exposure is increased and when SS RBC adhesion receptors are activated. Furthermore, our preliminary studies show that in steady-state, exchange transfusion reduces neutrophil activation. Based on the preliminary data presented in this application, we will test the hypothesis that intact SS RBCs induce a specific neutrophil activation profile which recapitulates neutrophil dysfunction in SCD. We also hypothesize that therapies that reduce the RBC characteristics enabling this effect might both reduce neutrophil activation and decrease the frequency and severity of vaso-occlusive events. In Aims 1 and 2, we will delineate upstream characteristics of RBCs contributing to neutrophil activation as well as downstream consequences of SS RBC-induced neutrophil interaction in vitro. In Aim 1, we will establish the effect of SS RBCs on neutrophil phenotype, function, and gene expression. In Aim 2, we will establish the requirements needed for SS RBCs to activate neutrophils by examining physical requirements such as concentration thresholds and need for contact. We will also establish the role of PS exposure and the known activatable RBC membrane adhesion receptors (BCAM/Lu, ICAM4, CD47, and CD44) on neutrophil activation. In Aim 3, we will determine if the SS RBC-neutrophil interactions and measures of neutrophil activation we have described in vitro reflect those seen in patients during acute chest syndrome (ACS). In addition, we will determine the effect of transfusion, which we have shown affects neutrophil activation in steady-state, on in vivo neutrophil activation during acute illness. Together, these studies build on our novel observation that SS RBCs are able to directly induce neutrophil activation. The work outlined in this proposal will systematically define the characteristics of SS RBCs which cause neutrophil activation and the functional/phenotypic/transcriptional changes seen in neutrophils after activation by SS RBCs. These results will potentially identify new therapeutic targets and will provide significant biologic insight into the role of neutrophil-RBC interactions in SCD.

NIH Research Projects · FY 2025 · 2024-08

While antiretroviral therapy (ART) can control the replication of human immunodeficiency virus (HIV) and delay disease progression, there is still no cure, and HIV remains a global public health challenge. A better understanding of early and persistent immunological events in HIV infection is critical to inform novel interventions. The majority of current strategies aiming to prevent, control or eradicate HIV rely on harnessing effector functions of cytotoxic T cells, helper T cells, B cells and antibodies to attack HIV and HIV-infected cells. However, natural killer (NK) cells might represent another subset for therapeutic modulation. Recently, our lab has carried out in-depth, yet preliminary research into NK cells expressing the IgA receptor, CD89, using both human and nonhuman primate samples. We have generated preliminary data showing that: (i) CD89+ NK cells can be readily identified in various tissues including peripheral blood and mucosal tissues; (ii) CD89+ NK cells display an altered signaling phenotype compared to CD89- NK cells; (iii) CD89+ NK cells are significantly restricted in their activation potential; and (iv) CD89+ NK cells can be identified through multiplex imaging indicating their relevant proximity in the GI mucosae. Collectively these data form the basis for our overarching hypothesis that CD89 acts as an inhibitory checkpoint to regulate NK cell mucosal functions, and, therefore, may serve as an attractive target for NK cell-based interventions and therapeutics in lentivirus infections. We will test this hypothesis through two focused Exploratory Aims: (i) Characterize the role(s) and functional regulation of CD89+ NK in the mucosae in normal and SIV/SHIV-infected macaques; and (ii) Investigate the role of autologous CD89+ NK cells in therapeutic modulation of SIV infection. Ultimately, this knowledge has the potential to inform strategies to tune CD89+ NK cells for preventive or therapeutic interventions and personalized treatments, vaccine development, and strategies for reducing viral reservoirs.

NIH Research Projects · FY 2025 · 2024-08

SUMMARY Alveolar tissues must maintain proper cellular organization to perform vital functions such as gas- exchange at homeostasis and during repair. In human lungs, type-1 alveolar epithelial cells (AT1), a key cell type that serves as a barrier and facilitates gas exchange, are extremely thin, large, and estimated to cover 95% of the surface. Aging, genetic alterations, metabolic dysregulation, and environmental exposures, all are well recognized etiological factors in fatal lung diseases such as pulmonary fibrosis and emphysema, are known to impair replenishment of AT1 cells after injury. Significant progress has been made in understanding the pathways controlling differentiation of type-2 alveolar epithelial cell (AT2) into AT1s after injury. Currently we lack a comprehensive understanding of the mechanisms regulating proper establishment and maintenance of AT1 cellular organization (ex: thickness, area) during repair after injury and how they intersect with age-related genetic alterations and cellular dysfunction remain elusive. Here, we identified MAPT (microtubule associated protein, also known as Tau) as a key regulator that is essential for AT2 to AT1 cell differentiation and AT1 cellular organization. Significantly, this co-insides with recent genome-wide association studies that identified potential risk variants in MAPT in COPD and pulmonary fibrosis patients. Using genetic loss of function and dysfunctional Tau mutants, our preliminary data suggested a key role for Tau in AT1 cellular organization by regulating microtubule bundles and mitochondrial dynamics during lung repair in young and aged lungs. We hypothesize that Tau mediated microtubule bundling and mitochondrial dynamics control proper differentiation of AT2s into large and thin AT1 cells and that Tau mutations or its age-associated abnormal phosphorylation impairs mitochondrial dynamics, mitophagy, and function during alveolar repair after injury. The major goals of this proposal are: In Aim1, we will test the requirement of Tau and consequences of expression of a human relevant pathological form of Tau in alveolar stem cell mediated regeneration. In Aim2, we will test the hypothesis that genetic loss or age associated dysfunctional Tau impairs alveolar epithelial cell microtubule dynamics and mitochondrial remodeling, and function. We will use genetic loss of function, tubulin and mitochondrial reporter mouse models, confocal and electron microscopy, pulmonary function tests, RNA-seq, co-cultures, live imaging, metabolic assays to assess cellular organization, microtubule and mitochondrial dynamics during lung regeneration in young and aged mice following Tau modulation. The outcomes from the proposed studies will have broader impact on lung regenerative medicine and will form the basis for development of therapeutics to lung diseases.

NIH Research Projects · FY 2024 · 2024-08

Abstract Vascular composite allotransplantation (VCA) is the most immediately available therapy for individuals who have suffered irreparable tissue damages or deformities. While the technical aspects of VCA have rapidly advanced for these patients, the outcomes of VCA still lag behind those of other solid organ transplantation. The dramatic difference in outcomes highlights the inadequacy of current immunosuppressive regimens in VCA, which are largely borrowed from other organ transplantation, particularly kidney transplantation, where patients are immunologically more naïve. The higher immunogenicity (or susceptibility to rejection) of VCA may be attributed to (1) the inclusion of multiple tissues (i.e. muscle, skin, nerve etc.) in the transplant, (2) the exclusive use of deceased donors for VCA, and (3) pre-transplant management of trauma including transfusion prior to VCA. These factors will contribute to VCA rejection by expanding allo-specific immune cell repertoire, priming innate cells (trained immunity), and sensitizing recipients, respectively.We have shown that targeting the CD40/CD154 signaling pathway with anti-CD154mAb successfully promote long-term graft survival of kidney allograft in naïve recipients. Furthermore, anti-CD154mAb showed superior efficacy in sensitized recipients compared to tacrolimus-based conventional immunosuppression. Together with cytolytic induction, anti-CD154mAb effectively prevented post-transplant humoral response, eliminated antibody-mediated rejection (AMR) and significantly prolonged graft survival in sensitized recipients, all without introducing additional viral complications or malignancy. Given its exceptional efficacy in organ transplantation, particularly in sensitized recipients, we hypothesize that targeting the CD40/CD154 singling pathway can efficiently regulate the host immune response following VCA, even in cases where recipient have been sensitized by primary trauma care. This approach may create a therapeutic window to induce donor-specific tolerance. We will evaluate anti-CD154mAb approach in combination with either apoptotic donor cells or complement inhibition to re-establish an immune repertoire that favors transplantation tolerance. To explore this hypothesis, we propose 3 specific aims: 1) To test the efficacy of anti-CD154mAb in a naïve and sensitized nonhuman primate VCA models. 2) To determine efficacy of antigen-specific and non-specific pro-tolerance approaches in NHP VCA recipients. 3) To identify the functional phenotype of allo-specific T and B cells repertoires required to establish tolerance in VCA recipients.

NIH Research Projects · FY 2025 · 2024-08

HIV disproportionately affects people living in the United States southeast threatening progress toward the Ending the HIV Endemic initiative’s 2030 goals. Although Pre-exposure Prophylaxis (PrEP), an oral or injectable medication that if taken is highly effective in preventing HIV, at-risk people in the US southeast have not equitably benefited from its use due to multiple complex factors. For example, lack of awareness and knowledge to PrEP, not trusting PrEP, PrEP stigma, providers not knowing about or offering PrEP, accessibility, and cost. Thus, interventions that take into consideration the lived experiences and needs of this at-risk population are urgently needed to take a person in these geographic areas from medication precontemplation to uptake to maintenance. In partnership with communities, an established community advisory council (CAC), an online telehealth platform (Q Care Plus), and beauty salon stylists, the research team co-developed Using PrEP, Doing it for Ourselves (UPDOs) Protective Styles, an e-Health intervention that strongly considers the unique needs of at-risk people, consisting of a training for stylists to become opinion leaders (trusted gatekeepers who share health information in the community) in HIV prevention (i.e., PrEP) and a 6-week web-based, edutainment video series (i.e., six 20-minute episodes), structured debrief blogs, and telehealth service access. The CAC was invaluable in this development process having collaborated with the research team across sexual health-based projects that informed and contributed to UPDOs preliminary research. UPDOs web content share core concepts by telling the stories of at-risk people in the US southeast from various backgrounds and role-plays the PrEP decision-making process. Pilot research found UPDOs acceptable, improved PrEP trust, increased knowledge – for both PrEP aware and unaware participants, and decreased perceptions of PrEP stigma within personal relationships. This proposed effectiveness-implementation type I hybrid study will test UPDOs effectiveness in a larger, more geographically diverse sample using a cluster-randomized control trial and examine implementation determinants of UPDOs. In collaboration with Q Care Plus, a secure online platform to access telehealth services for home delivered HIV testing and PrEP prescriptions, we will track how many at-risk people within counties of increased HIV infections reach out to a provider, get HIV testing, start PrEP, and maintain PrEP as prescribed. A cohort of 32 beauty salons will be randomized to either an intervention group (n=16) or control group (n=16). Salons (1 salon = 1 cluster) will be randomized to UPDOs (Edutainment videos + blogs + Q Care Plus) or usual care (CDC videos + website) conditions. Once salons are randomized, the recruitment and enrollment period of customers will occur over 24 months. Study participation will include data collection at baseline with follow-up measures at 6, 12, 24, 32, and 52 weeks. To assess implementation outcomes and context, we will use a mixed methods approach guided by the Consolidated Framework for Implementation Research (CFIR).

NIH Research Projects · FY 2025 · 2024-08

There are more than 600,000 adolescent and young adult (AYA; age 15-39 at diagnosis) cancer survivors in the U.S. The number of AYA survivors continues to grow due to both an increased cancer incidence and treatment advances (i.e., five-year survival rates > 80%). For AYA survivors, the impacts of treatment are significant and long-lasting, including difficult physical symptoms (e.g., pain, fatigue), emotional distress (e.g., anxiety, depression), and an increased risk of long-term health problems (e.g., second cancers, early-onset cardiovascular disease). Persistent physical symptoms and emotional distress contribute to significant social, economic, and health burden, disrupting AYA survivors’ abilities to complete their education, achieve autonomy, build a career, establish peer and romantic relationships, and build a family. AYA survivors report symptom management to be a critical, unmet healthcare need; yet, there is a paucity of interventions to address their unique needs. Following completion of cancer therapy, many AYA survivors are gradually lost to follow-up with their oncology team while concurrently failing to establish care with health care providers who are aware of their risks and health care needs. Barriers to follow-up care for AYAs are multifaceted, and may include survivors’ beliefs about transitioning care to and navigating health care models centered around older adults due in part to age-specific competing demands (e.g., childcare, work, school) and the financial costs associated with care (e.g., being uninsured or underinsured). As a consequence, AYAs experience inadequate surveillance for late effects and missed opportunities for symptom management and psychological support, which further perpetuates their unmet needs. We have developed an accessible digital health intervention, AYA STEPS (Symptom Management and Transitioning to Engagement with Post-Treatment Care for AYA Survivors), designed to enhance AYA survivors’ abilities to manage their high symptom burden and engage in follow-up health care. Informed by the ORBIT Model of intervention development, AYA STEPS has been systematically and rigorously developed and refined through the PI’s prior work (K08CA245107). AYA STEPS is organized into six remotely delivered sessions providing cognitive-behavioral and patient activation theory-based skills expected to lead to lower symptom burden and increased health care engagement by improving AYAs’ self-efficacy for symptom management and activation. We propose a randomized controlled trial to examine the efficacy of AYA STEPS compared to AYA educational information for improving symptom burden and health care engagement for AYA survivors (N=260) who received cancer care in diverse health care settings (i.e., rural, urban, medically underserved areas) across North Carolina. Self-efficacy and patient activation will be examined as mediators of intervention effects. The planned study has the potential to produce clinically impactful health benefits for an underserved and understudied group of cancer survivors who have significant symptom burden, experience barriers to care engagement, and have limited access to AYA-specific behavioral interventions.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction that affects up to 20% of school children worldwide. Dietary interventions, particularly those removing fermentable oligosaccharides disaccharides monosaccharides and polyols (FODMAP) carbohydrates from the diet, may be helpful in both adults and children with IBS. Unfortunately, there are significant practical and potential health challenges (e.g., unintended weight loss) to following a FODMAP restriction diet. Identifying new therapies beyond dietary restriction alone for FODMAP-induced symptoms, particularly in children, is needed. Fructans are a type of FODMAP that are naturally occurring, abundant in our diet, and are a major focus of restriction in the low FODMAP diet. After ingestion, fructans arrive in the colon essentially intact where they are fermented rapidly by gut microbiota. We identified that a subset (~50%) of children with IBS are fructan- sensitive meaning they experience worsening abdominal pain when fed fructans. The biggest distinguishing feature between those who are fructan-sensitive vs. fructan tolerant (do not develop worsening pain) is a distinct microbial composition and fermentation pattern. These data suggest fructan fermentation by the gut microbiota is an important factor in determining whether subsequent gastrointestinal symptoms develop. Psyllium is a viscous, soluble, poorly fermented fiber that we demonstrated in children with IBS decreases abdominal pain frequency. However, psyllium efficacy is modest and the mechanism by which it ameliorates IBS is unknown. Importantly, a recent study reported that psyllium administered concurrently with fructans affected fructan fermentation: Adults who consumed fructans with psyllium (vs. fructans alone) had both decreased colonic gas production and overall colonic volume. This means psyllium represents a potentially important clinical intervention that may avoid the need for dietary fructan (and other FODMAPs) restriction and needs to be tested. To begin to investigate psyllium treatment for FODMAP (fructan)-induced pain, we will first identify children with IBS who are fructan-sensitive using our established randomized crossover protocol. Following a two-week baseline period In those who are fructan-sensitive (n=45), we then propose a two-week double-blind randomized parallel-group study in which participants receive either psyllium (1 g/year of age or 0.5 g/year of age per day) with fructans or a placebo (glucose) with fructans. Our central hypothesis is that psyllium given with fructans to fructan-sensitive children with IBS will decrease colonic fermentation of fructans and fructan-induced gastrointestinal symptoms. The Specific Aims of the project are to: 1) Investigate the effect of psyllium at two doses given with a fructan meal on microbial fructan fermentation; 2) Determine the effect of psyllium given with a fructan meal on fructan-induced gastrointestinal symptoms. The knowledge gained will lay the foundation for future longer-term comparative studies assessing psyllium given with meals vs. other interventions (e.g., restrictive low FODMAP diet) for FODMAP-induced symptoms in children with IBS.

NIH Research Projects · FY 2025 · 2024-08

Project Summary/Abstract The explosive growth of spatial transcriptomics technologies has revolutionized the study of tissue spatial architecture and development. In contrast to microdissection and spatial barcoding methods, which may not always achieve single-cell resolution, in situ spatial transcriptomics provides unparalleled detail by recording the spatial locations of individual RNA transcripts. Though specialized computational methods have been developed to tackle the unique challenges of analyzing in situ spatial transcriptomics data, substantial obstacles still exist in accurately identifying cell boundaries, distinguishing cell clusters and cell types, and understanding cells' interactions with their microenvironment. In this project, we propose to develop a suite of computational tools to address these challenges. First, we will develop a generally applicable framework for optimized cell segmentation that integrates RNA spatial location information with imaging information, capitalizing on the latest segmentation algorithms, such as those based on transformers. To evaluate their performances, we will generate a benchmarking dataset by manually annotating cell boundaries in real in situ data from various tissues and disease conditions. Second, we will establish a framework of cell clustering and cell type annotations for in situ data, blending gene expression information with cell morphology and cell density information learned from images. We will also test different combinations of computational methods for data transformation, dimension reduction, and clustering. The performance will be evaluated on simulated datasets derived from single-cell RNA-seq data with ground truth cell clusters and cell types. Finally, we will develop a flexible method to systematically study cellular microenvironment for data from both in situ and other types of spatial profiling technologies, taking into account diverse cell types, molecules, and different types of cell-cell interactions based on spatial proximity. These methods will facilitate deeper understandings of the spatial distributions and interactions of different cell types, providing new biological insights into cell senescence, tumor microenvironment, and more.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Biotechnology advances in research settings are rapidly growing, but the gap between translational medicine to clinical utility is lacking. In addition, there is a disconnect between undergraduate bioengineering education and workforce skills development that reduces the bioeconomy human capital needed to address critical biotechnology and biomanufacturing infrastructure in the United States. The proposed project aims to bridge the gap between biotechnology research and clinical applications by developing a bench-to-industry-to-bedside pipeline for undergraduate and graduate biomedical engineering students. Through team-based learning experiences, the project emphasizes collaboration and feedback cycles among critical stakeholders in biotechnology and biomanufacturing. The objectives include augmenting existing biotechnology design courses with emerging technologies such as adeno-associated viruses, recombinant protein production, and chimeric antigen receptor T cells that reinforce common innovation and manufacturing pipelines for student teams. We will also integrate industry and clinical mentorship from local biotechnology companies and medical practice and incorporate ethical frameworks in biotechnology design cycles. To address healthcare equity with rising costs of novel biotechnologies and information access, student designs will emphasize human-centered universal design and education to diverse populations as part of comprehensive needs assessment and stakeholder analyses. By enhancing the Duke Biomedical Engineering curriculum with advances in gene, cell, and molecular therapy, the project seeks to cultivate essential bioengineering skills for a future in molecular and cellular medicine. The intended educational outcomes include fostering skill development in molecular, cellular, and genetic engineering, promoting successful transitions into careers in the biomedical research workforce, and equipping students with the knowledge and experience to navigate the evolving biotechnology landscape and needs of all biotechnology stakeholders. With an estimated impact on approximately 100 undergraduate students and 50 graduate students over the five-year duration of the project, this program aims to significantly contribute to the bioeconomy and advance the translation of biotechnology advancements into clinical applications.