Duke University

NSF Awards · FY 2024 · 2024-07

Technical and Non-technical Abstract This proposal seeks support for the International Soft Matter Conference (ISMC2024) and a preceding Junior Investigator Workshop, which will take place in Raleigh, NC, July 29 – August 2, 2024, and July 27 to July 29, 2024, respectively. We expect 800+ participants to attend. This conference is organized by the recently formed Soft Matter Association of the Americas and is promoted by the IUPAP Working Group 15 – Soft Matter. The conference is meant to bring together scientists from different subfields of soft matter (polymers, colloids, biological systems) with different expertise (chemists, physicists, biologists, engineers) and is the first large-scale such conference organized in the Americas. The goal is to exchange ideas and techniques to accelerate progress in each area and soft matter science. Another objective of ISMC-2024 is to raise the international visibility of soft matter research in the US. A satellite Young Investigator Workshop for students and postdoctoral fellows will take place over 2.5 days before the International Soft Matter Conference. 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 · 2024-07

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Community health, including the conditions in which people are born, grow, live, and age, contribute to up to 80% of population health outcomes. Nurses, as the largest and most trusted segment of the healthcare workforce, are uniquely positioned to lead national efforts addressing population health. However, nurse scientists responsible for generating evidence for care models have not typically received specialized research training in addressing community health. Additionally, a lack of access to education in nursing science in certain geographical regions in the U.S. limits the profession's ability to engage all populations in research. Our proposed training program, Nurse LEADS (Training in Nurse-LEd models of care ADdressing Systems of Care and Community Health), is designed to provide innovative training to nurse scientists at the intersection of population and community health and nurse-led models of care. Trainees will develop skills in digital health, advanced analytics, engagement science, and multisector partnerships as essential methodological approaches and tools for promoting population health. Specifically, Nurse LEADS aims to: 1) recruit and retain pre- and postdoctoral trainees (N=10) in nursing science for advanced research training in community and population health and nurse-led models of care; 2) support trainees in contributing to emerging theoretical frameworks and methodological approaches for developing and scaling nurse-led models of care addressing community and population health; 3) develop trainee methodological expertise in leveraging digital health and advanced analytics for conducting cutting-edge research evaluating nurse-led models of care addressing population and community health; 4) and apply engagement science and multisector partnerships in the development of nurse-led models of care addressing population and community health. Trainees will be supported by mentoring teams that include mentors addressing digital health, advanced analytics, and community and population health from nursing and other interdisciplinary backgrounds. Trainees will participate in career development activities, monthly Nurse LEADS seminars, three courses involving experiential learning practicums, tailored learning experiences drawing from seminars, workshops, and courses from participating departments at Duke, and training in the responsible conduct of research. Additionally, postdoctoral trainees will be required to complete pilot research contributing to a nurse-led model of care addressing population and community health and mentor predoctoral trainees. This novel training will enhance the capacity of nurse scientists across to the U.S. to create novel, evidence-based models of care to improve population health.

NIH Research Projects · FY 2025 · 2024-07

PROJECT ABSTRACT. Despite significant advancements in treatment of children diagnosed with congenital heart defects (CHD), outcomes are inconsistent across the US. Studies have demonstrated that Parental Participation (PP), the act of parents’ performing caregiving activities for their hospitalized child, is pivotal in reducing complication and mortality in children with CHD. PP includes typical parent activities (e.g., comforting, diapering) and healthcare activities (e.g., medication administration, decision making). PP directly contributes to development of parenting confidence (PC), and leads to positive short and long-term outcomes for children and parents. Further research is needed to understand the mechanisms by which PP influences PC development. Each family’s unique life circumstances can positively or negatively impact PP. Factors which affect health, and by extension PP, include family structure, resources (income, insurance, access to transportation), and healthcare environment experiences. Despite the demonstrated benefits of PP and PC, there is paucity of research on the impact of family structure and resources on PP and PC in CHD care. A more nuanced understanding of individual factors is desperately needed to discern the ways unique family structure and external factors influence PP and PC in the CHD population. This mixed methods study seeks to examine the relationships among family structure, resources, PP and PC in CHD care among parents of children with CHD (n=110). The aims are to: Aim 1. Examine the influence of family structure, resources (income, insurance, access to transportation), and interpersonal experiences with providers in in the healthcare environment (HEE), and PP on PC using structural equation modeling (SEM) of data obtained via cross-sectional survey. Aim 2: Describe parental perceptions of how family structure, resources, HEE and PP affect development of PC in caring for their child with CHD using content analysis of narrative interviews among a group of parents purposively subsampled to encompass differing levels of PP and PC. Aim 3. Construct a comprehensive model of PP and PC, including the influence of resources, in a representative population of US parents using mixed methods integration of data from Aims 1 and 2. Without a more complete understanding of the impact that family resources and HEE have on PP and PC in CHD, creation of targeted interventions will fail to meet families’ individualized needs. Results from the proposed study will be foundational to informing explorations of: (1) additional influences on PP and PC in CHD care, (2) children’s perceptions of PP, and (3) creation of multi-level family support interventions to enhance PP in pediatric hospital care.

NIH Research Projects · FY 2024 · 2024-07

Opioid use disorder (OUD) and overdose rates have seen a stark rise in incidence throughout the last decade and continue to pose a devastating threat to the victims, families, and communities affected by addiction. The emergence of a negative emotional state reflecting a motivational withdrawal symptom when access to the drug is prevented is a core characteristic of drug addiction and is specifically exacerbated with opioid abuse. However, current treatment options for those suffering from OUD fail to provide therapeutic relief for many individuals and effectively substitute more addictive opioids for less addictive versions. Given the role withdrawal avoidance behavior plays in yielding an exaggerated motivational drive for addictive drugs while simultaneously compromising executive and inhibitory control of decision making, the central goal of this proposal is to elucidate a neural code underlying opioid withdrawal and its ability to induce relapse. In Aim 1 (F99), I explain the use of a custom designed multisite electrode to target 13 brain regions to monitor neural dynamics in opioid withdrawing mice. Neural features extracted from these recordings are used to train a machine learning model to identify latent representations that can most optimally and parsimoniously explain and reconstruct the original neural features. Importantly, in a holdout dataset, this model integrates information that can predict if, and when, a mouse is in opioid withdrawal. This predictive capacity can generalize to a novel cohort of mice and across multiple opioid drugs. The discovered network is primarily governed by gamma frequency oscillations between the ventral tegmental area (VTA) and nucleus accumbens shell (NAcS). In the remainder of my predoctoral training, I will investigate the contribution of this circuit activity in withdrawal behavior. I will develop a novel optogenetic targeting approach to establish a causal link between activity across this circuit, brain-wide network interactions, and withdrawal-specific behavioral responses. In Aim 2 (K00), I pivot my focus towards understanding the cellular contributions of distinct cell types in intravenous self-administration models of opioid relapse and vulnerability to relapse. I am primarily interested in understanding how distinct cell types within individual brain regions that are predominantly affected by chronic opioid exposure confer aberrant cellular physiology, leading dysfunction of cells, circuits, networks, and behavior. Moreover, I outline a plan to expand my existing technical skills to include transcriptional profiling, monitoring of in vivo cellular dynamics, and new addiction paradigm. In my Training Plan, I detail past, ongoing, and future efforts to further cultivate my technical development, professional and career development, written and oral communication, and mentorship and leadership. This proposal seeks to address BRAIN Initiative's Scientific Review and High Priority Research Areas for monitoring neural activity, interventional tools, and theory & data analysis tools. Together, these specialized and creative training skills cultivate a unique scientific repertoire that positions me initiate my transition to an independent academic research career.

NIH Research Projects · FY 2025 · 2024-06

SUMMARY The rotator cuff is composed of 4 muscles that stabilize the shoulder and controls upper arm range of motion. Tears in the tendons of these muscles, known as rotator cuff tears (RCTs), are among the most common debilitating shoulder injuries. While RCTs can be surgically repaired, the rate of retear is significant and has been correlated to high levels of rotator cuff muscle fatty infiltration, fibrosis, and muscle atrophy. A heterogeneous population of muscle resident non-myogenic mesenchymal cells, known as fibro-adipogenic progenitors (FAPs), have been implicated in many skeletal muscle pathologies in which intramuscular fat and fibrosis are abundant. We and others have recently demonstrated that PDGFRa-expressing FAPs expand during a 2-week period following massive RCTs in mice and contribute to the accumulation of intramuscular fat and fibrosis that accompanies rotator cuff muscle atrophy by 8-weeks post injury (wpi). While these findings are important, virtually nothing is known regarding the molecular signals associated with the promotion of FAP differentiation into fibrogenic and adipogenic fates, nor the factors that may be secreted by FAPs to drive rotator cuff muscle atrophy following RCT. Utilizing a murine model of massive RCTs, genetic lineage tracing/reporter analysis, as well as sophisticated bulk RNA-sequencing assays from isolated FAPs and other gene expression studies in muscle fibers, we identified several important molecular regulators of adipogenesis, fibrosis, and muscle atrophy that are likely key factors in promoting the RCT pathology. Validation of signaling and functionality of these molecules/pathways were demonstrated in our mouse model of RCTs (in vivo). In this application we will utilize conditional genetic approaches to delete the relevant genes specifically in FAPs and muscle fibers following RCTs, while also performing genetic reporter analysis, histology, IHC/IF, bulk-RNA sequencing, and sophisticated single cell RNA-sequencing assays, to determine whether cell-type specific signaling activation is necessary to promote the RCT pathology following massive RCTs in mice and determine whether the presence or absence of these molecular regulators affects FAP heterogeneity of rotator cuff muscles following RCTs. Further, we will perform proof-of-concept studies demonstrating the utility of prophylactic and therapeutic pharmacologic approaches to the inhibition of this pathway following RCTs. This work will provide vital information to our understanding of the cellular and molecular roles for FAPs in RCT induced fatty infiltration, fibrosis, and the muscle atrophy associated with massive RCTs, while also testing clinically relevant therapies for the treatment of the RCT pathology.

NIH Research Projects · FY 2026 · 2024-06

When admitted to the hospital, Black and Latino children are at greater risk of medical errors, surgical complications, longer, more-costly hospital stays, and mortality. Although many factors play a role, poor clinician communication likely contributes to these disparities in health outcomes. Across settings, including our preliminary work in the inpatient pediatric environment, Black and Latino patients have been shown to experience worse communication quality, particularly in domains of relational practice such as collaboration and empowerment. Despite robust evidence that differences in communication exist and influence health outcomes, few have developed and tested communication interventions grounded in a praxis of relational neuroscience. To meet this evidence gap we will test the feasibility, acceptability, and preliminary efficacy of a relational communication intervention that teaches clinicians communication skills aligned with principles such as collaboration, empowerment, and trustworthiness. To do this, we will co-develop and refine a clinician coaching communication intervention with iterative feedback from Black and Latino caregivers as well as clinicians of children in the hospital. We will then randomize 10 clinicians to an intervention or waitlist group; clinicians in the intervention group will receive the intervention immediately, while clinicians in the waitlist group will initially serve as the control arm then receive the intervention to provide feasibility and acceptability data. We will assess the feasibility of recruiting and collecting data as well as acceptability of the intervention by clinicians. We will explore preliminary efficacy for the effect of the intervention on clinician-caregiver communication quality. We hypothesize that our intervention will improve clinician communication quality through increasing behaviors of partnership, affirmation, support, respect, and interpreter best practice, which will lead to greater caregiver participation during family-centered rounds. We will explore the effect of the intervention on caregiver empowerment, adverse events, length of stay, and child 7 and 30 day unplanned readmission. The new knowledge generated from the proposed research will guide our research team in designing and conducting an NIH R01 clinical trial of the intervention to enhance the standard of care for children admitted to the hospital.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY/ABSTRACT Heart failure (HF) affects more than 6 million adults in the U.S. alone, with increasing prevalence. Cardiovascular congestion with resultant limitation in physical activity is the hallmark of chronic and decompensated HF. The current HF physiologic model suggests that congestion is the result of volume retention and, therefore, therapies (such as diuretics) have generally been targeted at volume overload. Yet therapeutic approaches to reduce congestion have failed to show significant benefit on clinical outcomes, potentially due to an untargeted approach of decongestive therapies. Our preliminary work suggested a complimentary contribution of volume redistribution to the mechanism of cardiac decompensation. We identified the splanchnic nerves as a potential therapeutic target and showed that short-term interruption of the splanchnic nerve signaling could have favorable effects on cardiovascular hemodynamics and symptoms. As part of our proposal, we will: (1) Investigate the impact of prolonged splanchnic nerve blockade on the cardiovascular system in patients with HF and reduced ejection fraction (HFrEF); (2) Visualize splanchnic nerves using intravascular imaging tools, and demonstrate technical success of the splanchnic nerve blockade; and (3) Define the mechanisms of action of splanchnic nerve blockade and identify congestion phenotypes that respond favorably to splanchnic nerve blockade. The results of the proposed scientific aims will help test the paradigm shifting hypothesis of volume redistribution as a driver of cardiovascular congestion and functional limitations and pave the way for splanchnic nerve blockade as a novel therapeutic approach to HF.

NSF Awards · FY 2024 · 2024-06

This CAREER project provides new insights at the intersection of organizational sociology and legal sociology by advancing our understanding of how street-level bureaucracies circumvent the regulatory constraints imposed on them as public sector agencies. The objective of this research is to provide a theoretical and empirical account of what it is calling “pseudo-state entities” of street-level bureaucracies. Street-level bureaucracies are schools, hospitals, police and other public institutions that provide services directly to the public. The project argues street-level bureaucracies, establish pseudo-state entities like foundations, unions, associations, and other entities to circumvent the regulatory constraints imposed on them as public sector agencies. The project will feature research and educational components to create novel scientific knowledge about how street-level bureaucracies utilize external organizations to benefit their interests. First, it will introduce an original theory of how state actors establish private organizations that enable them to engage in otherwise regulated activities. Next, based on interviews and a variety of public records and datasets this project will examine the origins, diffusion, and impact of (a) nonprofit foundations and (b) political action committees. The analysis of these two cases together will contribute new understandings of how the pursuit of bureaucratic autonomy can motivate the establishment of new organizational structures. Finally, this project will integrate educational initiatives—an Online Summer Academy, (under)graduate courses, unique publication opportunities for undergraduates, and a Shared Spotlight Series between scholars and organizers—to cultivate a research community for academics and non-academics whose work is already informed by, or seek additional resources for pursuing, research based on public institutions. 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 · 2024-06

This project aims to serve the national interest by enhancing Peer+, a free tool that supports Peer Instruction. When using Peer Instruction an instructor displays a question that students answer individually. The students then discuss the question with nearby peers and refine their answers. Peer+ will add two new ways for students to discuss the question with their peers through (1) a text-chat for answering questions during lecture, and (2) a pseudo text-chat for answering questions after lecture. While there is substantial evidence for the effectiveness of Peer Instruction, preliminary research at the University of Michigan has found that using text-chat during lectures improved learning. Peer Instruction is known to improve retention in STEM classes, especially for students from minoritized groups. Providing new types of peer discussion could further improve retention and thus increase the number and diversity of students who succeed in STEM classes. The research associated with this project will increase knowledge about effective STEM education and approaches that attempt to reduce barriers to adoption of Peer Instruction. Since it can be hard for instructors to find the time to adopt new teaching methods, a summer instructor workshop will be offered, and follow-up support will be provided. The project will investigate (1) the effect of three different modes for peer discussion on learning and student satisfaction at four institutions and in a variety of courses, (2) the effect of the Peer+ tool on student retention, and (3) how instructor attitudes towards and knowledge of Peer Instruction change due to a workshop, follow-up support, and use of Peer+. A design-based research approach will be used, based on theory, and the system will be evaluated in real educational settings. The research will be evaluated using both qualitative and quantitative measures. The NSF IUSE:EDU Program supports research and development projects to improve the effectiveness of STEM education for all students. Through the Engaged Student Learning track, the program supports the creation, exploration, and implementation of promising practices and tools. 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 · 2024-06

The research in this project will address a fundamental challenge in a variety of critical fields such as medicine, finance, and robotics: making decisions that not only aim for the best average outcomes but also minimize risks to individuals. For instance, when selecting a medical treatment, it is not enough to know that a treatment works well on average; we need to ensure that it benefits a large proportion of patients, say 95%, without causing harm. Current statistical learning methods, however, often overlook such nuanced considerations of risk, leading to a significant disconnect between theoretical advancements and practical needs. This proposal seeks to close this gap by developing a new framework for risk-sensitive decision-making. By incorporating risk assessments into the decision-making process, our research aims to advance scientific knowledge and contribute to the general interest by improving healthcare outcomes, financial stability, and the safety and effectiveness of robotic systems. The project will also support education and promote diversity by providing training opportunities for students at various levels and developing user-friendly, open-source software to make these advanced methods accessible to practitioners. The research will focus on the development of innovative methods for risk-sensitive statistical learning, aiming to improve decision-making processes in areas where outcomes' variability can significantly impact overall success. The project is structured around four specific aims. The first aim is to develop quantile-constrained statistical learning. A particular example is to optimize average outcomes under constraints that ensure a minimum benefit level across a defined proportion of a population. This involves formulating the problem as a constrained optimization issue with stochastic boundaries, proposing novel algorithms, and deriving asymptotic results for estimator analysis. The second aim is to develop methods for risk-sensitive deep reinforcement learning. This is to create theoretically grounded algorithms that utilize deep neural networks to derive optimal decision rules, incorporating variance and other risk considerations to ensure decisions are robust under uncertainty. The third aim is to address risk-sensitive bandit problems through the development of both frequentist and Bayesian models and algorithms, aiming to achieve optimal regrets while considering risk. The final aim is to extend the methods and results to encompass the broad class of coherent risk measures, thereby enhancing the applicability and impact of the research across various domains. 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 · 2024-06

This study will assess how the design of transitional justice institutions in countries affected by conflict and/or authoritarianism affects public opinion, thereby shaping long-run national outcomes including regime type and conflict recurrence. Existing literature on the effects of transitional justice is inconclusive; such work is divided between micro-level, single-country studies and macro-level, cross-country studies as well as between studies of post-authoritarian and post-conflict contexts. By collecting comparable survey measures across countries that vary along several theoretically relevant dimensions and by building a cross-national dataset, this project will bridge these gaps. Further, the researchers will develop and test a novel theory about how public attitudes mediate the relationship between transitional justice institutions and long-run outcomes. Given the widespread use of transitional justice in post-conflict and post-authoritarian countries as well as democracies around the world, there is an urgent need for the field of transitional justice studies to develop a stronger base of evidence for policymaking. This project will shed light on which forms of transitional justice effectively promote peace, democracy, justice, and reconciliation as well as provide insights into how countries’ unique histories may shape the impact of transitional justice there. This project will investigate three questions. First, which kinds of transitional justice do people see as more legitimate? Second, how do people’s perceptions of the legitimacy of transitional justice institutions affect their broader political attitudes concerning the government, principles of democracy and autocracy, and out-groups? Third, do transitional justice institutions perceived as more legitimate contribute to stability following conflict? To address these questions, the research team will draw on their extensive thematic, regional, and methodological expertise to employ a mixed-methods research design which combines survey experiments, qualitative evidence collected from focus groups and elite interviews, and original cross-national data. This approach will leverage the strengths of diverse methodologies by combining (A) micro-level survey and qualitative data that will enable the investigators to assess the effects of varying transitional justice processes on individual attitudes with (B) macro-level cross-national data that will provide insight into the effects of institutions and historical context on national-level outcomes. 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 · 2024-06

Abstract In case of radiation accidents or nuclear warfare, exposure of the small intestine and colon to high-dose irradiation results in delayed injury, manifested by an increase in fibrosis, that significantly impacts organ function. There are no current FDA-approved medical countermeasures to prevent, mitigate, or treat delayed radiation injury of the small intestine and colon. However, one major challenge for the development of such therapies is to understand how fibrosis associated with DEARE (Delayed Effects of Acute Radiation Exposure) is impacted by biological sex, as recent studies suggest that females may be more sensitive to delayed radiation-induced fibrosis compared to males. Our long-term goal is to uncover the mechanisms underlying the effects of biological sex on acute and long-term radiation injury of the GI tract. Type I IFN has been proposed as a potential mitigator of acute radiation injury to the intestine by promoting epithelial regeneration. Furthermore, Type I IFN is activated in the intestine and colon following acute radiation injury and is persistently upregulated in our model of DEARE. In preliminary studies, we evaluated radiation-induced delayed colonic fibrosis in male and female Irgm1-/- mice that are known to potently activate Type I IFN and found that germline Irgm1 deletion results in substantially greater colonic fibrosis in females compared to males. Therefore, in this application, we hypothesize that Type I Interferon signaling, while preventing acute radiation injury to the GI tract, promotes long-term intestinal fibrosis to a greater degree in females vs. males. We will test this hypothesis through the following Specific Aims: Aim 1: To determine the molecular mechanisms of sex-dependent, Type I Interferon signaling in radiation-induced fibrosis. Aim 2: To determine the cellular origins of sex-dependent, radiation-induced fibrosis. Aim 3: To determine the efficacy of FDA approved Type I Interferon inhibitors to prevent the development of radiation-induced intestinal fibrosis in females vs. males. Together, these studies will reveal novel mechanisms by which activation of Type I Interferon promotes the development of chronic submucosal fibrosis in the gastrointestinal tract in sex- dependent manner, which is a major complication of survival from gastrointestinal acute radiation syndrome (GI-ARS). These results will inform the future development of mitigators of DEARE in female and male populations.

NIH Research Projects · FY 2025 · 2024-06

Project Summary/Abstract Zika virus, a small positive-stranded RNA virus, causes a remarkable spectrum of infection outcomes, ranging from asymptomatic infection in up to 80% of individuals to microcephaly in congenital Zika syndrome. This variation in human susceptibility was highlighted during the 2015-2016 epidemic of the Americas that resulted in over a million infections and 3,500 cases of microcephaly in Brazil alone. These differences in outcome arise from the complex interplay of exposure, environment, age, Zika virus genetics, and human genetics. The overall goal of my lab is to understand how human genetic diversity regulates susceptibility and severity of infections. Famous examples of genetic differences that profoundly impact susceptibility include sickle cell allele protection against malaria and CCR5 deletion protection against HIV. Such genetic differences can lead to insights on pathogenesis, drug targets (e.g. CCR5 inhibitors), and more personalized care. While genome-wide association studies (GWAS) are a powerful approach to discover common genetic differences that confer disease resistance, there are no published GWAS of human Zika virus infection. However, studies of dizygotic twins with discordant outcomes have demonstrated that cells from the twin exhibiting congenital Zika syndrome are more susceptible to infection in vitro. Therefore, we hypothesize that human genetic differences that regulate Zika infection can be identified through measuring inter-individual variation in cellular infection phenotypes. To facilitate identification of genetic variants that affect cellular infection phenotypes, we developed a rapid single- cell GWAS approach called scHi-HOST (single-cell High-throughput Human in vitrO Susceptibility Testing). scHi- HOST facilitates assignment of each cell to a genotyped individual, phenotyping of each cell for viral entry and burden, and measurement of host transcriptomic response, all from a single scRNA-seq experiment. We propose that coupling cell-based human genetics and functional validation will facilitate discovery of novel pathways and genetic determinants of susceptibility. Specifically, we will 1) identify human genetic variants that confer susceptibility/resistance to cellular Zika virus infection for strains representing the major Zika virus lineages, and 2) experimentally validate genetic variants and causal genes associated with cellular susceptibility to Zika virus using CRISPR-based approaches in diverse cell types. Thus, this project will generate an experimentally validated, high-resolution analysis of how human genetic variants impact cellular infection phenotypes during Zika virus infection. This will serve as a springboard for characterizing identified variants more deeply through future mechanistic studies and examining clinical relevance in human studies. Understanding these differences could lead to new diagnostic approaches in identifying at-risk individuals and novel therapeutic strategies for treatment.

NIH Research Projects · FY 2026 · 2024-06

ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is the 7th most prevalent cancer globally, resulting in 930,000 new cases and 467,000 deaths annually. Alongside tobacco and alcohol use, human papillomavirus (HPV) infection contributes to HNSCC development. Regardless of their clinical stage or location, these tumors exhibit significant heterogeneity in gene expression and treatment response. While immunotherapy has revolutionized treatment approaches for many cancers, its impact on HNSCC remains limited. This suggests aspects of HNSCC tumor immunology – including the role HPV plays in immune dysregulation – are not well understood. Thus, the objective of this research is to develop, validate, and implement advanced computational tumor phenotyping techniques to characterize HNSCC at multiple levels of biological organization. Our approach involves high-throughput analysis of quantitative features from both radiology images (i.e., radiomics) and digital pathology images (i.e., pathomics) to generate a multiscale depiction of the HNSCC phenotype. We hypothesize that tumor-specific radiopathomic expression patterns of HNSCC are connected to fundamental biological and immunomolecular processes driving therapeutic resistance. In Aim 1, the prognostic value of radiomics will be evaluated in both HPV+ and HPV− HNSCC patients treated with radiotherapy as part of a previously conducted prospective clinical trial (NCT01908504). Changes in radiomic expression after initial 20 Gy will be quantified via data assimilation of PET/CT imaging and stochastic models of tumor dynamics. In Aim 2, the tumor immune microenvironment of these patients will be characterized via pathomic analysis. Single-cell interactions will be measured between different immune compositions and compared to single-cell transcriptomics data to gain mechanistic insight into the genes driving pathomic expression. Radiomics (Aim 1) and pathomics (Aim 2) will each be experimentally confirmed and mechanistically validated in novel carcinogen-induced and genetically engineered mouse models that co-evolve with an intact immune system, where we will dissect mechanisms of treatment resistance and interrogate immune dysregulation in mice that spontaneously develop HPV+ vs. HPV− HNSCC. In Aim 3, our scientific findings will be independently tested in an ongoing prospective interventional study (NCT04667585) to evaluate radiopathomic expression as a potential biomarker to guide adaptive therapy for HPV+ HNSCC. Candidate biomarkers identified in NCT01908504 will be independently tested in NCT04667585 to provide an unbiased evaluation of their prognostic value. The rationale for these studies is to enhance understanding of HNSCC biology to guide improved treatment approaches for this urgent, unmet clinical need. By leveraging innovative radiopathomic strategies, novel clinical trial data, and complementary mechanistic interrogation, our proposed research will be an important advancement in computational oncology and precision treatment of HNSCC. We anticipate that our results will improve our understanding of HNSCC treatment resistance and will bridge a knowledge gap between abstract image representation and basic biology.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY Chromatin-associated proteins are a major class of genes mutated in autism spectrum disorder (ASD) and intellectual disability (ID). These genetic data indicate the importance of gene regulation for brain development, however a significant challenge for the field is to determine how disruptions of chromatin regulators may converge on specific biological processes in developing neurons. To address this challenge, here we focus in detail on the biochemical and cellular mechanisms by which ID-associated frameshift mutations in the linker histone H1.4 result in impaired neuronal development. As a histone, H1.4 is a direct component of chromatin; thus, studying how mutations in this gene impair neural development offers the opportunity to gain specific biochemical insight into mechanisms of chromatin regulation in neurons. Rahman Syndrome (RMNS) is a rare, genetic form of ID caused by de novo heterozygous mutations in H1-4, which encodes histone H1.4. All RMNS-associated mutations in H1-4 are small insertions or deletions that create a shared C-terminal frameshift. Genetic data indicate that the mutant protein likely functions in a dominant negative or neomorphic manner to lead to RMNS phenotypes, but the biochemical and cellular consequences of expressing RMNS mutant histone H1.4 are poorly understood. We have found that expressing RMNS mutant histone H1.4 in rat hippocampal neurons leads to the disruption of synaptic gene expression and neuronal firing. We hypothesize that RMNS mutant H1.4 disrupts chromatin architecture in differentiating neurons to impair gene expression programs that are required for synapse development and neuronal function. To determine how the RMNS mutation of histone H1.4 leads to aberrant transcription and to evaluate the consequences for brain development, we will use both biochemical and molecular genetic approaches in the developing mouse brain and in human neurons. In Aim 1, we will build a foundation for these studies by using leading edge proteomic and molecular genetic methods to characterize the expression, regulation, and chromatin distribution of histone H1.4 over the course of neuronal differentiation in the mouse. To determine how RMNS mutations disrupt synaptic gene expression in brain development, in Aim 2 we will use a novel in vivo protein tagging strategy to identify proteins that interact with wildtype versus RMNS mutant H1.4. Finally, to determine how RMNS mutations disrupt chromatin regulation, in Aim 3 we will study generate RMNS mutant H1.4 expressing iPSC- derived neurons for biochemical histone H1 proteomics and gene expression analyses. We will then use a novel method for low-input three-dimensional chromatin conformation capture to test the hypothesis that RMNS mutant histone H1.4 disrupts higher level chromatin architecture. These studies will advance knowledge of the causes of brain developmental abnormalities in RMNS, and they will contribute to understanding of the specific mechanisms of linker histone dependent chromatin regulation that are key for neuronal maturation.

NIH Research Projects · FY 2026 · 2024-06

Project Summary Over half of the 6.7 million adults with heart failure in the United States have a normal or near-normal left ventricular ejection fraction, or heart failure with preserved ejection fraction (HFpEF). The prevalence of HFpEF is increasing over time, due to ageing of the population and other factors. Morbidity and mortality for patients with HFpEF remains high; rates are similar to those observed in HF with reduced ejection fraction. Poor outcomes in HFpEF are related to a lack of evidence-based therapeutic options. There is an urgent need to efficiently conduct large, simple, streamlined trials with clinically relevant endpoints comprised of therapeutic interventions for HFpEF patients. Mineralocorticoid receptor antagonists (including spironolactone) present one promising treatment for HFpEF. In clinical trials of participants with HF with reduced ejection fraction, mineralocorticoid receptor antagonists have consistently demonstrated their ability to improve symptoms, and reduce mortality and hospitalizations. However, the TOPCAT trial was the largest study of mineralocorticoid receptor antagonists in HFpEF. In TOPCAT, spironolactone did not significantly reduce the primary outcome (a composite of cardiovascular death, aborted cardiac arrest, or hospitalization for HF) relative to placebo, but did reduce a secondary endpoint of HF hospitalization (HR 0.83, 95% CI 0.69–0.99, p=0.04). A post-hoc regional analysis of TOPCAT, limited to North and South America, found that spironolactone reduced the primary endpoint (HR 0.82, 95% CI 0.69–0.98) compared to placebo. Therefore, TOPCAT demonstrated the potential promise of mineralocorticoid receptor antagonists in HFpEF but was not definitive. The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT- HFpEF) randomized clinical trial was funded in 2018 for 5 years and has now randomized >1900 participants. The primary aim of SPIRRIT-HFpEF is to test the hypothesis that use of spironolactone will reduce total HF events (total hospitalizations for HF and death from cardiovascular causes). SPIRRIT-HFpEF will complete enrollment December 31, 2023. The current application for SPIRRIT-EX is for a free-standing extension of the SPIRRIT-HFpEF trial to extend follow-up through December 31, 2025 and to allow for accrual of additional clinical events. The application will specifically support extended follow-up, secondary analyses (including a pre-specified meta-analysis of data from another ongoing HFpEF clinical trial), dissemination of results, and closeout activities of participants previously randomized in SPIRRIT-HFpEF. Resolving whether spironolactone is beneficial in patients with HFpEF would have tremendous public health implications.

NIH Research Projects · FY 2025 · 2024-06

The purpose of the Duke Environmental Analysis Laboratory (DEAL) Hub is to offer a comprehensive suite of analytical services to support epidemiologists and health researchers conducting studies focusing on the impact of environmental exposures on human health. This research is vital to understanding the links between chemical exposures and human health endpoints, knowledge which is essential in mitigating disease risk and improving quality of life. DEAL will be co-directed by Dr. Heather Stapleton, a trained environmental chemist and exposure scientist, and Dr. Lee Ferguson, a trained mass spectrometrist and environmental analytical chemist. Drs. Stapleton and Ferguson each have over 20 years of experience using mass spectrometry to detect and quantify contaminants in environmental samples and are pioneers in the fields of emerging contaminants, exposure science, and non-targeted analytical methods. The long-term objectives of the DEAL Hub are to: 1) provide consultation and advice to environmental health researchers to support human health studies ; 2) provide comprehensive and state-of-the-art analytical services to supporting environmental health research; and 3) develop new analytical methods for the quantitation of emerging contaminants of interest to environmental health community and develop new technologies and tools for characterizing the exposome. To meet these objectives, DEAL consists of three internal cores. The first is the Environmental Sample Analysis Core (ESAR) that will support exposomic researchers by providing services for project consultations, sample preparation, extraction, and quantitative analysis of contaminants in environmental media using three distinct sample laboratories, the Targeted Organic, Targeted Inorganic, and Untargeted Organic labs. Through these three Labs, ESAR and DEAL as a whole can provide comprehensive services for a wide variety of analytes and support a larger breadth of environmental health researchers. Second is the Developmental Core that will create new analytical methods for the quantitation of emerging contaminants and develop new technologies and tools for characterizing the exposome. Finally, the Deal Hub will provide administrative management and coordination with the ESAR and Developmental Cores through the Administrative Core. This Administrative Core will also serve as the liaison between the DEAL Hub and the broader HHEAR Network, with Dr. Heather Stapleton as its Director. The intense collaboration of ESAR, Developmental, and Administrative Cores of the DEAL Hub will facilitate more and higher quality exposomic research that is essential for continued understanding of risk mitigation and environmental health interventions in at-risk populations.

NIH Research Projects · FY 2026 · 2024-06

Project Summary: Over half of the 6.7 million adults with heart failure in the United States have a normal or near-normal left ventricular ejection fraction, or heart failure with preserved ejection fraction (HFpEF). The prevalence of HFpEF is increasing over time, due to ageing of the population and other factors. Morbidity and mortality for patients with HFpEF remains high; rates are similar to those observed in HF with reduced ejection fraction. Poor outcomes in HFpEF are related to a lack of evidence-based therapeutic options. There is an urgent need to efficiently conduct large, simple, streamlined trials with clinically relevant endpoints comprised of therapeutic interventions for HFpEF patients. Mineralocorticoid receptor antagonists (including spironolactone) present one promising treatment for HFpEF. In clinical trials of participants with HF with reduced ejection fraction, mineralocorticoid receptor antagonists have consistently demonstrated their ability to improve symptoms, and reduce mortality and hospitalizations. However, the TOPCAT trial was the largest study of mineralocorticoid receptor antagonists in HFpEF. In TOPCAT, spironolactone did not significantly reduce the primary outcome (a composite of cardiovascular death, aborted cardiac arrest, or hospitalization for HF) relative to placebo, but did reduce a secondary endpoint of HF hospitalization (HR 0.83, 95% CI 0.69–0.99, p=0.04). A post-hoc regional analysis of TOPCAT, limited to North and South America, found that spironolactone reduced the primary endpoint (HR 0.82, 95% CI 0.69–0.98) compared to placebo. Therefore, TOPCAT demonstrated the potential promise of mineralocorticoid receptor antagonists in HFpEF but was not definitive. The SPIRRIT-HFpEF (Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction) randomized clinical trial was funded in 2018 for 5 years and has now randomized >1900 participants. The primary aim of SPIRRIT-HFpEF is to test the hypothesis that use of spironolactone will reduce total HF events (total hospitalizations for HF and death from cardiovascular causes). SPIRRIT-HFpEF will complete enrollment December 31, 2023. The current application for SPIRRIT-EX is for a free-standing extension of the SPIRRIT-HFpEF trial to extend follow-up through 2025 and to allow for accrual of additional clinical events. The application will specifically support extended follow-up, secondary analyses (including a pre-specified meta-analysis of data from another ongoing HFpEF clinical trial), dissemination of results, and closeout activities of participants previously randomized in SPIRRIT-HFpEF. Resolving whether spironolactone is beneficial in patients with HFpEF would have tremendous public health implications.

NIH Research Projects · FY 2025 · 2024-06

Retinal photoreceptors are specialized neurons responsible for detection and primary processing of the information entering the eye in the form of light. These first steps of vision take place in the photoreceptor outer segment, which contains proteins performing visual signal transduction. It is connected to the cell soma (or the inner segment) through the connecting cilium, which serves as a trafficking route for the outer segment proteins synthesized in the inner segment. The cellular structures immediately adjacent to the connecting cilium are also engaged in performing critical photoreceptor functions. At the distal end of the connecting cilium is the site of photoreceptor disc morphogenesis where several dozen new discs are formed on a daily basis to sustain the ever-going process of outer segment renewal. At the proximal end of the connecting cilium, there are structures forming a sorting gate that regulates the outer segment entry and exclusion of membrane proteins. Defects in any of these processes have been implicated in a wide range of photoreceptor degenerative diseases. Despite many proteins already being mapped to the connecting cilium and other parts of the outer-inner segment junction using conventional biochemical and genetic approaches, our knowledge of the protein composition of this cellular region remains far from complete, which hinders the progress in elucidating the molecular mechanisms of protein trafficking, sorting, outer segment maintenance and disc morphogenesis. The goal of this proposal is to reduce this knowledge gap by characterizing the unique proteome of the photoreceptor outer-inner segment junction. In Aim 1, we will employ a cutting-edge application of quantitative proteomics, called protein correlation profiling. Unlike traditional biochemical techniques, this methodology allows analyzing the unique protein composition of subcellular structures that can be enriched but not purified, as in the case of the connecting cilium and its adjacent regions. We will obtain thin serial tangential sections through the outer-inner segment region of a frozen flat-mounted retina and characterize the protein composition of these sections using label-free quantitative mass spectrometry. The resulting protein distribution profiles will be compared to those of well-characterized connecting cilium markers. Proteins distributed similarly to these markers will be considered as candidate unique components of the outer- inner segment junction, and their localization will be verified using immunolocalization techniques. In Aim 2, we will employ a novel, highly accurate approach of multiplex protein quantification to simultaneously determine absolute amounts of large groups of previously known and newly identified proteins residing at this cellular location. This analysis will suggest which proteins may exist within multi-subunit stoichiometric complexes and/or specific subcellular structures, thereby facilitating uncovering their functional roles. The information generated in this resource- and hypothesis-generating study will undoubtedly facilitate the efforts of many laboratories addressing a broad array questions related to photoreceptor biology and disease.

NIH Research Projects · FY 2025 · 2024-06

Enter the text here that is the new abstract information for your application. Despite the significant advances in HIV antiretroviral therapies for effective treatment and prophylaxis regimens, young Black men in North Carolina (NC) continue to be affected by HIV at nearly the same rates over the last 10 years. The new diagnosis rate in NC for Black men aged 13-24 years was 104.7/100k population in 2009 and 114.6/100k population in 2019. Viral suppression failures lead to higher rates of uncontrolled HIV in the sexual networks of young Black men who have sex with men (YBMSM). YBMSM who are HIV-negative are significantly less likely to be on pre-exposure prophylaxis (PrEP), especially in states which have not or have only recently expanded Medicaid. There are both clinical and public health points of intervention where YBMSM could be given greater access to PrEP. Clinical guidelines indicate PrEP based on individual-level risk factors (e.g., bacterial diagnosis) or on partner-level risk factors (e.g., HIV+ partner). However, YBMSM are more likely to be part of a sexual network where both HIV and bacterial sexually transmitted infections are circulating. If using the concept of “degrees of separation”, YBMSM in the US South tend to be fewer degrees away from someone with HIV, so accounting only for their person-level or first degree partner-level risk factors fails to place the person in context. Clinically, an understanding of the partners of the partners may turn out to be an indicator for PrEP that is not currently assessed. From a public health standpoint, PrEP can benefit not only the person taking it but also the larger community if preventing one person’s infection also protects future partners. It can thus have a positive effect across the sexual network, as has been demonstrated by simulation studies. As resources to provide PrEP are extremely limited, identifying network members who would themselves benefit from PrEP and whose partners would benefit as a result is key. These gaps suggest that to better assess HIV risk – and recommend prophylaxis – an understanding of risk within the entire sociosexual network is needed as the individual-level risk is a product of the local network beyond just partners. In this project, we aim to quantify the additional risk of HIV among YBMSM who are positive for syphilis or who are partners of someone positive for syphilis compared to the risk among other demographic groups and to develop a model that can be applied at the time of the public health interview to predict HIV seroconversion within 3 years. We also aim to test methods to scale up to the underlying transmission network using the subset of relationships which are observed during public health interactions.

NIH Research Projects · FY 2025 · 2024-06

B.1 ABSTRACT TEXT-WHAT ARE THE MAJOR GOALS OF THE PROJECT? The Aims of the project are as follows: 1. To attract talented medical students into the Duke psychiatry residency program and train them to become psychiatrist- scientists in basic, translational, and human subjects research by integrating clinical and research rotations, didactics, and expert mentoring in an individualized training pathway. 2. To provide early, dedicated, and flexible time and training for research over the course of residency. B.4 Training and Professional Development Activities: During this reporting period, the Duke Psychiatry Physician Scientist Track Program (Duke-PPST) provided robust training and professional development opportunities tailored to the program's objectives. These included opportunities for residents to engage in advanced skills development and professional growth through structured activities and individualized support. 1. Training Activities: o Residents engaged in one-on-one mentorship with faculty who provided guidance on research methodologies, career planning, and professional skill-building. o Workshops were held to develop competencies in critical areas, such as scientific writing, computational techniques, and research design. o Residents actively participated in interdisciplinary seminars aimed at deepening their understanding of cutting-edge methodologies and their applications in psychiatry research. 2. Professional Development Activities: o Professional growth was supported through participation in workshops and external conferences that broadened residents’ exposure to the latest research trends and fostered networking opportunities within the field. o The program emphasized the importance of wellness and work-life balance, incorporating activities designed to enhance personal and professional sustainability during residency training. Our structured combination of training and professional development opportunities ensures that participants not only gain technical expertise but also develop as well-rounded psychiatrist-scientists equipped for future leadership in their field. Duke University establishes Individual Development Plans (IDP) for postdoctoral researchers (scholars, trainees and fellows) and graduate students upon entry into the training programs. The IDP documents career objectives and specific measurable goals through a yearly planning process for both professional development needs and career objectives. Written evaluations by both the trainee and the mentor are completed on a yearly basis.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY/ABSTRACT: Human cytomegalovirus (HCMV) infection is among the most common congenital infections, occurring in approximately 1 out of every 200 pregnancies. Congenital HCMV infection can lead to a wide range of developmental complications including intrauterine growth restriction, sensorineural hearing loss, microcephaly, and fetal demise. To infect and directly damage the developing fetus, HCMV must cross the placenta, which is the primary barrier between maternal and fetal circulation. HCMV infection has also been proposed to impair several critical functions of trophoblasts, the predominant cell type of the placenta, suggesting HCMV infection could indirectly damage the fetus through placental dysfunction. However, due to limited models of HCMV infection at the maternal-fetal interface we currently have an incomplete understanding of 1) how trophoblasts defend against HCMV and 2) how HCMV infection alters normal trophoblast function. I propose to use trophoblast organoids (TOs) to model HCMV infection. TOs are a novel model that recapitulates many key aspects of the cellular and immunological complexity of the human placenta. Our lab has reported that TOs are refractory to HCMV replication. My preliminary data demonstrate that this occurs post-viral entry, signifying that trophoblasts may express cell-intrinsic factors that restrict HCMV replication. I have preliminarily identified that the transcription factor DUX4 and its target gene TRIM43 (a recently described herpesvirus restriction factor) are uniquely induced following HCMV infection in TOs, suggesting this pathway may contribute to trophoblast resistance to HCMV replication. Aberrant expression of DUX4 in adult muscle cells alters normal cellular function and drives pathology in facioscapulohumeral muscular dystrophy. My preliminary data suggest that DUX4 expression in trophoblasts may similarly impair normal trophoblast function. The objectives of this proposal are to identify factors that restrict HCMV replication in trophoblasts, uncover the impacts of HCMV infection on normal trophoblast function, and build upon TOs as a model of HCMV infection at the maternal-fetal interface. The specific aims of this proposal are 1) to determine if TRIM43 and DUX4 restrict HCMV replication in TOs and 2) define the impacts of HCMV-induced DUX4 expression on trophoblast function. Aim 1 will define the expression kinetics of TRIM43 and DUX4 in TOs following HCMV infection. It will then test whether TRIM43 and DUX4 restrict HCMV replication in TOs. Finally, this aim will test whether TRIM43 and DUX4 restrict the replication of other teratogenic herpesviruses in TOs. Aim 2 will map the trophoblast cell type- specific transcriptional response to DUX4 expression to define potential mechanisms by which HCMV can cause dysfunction in trophoblasts. Aim 2 will test whether HCMV-induced DUX4 expression impairs trophoblast differentiation as well as key functions of trophoblasts such as hormone secretion and invasion. Completing the proposed aims will provide training in several key areas, better equipping me to progress towards independence as a scientist.

NIH Research Projects · FY 2025 · 2024-06

ABSTRACT Prognosis for patients with small cell lung cancer (SCLC) remains poor due to high rates of metastatic disease, vast intra-tumoral heterogeneity, limited therapeutic options, and rapid development of therapeutic resistance. Our lab has recently shown that Abelson (ABL) family kinase inhibitors are effective in the treatment of SCLC metastases in vivo. Targeted combination therapies can minimize cytotoxic adverse events and impair the development of resistance. Thus, we performed a whole-genome CRISPR/Cas9 loss-of-function sensitization screen to identify synergizing combination therapy targets with the ABL allosteric inhibitor ABL001. Consistent with prior observations that ABL kinase inhibition dysregulates mitochondrial and metabolic function in lung adenocarcinoma, numerous top sensitizers to ABL kinase inhibition revealed by the screen are involved in the processing and clearance of metabolic products. Preliminary validation of the screen has shown that inhibition of organic anion MCT transporters synergizes with ABL001 to cause cell death as a consequence of a mitochondrial dysregulation phenotype observed in lung cancer cells following treatment with allosteric ABL kinase inhibitors. Furthermore, targeted metabolomic sequencing revealed that following combination treatment with ABL and MCT inhibitors, the levels of numerous metabolite species become significantly dysregulated. These changes are consistent with the stalling of glutaminolysis and are most strikingly characterized by a significant decrease in glutathione, an important mediator of metabolic stress responses. My hypothesis is that the metabolic stress induced by inhibition of the ABL kinases when paired with MCT inhibition, results in the stalling of glutaminolysis and the subsequent loss of glutathione, thereby promoting ferroptosis, and contributing to the synergistic cell death phenotype observed. The aims of this proposal are 1) to determine how the ABL kinases mediate homeostatic metabolic function and define the mechanism of metabolic dysregulation following ABL kinase inhibition, 2) to determine the mechanism of dysregulation of glutaminolysis following combined ABL kinase and MCT inhibition, and 3) assess the extent to which this combined therapy contributes to cell death via ferroptosis. Approaches to address these objectives include metabolic profiling via stable isotope tracing of glucose and glutamine, and Seahorse assays to measure oxidative and glycolytic energy metabolism. We will also assess the extent to which this combination treatment induces ferroptotic cell death by in vitro drug- treatment and isogenic knockout experiments. Subsequently we will perform in vivo drug treatment experiments to assess the efficacy of combined ABL and MCT inhibition in the treatment of SCLC in mouse models. This investigation into the role of the ABL kinases in metabolic dynamics will explore a novel mechanism of regulation of mitochondrial homeostasis by the ABL kinases, as well as evaluate a potential treatment modality for patients with SCLC.

NIH Research Projects · FY 2025 · 2024-06

Healthy skeletal muscle is capable of multiple cycles of regeneration in response to small tears that occur during daily activity and exercise. Central to this regenerative capacity are the muscle stem cells termed satellite cells (SCs), which reside in specialized tissue “niches” and in response to injury activate, proliferate, and fuse to form new or repair damaged muscle fibers. Dysregulation of SC niche leads to loss of muscle repair ability found in aging, congenital neuromuscular and metabolic disorders, and acquired diseases such as cancer or volumetric muscle loss. Function of healthy SC niche is regulated by a complex interplay of biochemical and biophysical inputs from surrounding extracellular matrix, muscle fibers, blood vessels, neurons, immune and connective tissue cells. While specific roles of these regulatory mechanisms are difficult to dissect in vivo, engineered 3- dimensional (3D) skeletal muscle tissues offer the opportunity to recapitulate and systematically study SC niche function in vitro. However, current engineered muscle tissues lack the complex heterocellular milieu of native muscle, along with the factors known to control SC niche homeostasis and response to injury. Our group has been the first to engineer 3D functional human skeletal muscle tissues (“myobundles”) from primary myoblasts and induced pluripotent stem cells and utilize them for studies of muscle exercise, metabolism, inflammation, drug response, and modeling of congenital muscle diseases. While in human myobundles made of myogenic cells, SCs attain a peri-myofiber position, quiescent phenotype, and heterogeneity akin to those of native SCs in vivo, their regenerative response is less robust than observed in native skeletal muscle. We thus propose to increase the cellular complexity of SC niches in myobundles to approximate that of native skeletal muscle by incorporating capillary networks and functional motoneurons known to support niche function in vivo. The improved biomimetic nature of vascularized and innervated myobundles developed in this project will allow us to further investigate cell-specific roles and cross-cellular interactions regulating the human SC niche maintenance, heterogeneity, and response to muscle exercise and injury. Ultimately, we anticipate that this novel heterocellular model of engineered skeletal muscle tissue will enable improved in vitro modeling, mechanistic, and therapeutic studies of human muscle disorders involving dysregulation of SC niche.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY Building realistic models for disease transmission is deeply challenging. While classic epidemiology models are powerful for building general insight, real epidemics rarely meet model assumptions. Network-based models promise greater accuracy, but depend on data that are difficult and expensive to collect and simula- tion toolkits that either make the same simplifying assumptions of classic models or build realism in largely ad hoc ways. Here we leverage community science to build a collective repository for network data and sim- ulation code to allow multiple investigators easier access to a wider and more diverse data foundation. In Aim 1, we will build a secure-but-shareable repository of village and rural community networks to serve as a general (and ultimately expandable) resource for disease simulation modeling. Village network data have been collected by multiple investigator teams, with an initial literature search yielding over 1000 village net- works covering over 80,000 unique people. We will regularize the data structure and harmonize data con- tent to provide a composite contact-propensity score necessary for modeling disease. Rural settings are at significant risk of zoonotic spillover and are thus a key study setting to understand early-phase outbreaks that could lead to future pandemics. Our repository leverages advances in secure data storage and sharing that allow us to automate the production of data use agreements for sharing and distributing sensitive data. In Aim 2, we similarly extend the model toolkit by (a) providing tools to automatically link deposited data to extant disease simulation packages (EpiModel) and (b) providing an extendable network agent-based simu- lation codebase that can model multiple types of pathogens, agent responsiveness to disease, competing information flow, and policy interventions. The toolkit will be modular, with multiple examples so that it is easy to use and customizable for investigator-driven analyses of disease spread for multiple types of patho- gens, accommodating dynamic changes to the network as a result of agents’ real-time behavioral adapta- tions to disease and information flow. In Aim 3, we will run two illustrative computational experiments that create the foundation for a future substantive R01 on the conditional effects of behavior responsiveness by network position and overall structure. First, we will examine how different levels of disease-relevant cau- tious behavior - avoiding contact to stay safe - interact with network cohesion to shape disease trajectories. Second, we will examine how multiple information and disinformation flows compete over real networks and how their effect on behavior promotes disease spread. This project will make significant advances in the re- search community’s ability to build realistic models that integrate actor attributes, interests and behavior with disease and network structure for understanding and predicting future outbreaks by providing a public resource that can leverage past data collection and modeling investments in new ways.