Emory University

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT This study is responsive to the Notice of Special Interest (NOSI) NOT-OD-24-079 “Women’s health research” objectives to “advance research to reduce health disparities and inequities affecting women’s health, including those related to race, ethnicity, age, socioeconomic status, disability, and exposure to environmental factors and contaminants that can directly affect health." Globally, more than 250,000 women die from complications related to pregnancy and childbirth. The World Health Organization estimates that almost 95% of these deaths occur in low- or middle-income countries, with most fatalities considered preventable. Worldwide, many women employ traditional methods, including medicinal plants, to support their postpartum health, particularly when biomedical healthcare is unavailable. These plants are typically prepared as topical washes or baths to prevent infection and promote wound healing after birth. Therefore, the phytochemicals present in these plants come into direct contact with the vagina, including epithelial cells and beneficial or pathogenic vaginal microbes. Many of the plants used in these preparations are globally recognized medicinal plants that are shared across cultures and geographic regions. Furthermore, these shared plant species are often prepared in herbal mixtures with each other, along with other botanical ingredients, as postpartum washes. Since these plants are often combined for this purpose, they may have synergistic properties that support their ethnobotanical use. Due to their global ethnobotanical significance, there is an urgent need to assess these plants and traditional preparations for their efficacy and safety concerning postpartum women’s health. While the prioritized species from our preliminary data are generally well-studied medicinal plants, they have not been investigated, alone or in herbal mixtures, for their effects on vaginal epithelial cells and common puerperal pathogens such as Gardnerella vaginalis and Streptococcus spp. In this proposal, we aim to evaluate plants and popular traditional preparations for their impact on the vaginal ecosystem, including vaginal bacteria and epithelial cells. We hypothesize that the medicinal plants used in postpartum herbal washes contain bioactive compounds that support their traditional use for postpartum recovery. To accomplish these goals, we propose the following specific aims: 1) Assess the in vitro effects of popular medicinal plants on postpartum women’s health; 2) Assess the synergistic effects of traditional herbal mixtures on postpartum women’s health. Both aims will implement cutting-edge analytical techniques and data processing methods, such as interaction metabolomics, and microED for the structural elucidation of bioactive compounds. We anticipate that these studies will provide objective, evidence-based information on popular medicinal plants and herbal preparations in the context of postpartum women’s health and build upon my foundation as an independent researcher, aiming to advance public health in marginalized communities.

NSF Awards · FY 2025 · 2025-09

Many types of disease can be treated with ablation, a medical procedure which applies energy to destroy small regions of tissue that do not behave normally. Ablation therapy can be used to treat conditions like arthritis, uterine fibroids, and cancer. It can also treat disruptions of the heart’s regular rhythm, such as atrial fibrillation. Ablation procedures can be difficult to perform, and sometimes multiple treatments may be necessary. A deeper understanding of exactly how the settings associated with the ablation procedure affect the biological tissue could lead to better results. This project aims to improve the understanding of radiofrequency ablation’s interactions with heart tissue through a combination of theory, multi-physics and machine-learning models, and experiments. To ensure the experiments reflect the differences in tissue structures and properties of real patients, tissue from human hearts no longer needed after being replaced by transplants will be used when possible. Medical doctors will help assess the practical significance of the project’s results. This study has the potential to lead to improved ablation treatments and patient outcomes, and the new methodology can be extended, with minor adaptations, to other types of diseases. Educational components include training of graduate and undergraduate students, contributions to undergraduate and graduate courses, and engagement of the general public with interactive programs available through a website. Radiofrequency ablation (RFA), used for a wide variety of physiological systems, faces limitations from an imprecise understanding of ablation and tissue interactions, along with challenges in optimizing the procedure given the many parameters associated with ablation and patient variability. This project aims to develop and validate a detailed multi-physics mathematical RFA model with an unprecedented level of accuracy and analysis. It will focus on cardiac tissue, but the tools can be adapted for other biological tissues and ablation therapies. First, the novel computational model will include advanced methods of domain decomposition and model reduction to address the multi-physics nature of the problem and will incorporate important physiological parameters of ablation-tissue interactions. Second, the model will be enhanced by rigorously integrating the sizes, thicknesses and thermal profiles of ablation lesions in cardiac tissue from varying thermal doses, contact angles, and pressures and by comparing with experiments. This project will be enhanced by using optical-mapping methods during ablation in live hearts, including live human explanted hearts from patients undergoing heart transplants, to simultaneously quantify the extent and sensitivity of the ablation at different tissue depths in real time as a function of ablation parameters. This information will enable continuous refinement of the computational model and accurate sensitivity analysis. Finally, simulations and experiments will be integrated to assess how ablation lesions will effectively terminate disorganized electrical wave propagation during fibrillation. The mechanistic RFA model will provide highly accurate predictions of ablation parameter effects on the success rate of terminating cardiac fibrillation. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Sepsis affects nearly 50 million people worldwide each year and the mortality rate for patients admitted to the intensive care unit (ICU) is between 20 and 30%. There is clinical need to understand this pathophysiology which causes the organ failure and high rates of mortality in order to identify efficacious therapies. Decreased microvascular perfusion and endothelial cell (EC) injury are known to be involved but the mechanisms underlying them remain incompletely studied. EC injury in sepsis promotes a change to a pro-adhesive, pro- thrombotic cell phenotype. Disturbances in microvascular rheology – the biophysical behavior of blood in the smallest blood vessels as a result of red blood cell (RBC) aggregation and cell membrane deformability – have been observed in patients with sepsis and contribute to reduced microvascular perfusion. Given the EC layer’s mechanosensitive nature, the central hypothesis for this project states that changes in microvascular rheology contribute to EC injury and are predictive of organ failure and mortality in patients with sepsis. It is further proposed that through manipulation of patient rheology with RBC and plasma transfusion we can augment this injury specifically to improve perfusion and reduce microvascular thrombosis. Using state of the art microfluidics assays, this project will characterize how RBC aggregation and membrane deformability affect EC expression of adhesion molecules and anti-coagulant factors using whole blood samples from patients admitted to the ICU with sepsis (Aim 1.1). Clinical correlates of these experiments will be defined through unbiased and supervised class analysis modeling using machine learning (ML) approaches to determine the impact of rheology (Aim 1.2). An array of RBC and plasma transfusions will be performed to assess the impact on measured rheologic parameters of patient samples and identify optimal transfusion strategies to reduce the risk of micro-thrombosis formation (Aim 2). The expected finding from this project is that blood from patients showing increased RBC aggregation and reduced RBC membrane deformability will induce greater levels of EC injury and class analysis will identify a group of patients with a hyperinflammatory and disturbed rheology endotype as a high risk group for severe organ injury and mortality. It is also expected that the patient samples which improve in rheologic measurements with transfusion will also demonstrate reduced microvascular thrombosis burden. The long term goal of this project is to facilitate the principal investigator’s career towards becoming an independently funded physician scientist studying microvascular physiology and thrombosis in pulmonary and critical illness. The short term goal is for the principal investigator to gain expertise in EC transcriptomics, transfusion and coagulation medicine, and ML approaches to answer complex clinical questions.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide. Hypertension (HTN) is the leading modifiable risk factor for death from ASCVD. HTN is a mechanistically heterogenous disease with heterogenous treatment response and without robust biomarkers of disease control, complicating treatment and motivating us to understand the pathophysiology of HTN at the molecular, cellular, and physiologic levels. Mechanistically, endothelial cell (EC) dysfunction is linked to both HTN and atherosclerosis via multiple pathways. In the vasculature, stable blood flow (s-flow) drives healthy, atheroprotective EC functions (including nitric oxide / redox signaling, barrier function, and anti-inflammatory programs) via the action of flow-sensitive genes and proteins. Our lab has identified one such flow sensitive gene Heart of glass 1 (HEG1) which plays a critical atheroprotective role regulating the activity of master transcription factors KLF2/4, and is also secreted from the cell in response to stable flow. Remarkably, we have shown that inducible, EC-specific knockout of HEG1 in mice causes hypertension and accelerated atherosclerosis relative to controls in a Western diet and PCSK9 background. Other groups have shown that in human patients, reduced levels of circulating HEG1 in the blood are associated with multiple disease processes, including HTN, dyslipidemias, as well as altered liver and kidney function. The mechanisms underlying HEG1-dependent hypertension and atherosclerosis are elusive. Moreover, the role of secreted HEG1 (sHEG1) in HTN and atherosclerosis is completely unknown, and it is unknown whether sHEG1 might drive ASCVD, or potentially serve as a useful biomarker of EC dysfunction in US patients with cardiovascular disease. In Aim 1 we will define the cellular and physiologic mechanisms of HEG1- dependent hypertension. We will determine the role of HEG1 in vascular reactivity and arterial stiffness employing in vivo and ex vivo approaches. We will determine the role of HEG1-dependent HTN in atherosclerosis progression using a pharmacologic approach in vivo. We will define the role of HEG1 in EC transcriptional reprogramming using scRNA-seq in our inducible, EC-specific HEG1 knockout mouse (HEG1-iECKO). In Aim 2 we will Determine the role of circulating HEG1 as a regulator or biomarker of EC function. We will perform cardiometabolic phenotyping of our HEG1-iECKO mice, interrogating their cardiac, renal and hepatic function. We will determine whether secreted forms of HEG1 are sufficient to rescue the HEG1-iECKO HTN and atherosclerotic phenotypes, and we will validate HEG1 as a potential biomarker for ASCVD using patient specimens. Together, these aims will define novel mechanistic connections between EC function, HTN and atherosclerosis, laying the groundwork for novel therapies. Moreover, this proposal will allow me to develop expertise in cardiovascular research and build a strong foundation for an independent research career.

NIH Research Projects · FY 2026 · 2025-09

Project Summary/Abstract Encopresis (fecal incontinence) and enuresis (urine incontinence) are prevalent in autistic youth and can have a negative impact on quality of life (Kroeger et al., 2009). Evidence supports behavioral interventions for enuresis. However, encopresis persists despite successful intervention for enuresis for a subset of autistic youth (Lomas Mevers et al., 2018). Unfortunately, the timeline for achieving fecal continence after successfully completing enuresis treatment is unclear and there is no available evidence on which individuals are likely to acquire fecal continence independently after urine treatment versus those who will continue to experience encopresis and require additional intervention. For those individuals who do require specific intervention for encopresis, our group has developed and tested the Multidisciplinary Intervention for Encopresis (MIE), which integrates physiological mechanisms (resolution of constipation before treatment and use of suppositories in treatment, if needed) and behavioral mechanisms (reinforcement of continent bowel movements). Randomized clinical trials (RCTs) of MIE have demonstrated feasibility, acceptability, and efficacy for improving encopresis with minimal side-effects when implemented in a specialty clinic with trained therapists. Unfortunately, this service model poses access barriers - especially for children in rural areas. This study aims to address these research gaps by assessing the progression from urine treatment to BM continence and evaluating a novel caregiver-mediated service model of MIE (CM-MIE) to improve accessibility. We will recruit two groups of participants: (a) autistic youth with both enuresis and encopresis and (b) autistic youth with encopresis alone. Those with both enuresis and encopresis (N=70) will enter a pre-randomization phase consisting of enuresis treatment and a monitoring period to assess fecal continence. This pre- randomization phase will allow determination of what proportion of youthbecome continent for bowel movements following enuresis treatment without additional intervention and how long after enuresis treatment this fecal continence emerges (Aim 1). We will also analyze participant characteristics that might relate to acquiring fecal continence in this phase (Aim 2). Those who continue to experience fecal incontinence in the pre-randomization period will join the participants who entered the study with encopresis alone and enter the randomized phase of the study (N=60; 30 per group) comparing CM-MIE to a parent education (PE) program focused on encopresis. Outcomes of the RCT (Aim 3) are the Clinical Global Impression – Improvement Scale rated by a treatment- blind Independent Evaluator and caregiver stress measured by the Caregiver Strain Questionnaire. An exploratory aim will evaluate participant characteristics that impact response to encopresis treatment. This innovative study will be the first to evaluate the progression from enuresis treatment to fecal continence in well- characterized autistic youth and the first to evaluate a caregiver-mediated intervention for encopresis.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Despite countless significant advances in the field of cardiovascular disease, it remains the number one cause of death worldwide. Several systemic risk factors which increase disease risk and include hypertension, high cholesterol, obesity, diabetes, smoking, and chronic inflammation. An additional local risk factor is disturbed blood flow (d-flow), which activates the endothelium to permit of atherosclerosis, and is accelerated when other risk factors are present. Despite our best efforts to treat these conditions to improve outcomes, cardiovascular disease remains the number one killer, which suggests that there remain residual unaddressed risk factors. We have identified through previous studies using the partial carotid ligation (PCL) model of d-flow causing atherogenesis that CCAAT/Enhancer Binding Protein β (C/EBPβ), a protein previously identified to play critical roles in development, cell differentiation, and inflammation, was upregulated at the mRNA level in d-flow exposed inflamed endothelial cells in vivo. We found in orthogonal studies that C/EBPβ was upregulated at the protein level in regions of d-flow, and that the compared to regions of stable flow, that the protein had localized to the nucleus, suggested that it was playing a role in downstream signaling and transcription. Three isoforms comprise C/EBPβ, which is translated from a single intron. The first isoform is LAP*, the full length protein, with activating and repression domains, the second isoform is LAP, which is nearly identical to LAP* but lacks 23 amino acids (and one of the activating domains) at the N terminal region. The short isoform is LIP, which lacks all activating domains and is thought to have a repressive role on the function of LAP* and LAP. We found that flag-tagged LIP isoform co-immunoprecipitated with the Protein Subunit Beta type-9 immunoproteasome component (PSMB9, alternatively named LMP2) in vitro, which notably, has also been implicated in atherosclerosis. Finally, we found that in contrast to stable flow, d-flow induced PSMB9 activity in vitro. Given these findings, we will set out to define the role of C/EBPβ and PSMB9 in atherosclerosis. We will determine whether C/EBPβ and PSMB9 are required for endothelial cell inflammation caused by d-flow in vitro using CRISPR-i and small molecule inhibition. We will employ a mouse model of endothelial-specific C/EBPβ or PSMB9 deletion combined with PCL and hypercholesterolemia to determine if these proteins are required by endothelial cells for the propagation of disturbed blood flow leading to endothelial inflammation and atherosclerosis in vivo. Finally we will determine whether those two proteins are over-expressed in endothelial cells from atherosclerotic regions compared to healthy control regions in human coronary arteries. We hypothesize that C/EBPβ is a key protein required for atherosclerosis, and that it exerts its pro-atherogenic effects by binding and activating the downstream PSMB9 immunoproteasome. We hope that our findings will further elucidate unaddressed risk factors which contribute to cardiovascular disease, and will lead to improved treatments for the number one cause of death.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Mpox, caused by the orthopoxvirus mpox virus (MPXV), became an infectious disease of worldwide concern following a 2022 global outbreak in which more than 80,000 cases were confirmed in more than 100 countries, mostly in countries outside the endemic regions of West and Central Africa. As reported in April 2024, there are currently record numbers of infections in the Democratic Republic of Congo, nearly 400 suspect cases reported each week. The circulating strain appears particularly deadly, with ~1 in 10 patients dying, appears to spread in new ways, and is able to evade diagnostic testing. Because of this and the risk of future outbreaks and global spread of mpox, there is a need to be prepared through the development of antiviral therapies targeting MPXV. Current therapies, comprised of tecovirimat (TPOXX), cidofovir (CDV), and brincidofovir, have concerns with toxicity and potential for emergence of drug resistance. Therefore, there are currently no mpox treatments that are both highly potent and well-tolerated. Research done by our lab has shown that the repurposed compounds tenofovir alafenamide (TAF) and adefovir dipivoxil (ADF), which are acyclic nucleoside phosphonates, inhibit MPXV. However, these compounds should be tested for the potential for antiviral resistance to emerge before they could be used in animal studies and clinical trials. In this proposal, my goals are to (Aim 1) identify and validate mutations in orthopoxviruses that confer resistance to acyclic phosphonates, (Aim 2) characterize the biochemical mechanisms of inhibition by and resistance to acyclic phosphonates, and (Aim 3) evaluate combination therapies to prevent the emergence of resistance. These studies will reveal how orthopoxviruses evolve resistance to TAF and ADF, give insights into downstream studies to minimize potential for resistance, and further my training and skills as an independent research scientist.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Alcohol-associated liver disease (ALD) accounts for approximately 45% of liver disease related deaths in the United States. However, there are no treatments for this significant health problem. A better understanding of the mechanisms underlying the progression from alcohol associated steatosis to hepatitis and cirrhosis would potentially lead to the development of novel therapeutic strategies for ALD treatment. Mitochondria plays an important role in supporting the oxidative metabolism of alcohol and acetaldehyde by expressing aldehyde dehydrogenase 2 (ALDH2) and regenerating NAD+, an essential cofactor for ALDH2 as well as alcohol dehydrogenase (ADH). Mitochondrial dysfunction is a hallmark change in chronic alcohol abuse and mediates exacerbated liver injury advancing the progression of ALD. However, the molecular foundation underlying ALD- associated mitochondrial abnormality remain to be elucidated. Iron is critical for mitochondrial respiration dependent on the biogenesis of iron-sulfur cluster (ISC) that mediates electron transfer in mitochondrial complex I-III. Our preliminary study identified that divalent metal transporter 1 (DMT1), an iron transporter that mediates endosomal iron exit and mitochondrial uptake, and frataxin (FXN), an essential mitochondrial iron chaperone that mediates ISC biogenesis, were markedly decreased in the liver of human patients with acute-on-chronic alcoholic hepatitis. This finding suggests that chronic alcohol consumption induces functional iron deficiency in the hepatocytes due to defective ISC biogenesis. Moreover, mice with hepatocyte-specific knockout of DMT1 displayed significantly increased liver injury and impaired alcohol metabolism. We thus hypothesize that chronic alcohol abuse induces hepatic FID-dependent mitochondrial dysfunction and impairment of alcohol metabolism promoting the progression of ALD. In Aim 1, we will identify the signature changes of hepatocellular iron metabolism in acute versus chronic alcohol drinking by utilizing chronic-plus-acute binge drinking mouse model and human liver samples and the cutting-edge multiplex microscopic analysis. Aim 2 will prove the detrimental role of functional iron deficiency as well as hepatic absolute iron deficiency in the pathogenesis of ALD by utilizing multiple hepatocyte-specific knockout mouse models. Aim 3 will attempt to unveil that endoplasmic reticulum stress of the hepatocytes induces DMT1/FXN downregulation impairing mitochondrial iron acquisition and ISC biogenesis in ALD. This exploratory study will demonstrate a paradigm-shifting concept that functional iron (ISC) deficit exerts strong adverse effects on alcohol-induced liver injury, shedding novel light on the development of new therapeutic modalities against ALD.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Michael Lowe, MD, MA, Associate Professor of Surgery and Director of the Melanoma Program at Winship Cancer Institute, seeks additional support to advance the institution’s participation in NCI-sponsored clinical trials. His ongoing contributions, trajectory of trial participation, emerging leadership, and exciting ideas make him an indispensable asset to Winship’s NTCN participation. Dr. Lowe is quickly become a nationally recognized leader in surgical oncology and cutaneous malignancies, and he is driven to bring as many concepts as possible through the NCI cooperative group mechanism. He is a member of the Winship Clinical Council and Protocol Review and Monitoring Committee and serves as the Director the Melanoma Program and Chair of the Melanoma Working Group. He is Clinical Director of the Morningside Center for Innovative and Affordable Medicine, which sponsors clinical trials investigating repurposed drugs in cancer. He is a member of the ECOG-ACRIN Melanoma and Surgical Committees and serves as the ECOG-ACRIN liaison to the SWOG Melanoma Committee and the liaison of the Melanoma Committee to the Surgery Committee. He is surgical chair of three NCTN clinical trials (EA6183, EA6212, and S1801) and is the ECOG champion of S2015. He serves as site PI of S1801 and S2015 and is one of the highest NCTN enrolling investigators at Winship. He is also site PI of numerous investigator-initiated and industry-sponsored clinical trials. Dr. Lowe has established himself as a dedicated researcher with a special interest in advancing concepts through the NCTN cooperative group mechanism. Over the next five years with support from this grant, he plans to increase institutional participation in NCI-supported research and personally propose and develop two specific trials. He will advocate for less traditional clinical trialists like surgeons, radiation oncologists, radiologists, and dermatologists to participate in the NCTN trials. Dr. Lowe will also strongly advocate to NCTN leadership to implement a more systemic process of patient engagement in the design of NCI-supported trials, including patient-centered focus groups and/or surveys designed to assess the patient’s perspective on the trial design. Given his experience in repurposed drug trials, he will advocate for disease-specific repurposed drug trials to be opened in the NTCN committees and work towards developing a Repurposed Drug Subcommittee within NTCN. Lastly Dr. Lowe will work with Winship CTO leadership to identify causes of NCTN trial opening delays and work on solutions to resolve them. He is motivated to make an even bigger impact through NCI-supported research, and this award would make a considerable impact on his ability to do so. His passion for improving the lives of patients through clinical research make his potential capabilities limitless, and providing the additional time provided by this award will help maximize that potential.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Glucagon-like peptide-1 receptor agonists (GLP-1RAs), which are indicated for type 2 diabetes, obesity, and cardiovascular disease, have been suggested as potentially effective treatments for alcohol use disorder (AUD). However, evidence from observational studies and randomized controlled trials has been limited. One cohort study found that GLP-1RAs may be associated with lower risk of subsequent hospitalization for AUD or purchase of medications for AUD (MAUD) compared to other T2DM medications. However, since this study was conducted in Denmark, the findings are not generalizable to patients with AUD in the United States. While trials of GLP- 1RAs for AUD are currently underway, these small trials will not provide direct comparative evidence across MAUD, and are likely to underrepresent older, rural, and racially and ethnically minoritized populations. These limitations have stimulated interest in using real-world data, causal inference methods, and novel machine learning subgroup identification approaches to generate evidence to guide the selection of optimal AUD treatment regimens in clinical practice. Therefore, we will use administrative claims data and linked electronic health record and laboratory result data from OptumLabs® Data Warehouse (OLDW), which includes health insurance claims for all Medicare fee-for-service enrollees and for commercial and Medicare Advantage enrollees across the United States, to generate evidence relevant to the use of GLP-1RAs in real-world clinical practice. We have identified 13,237 patients with AUD in OLDW who were prescribed GLP-1RAs from 2011- 2023. In Aim 1, we will follow the target trial emulation framework, which uses counterfactual theory to compare the effects of sustained treatment strategies, to evaluate the comparative effectiveness and safety of GLP-1RAs with both on-label (acamprosate, disulfiram, naltrexone) and off-label (gabapentin, topiramate, and varenicline) MAUD. These analyses will address the lack of direct comparative evidence between GLP-1RAs and other MAUD and will complement ongoing GLP-1RAs trials by providing evidence across more diverse and generalizable populations and practice settings with longer observation periods. In Aim 2, we will examine trends in GLP-1RA utilization among subgroups of patients with AUD, with a focus on potential differences in access to and use of these medications by key demographic and clinical characteristics, including race and ethnicity, rurality, gender, age, and co-morbidities. These analyses are essential to inform our understanding of potential inequities in GLP-1RA use among patients with AUD. In Aim 3, we will use traditional and novel machine learning subgroup methods to identify phenotypes of AUD patients more likely to experience beneficial or harmful outcomes with GLP-1RAs or other MAUD in real-world clinical practice. Identifying phenotypes of AUD patients will help guide clinical decisions, support higher quality AUD care, and inform the design of future clinical trials of GLP-1RAs among patients with AUD.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Recurrent wheezing in preschool children is highly problematic and results in disproportionate morbidity, with twice the rate of emergency department visits and three times the rate of hospitalization compared to older children. Unfortunately, many preschool children with recurrent wheezing are socially disadvantaged and have significant barriers to wheezing care. Consequently, many disadvantaged preschool children with recurrent wheezing have a high symptom and exacerbation burden that compromises quality of life (QOL). However, there is a paucity of research on symptoms and QOL in this young age group and even fewer studies of disadvantaged preschool children, who remain grossly underrepresented in research yet are at highest risk for poor wheezing outcomes. There remains a critical need to understand how symptoms relate to social determinants of health (SDOH), the biological factors associated with SDOH and QOL, and the factors influencing care. Our central hypothesis is that SDOH promote epigenomic modifications resulting in a sustained state of inflammation, which, in response to a respiratory virus, increases respiratory symptoms and impairs QOL. For this study, we will enroll a heterogenous sample of preschool children with recurrent wheezing aged 12-59 months (N=140) that is enriched for social disadvantage and pursue three specific aims: Aim 1: identify symptom profiles and their associations with SDOH and QOL over 12 months in preschool children with recurrent wheezing; Aim 2: Identify the epigenomic and transcriptional pathways associated with SDOH, symptoms and QOL; and Aim 3: Identify factors related to differential experiences of wheezing symptom management. Through this study, we hope to 1) understand the whole-person experience of recurrent preschool wheezing, 2) identify the social and biological attributes of differing symptom profiles, 3) identify care barriers, and 4) understand moderation by resilience, which could be targeted in future interventional studies aimed at improving QOL in this population. The proposal leverages established and productive scientific collaborations and the state-of-the art scientific infrastructure at Emory University, Children’s Healthcare of Atlanta, and Duke University to strategically investigate health equity and respiratory outcomes for preschool children with recurrent wheezing.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Integrin adhesion complexes (IACs) play a critical role in cardiomyocyte attachment to the extracellular matrix and in force transduction—both essential processes required for effective blood pumping. Mutations in several genes encoding IAC proteins are associated with cardiomyopathies, conditions with 50% lethality rate within five years of diagnosis. Notably, nearly half of known cardiomyopathy cases lack an identifiable genetic mutation, underscoring an urgent need to discover additional genes linked to the disease. To address this gap, we translated our findings from C. elegans to a mammalian model by generating a cardiomyocyte-specific knockout of β-PIX (β-PIX-cKO) in mice. In C. elegans, we identified PIX-1 (the β-PIX ortholog) as a guanine nucleotide exchange factor that regulates IAC assembly in muscle cells. β-PIX-cKO mice develop dilated cardiomyopathy by 8-months of age and exhibit premature lethality between 9- and 11-months. Additionally, I localized β-PIX to three key cardiomyocyte structures where IACs are present: costameres, intercalated disks, and Z-disks. Our research aims to identify the specific small GTPase and GAP involved in the PIX pathway in mouse cardiomyocytes. To this end, we will establish an overexpression model of two candidate GAP proteins, allowing us to conduct parallel studies with β-PIX-cKO mice. Using these murine models, we will examine how PIX pathway disruptions affect IAC protein localization, expression levels, and the functional adhesion strength of cardiomyocytes. These experiments will shed light on the mechanisms by which β-PIX deficiency leads to cardiomyopathy. Furthermore, our findings could support the inclusion of PIX pathway genes in genetic screens for cardiomyopathy, potentially enabling earlier diagnosis and more targeted treatments. While mutations in several IAC proteins are linked to cardiomyopathy, the mechanisms driving disease onset remain largely unknown; our model system may also offer broader insights into cardiomyopathy that develops from mutations in many other proteins.

NIH Research Projects · FY 2025 · 2025-09

Abstract When imaged using an optical microscope, a live cell will appear still, but in reality, cells are highly dynamic structures that are pulling and pushing on one another and also on their surrounding extracellular matrix. These pulls and pushes are mediated by minuscule forces – at the scale of tens of piconewtons, that are highly transient and dynamic. Nonetheless, these forces have profound impacts as they can modulate receptor conformation and function. This is akin to how a small posttranslational modification can potently activate an enzyme. For example, the rapidly fluctuating forces at the junction between an immune cell, such as a T cell, and a cancer cell can dictate the fate of the cancer cell and determine whether the T cell performs its cytotoxic functions. Despite the importance of mechanics and their dynamics there are limited methods to study forces. This is particularly the case for studying forces at the single molecule scale. My group is addressing this gap in knowledge by developing tools to map the molecular forces applied by cells. The current application will provide new tools to investigate force dynamics. The first aim will develop a universal tension sensor that can measure force loading rate with high resolution. Here we will create a library of probes with narrowed dynamic range that will validate whether loading rates are linear or dynamic and also will provide computational tools to relate force dynamics with downstream signaling. The second aim will develop tools to test the catch bond model which is a counter-intuitive enhancement in ligand-receptor binding when these complexes experience a moderate mechanical load of ~5-20 pN. This has been observed in single molecule force spectroscopy measurements and we seek to validate this observation in live cell-cell junctions using single molecule tracking of force duration and bond lifetimes. Finally, we will develop a new DNA origami probe to investigate models of anisotropic mechanosensing, where the orientation of a molecular force is thought to drive different signaling outcomes. This molecule force orientation sensor will allow us to measure force orientation in realtime. Taken together the application represents an important step toward better understanding the role of biophysical forces in cell signaling.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT South Asians (SA) make up over a quarter of the world’s population and represent one of the fastest-growing ethnic groups in the United States. SA have a disproportionately high prevalence of atherosclerotic cardiovascular disease (ASCVD) compared to other groups, which often occurs at younger ages and leads to worse outcomes. SA descent is a risk enhancer for ASCVD. Nonetheless, current prediction tools underestimate the risk in this population, likely due to underrepresentation in derivation studies. Coronary artery calcium (CAC) is a highly specific marker that enhances ASCVD prediction in diverse populations, including SA. However, implementation of CAC is limited in certain clinical settings such as remote, low-resource, or underserved communities. Our scientific premise is grounded in the critical need to identify high-risk individuals who could benefit from timely preventive interventions. Artificial intelligence (AI)-based deep learning methods have revolutionized the diagnostic potential of the 12-lead electrocardiogram (ECG-AI), a widely available and affordable tool. ECG-AI has accurately predicted CAC and identified individuals at increased risk of ASCVD, providing a practical, accessible, and scalable enhancement to the primary prevention of ASCVD. These advancements offer an opportunity to address gaps in care, particularly in underserved populations. The overarching goal of this project is to investigate the correlates, predictive performance, and clinical utility of an ECG-AI model that estimates CAC, specifically in SA, by leveraging the uniquely characterized Precision-Cardiometabolic Risk Reduction in South Asians (P-CARRS) Cohort. To achieve this goal, we propose the following specific aims: Aim 1. To investigate sociodemographic, behavioral, and biological mechanisms underlying ECG-AI-based CAC scores in SA and compare them to computed tomography (CT)- based CAC. Aim 2. To evaluate the agreement between ECG-AI-based CAC scores and CT- based CAC scores in SA as continuous measures and clinically actionable thresholds (e.g., CT-derived CAC = 0, 1–99, 100–299, >300), we will calculate model performance metrics (e.g., area under the curve, sensitivity, specificity, and accuracy), agreement metrics (e.g., concordance correlation coefficients and Bland-Altman plots), and calibration. Aim 3. We will assess the association between ECG-AI-based CAC scores derived from ECGs and incident ASCVD events in South Asians. ECG-AI will be evaluated both as a standalone and additive predictor alongside traditional risk factors while analyzing potential improvements in predictive accuracy and calibration. The proposed research is an important next step after an initial landmark finding and will also provide important training for the applicant as he seeks to train in a career in translational research. The proposed in- depth examination of this new ASCVD screening tool will not only have important public health implications for this high-risk SA group but also inspire similar investigations in other groups with disparate ASCVD outcomes. Lastly, it will set the stage for future career development awards evaluating interventions and other populations.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY: The rapid increase in painful intervertebral disc (IVD) degeneration (IDD) makes it an urgent need to develop solutions for stopping IDD progression. IDD is associated with cell senescence, chronic inflammation, loss of IVD cellularity, matrix alterations, and changes in mechanical properties. In the United States, approximately 28.6 million adults have a diagnosis of alcohol use disorder (AUD), and AUD has been associated with chronic musculoskeletal pain, including back pain, and IDD-related surgical complications after spinal procedures. Chronic back pain increases the risk of greater alcohol consumption, and increased alcohol intake is associated with higher risk of IDD. Despite the high prevalence of painful IDD and AUD, no studies exist that link chronic alcohol consumption and IDD. The overall goal of this proposal is to identify this link by elucidating the mechanisms that drive IDD during chronic alcohol misuse and therapeutically halting IDD progression. Alcohol is known to cause accumulation of reactive oxygen species (ROS) and advanced glycation endproducts (AGEs), which is the most striking evidence of oxidative damage to the IVD and is known to cause IVD matrix stiffness. We previously showed that pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma (PPAR) agonist and FDA approved drug, protects against ethanol (EtOH)-induced ROS accumulation by activating PPAR and decreasing the expression of NAPDH oxidase (NOX) 4 in alveolar macrophages. Here, we present exciting preliminary evidence that chronic alcohol consumption induces early degenerative changes by altering IVD morphology and stiffness. Aim 1 will establish the phenotype of chronic alcohol-induced IDD in mice. The effect of alcohol on IDD will be assessed for morphological, molecular, and biomechanical changes, as well as for pain. In vitro studies will evaluate the underlying pathways by exposing healthy human IVD cells to the EtOH metabolite, acetaldehyde. Effects on NOX4, ROS generation, cell senescence, and mitochondrial dysfunction will be determined molecularly and immunocytochemically and using an extracellular flux bioanalyzer. Aim 2 will test the therapeutic potential of PIO in stopping EtOH induced degenerative changes in human IVD cells using in vitro bulk-RNAseq, multiplex-ELISA, and immunocytochemistry. This project is highly significant because AUD and discogenic back pain are major burdens in the United States. New insights into mechanisms and treatments for IDD will combine mechanistic and translational studies. This study is conceptually innovative because the correlation between AUD and IDD has not been studied previously, and the use of an extracellular flux bioanalyzer to determine cell metabolic phenotype switching between glycolysis and oxidative phosphorylation in IVD cells is technically innovative. Outcomes will be impactful because PIO is an FDA approved drug and promising results can be readily translated to provide minimally-invasive treatments for people suffering from IDD, especially those with AUD.

NIH Research Projects · FY 2025 · 2025-09

The goal of this proposal is to investigate the contributors to infrared medical device errors and to develop correction algorithms to improve the accuracy of pulse oximeters and temporal thermometers in patients with acute respiratory failure. Over one million adults are admitted to intensive care units (ICUs) in the US every year for acute respiratory failure requiring mechanical ventilation. In these patients, it is essential to have accurate oxygen saturation and temperature measurements. Pulse oximeters and temporal thermometers, which measure oxygen saturation and body temperature, are the two most ubiquitous infrared devices in the ICU. However, these devices are significantly less accurate in Black patients, leading to delays in recognition and treatment of life-threatening hypoxemia and infection. There remains a gap in knowledge about the factors that contribute to racial disparities in infrared device accuracy. While it is hypothesized that infrared devices perform differently across racial groups due to differences in skin melanin, this hypothesis has not been rigorously tested in prior studies. Further, there are clinical factors such as anemia and chronic lung disease that could also affect the accuracy of these devices. There are known racial disparities in comorbidities such as anemia and chronic lung disease, which could then mediate the inaccuracy observed in infrared devices. In this proposal, we will quantify the role of melanin in association with infrared device errors in a multi-center, racially diverse cohort of critically ill patients with acute respiratory failure (Aim 1); we will use structural equation modeling to develop innovative correction algorithms that incorporate melanin, bilirubin, dyshemoglobins, age, sex, perfusion, and comorbidities to correct device errors (Aim 2); we will validate the correction algorithms and evaluate the clinical impact of the algorithms in accurately identifying clinically significant measurements (Aim 3). Through this proposal, we will develop an innovative publicly available de-identified dataset of critically ill patients enrolled across 9 ICUs in 3 hospitals with quantified melanin levels integrated with electronic health record (EHR) data that will enable researchers to investigate inaccuracies in other medical devices. Successful completion of this grant will significantly enhance our scientific knowledge of how individual patient factors influence the accuracy of infrared medical devices in real-world clinical settings. Although device development is often seen as the primary solution to addressing infrared device errors, it takes decades, is expensive, and may not comprehensively correct for all the complexities of physiology in critical illness. The ultimate public health impact of this work is developing EHR-based correction algorithms (Device+) as a complementary solution to device development. The Device+ solution will significantly impact clinical practice by improving the accuracy of vital sign measurements, which will lead to improved population-level as well as individual-level outcomes in critically ill patients.

NIH Research Projects · FY 2025 · 2025-09

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NSF Awards · FY 2025 · 2025-09

This award supports the "Conference: Advances and Connections of Modern Geometric Function Theory", which will be held at the University of Michigan, Ann Arbor, MI, October 25-26, 2025. Geometric function theory is a core subfield of mathematical analysis, and it has deep applications in many scientific fields, including physics, chemistry, biology, engineering, material science, and computer science. This conference will feature presentations from both leading experts and rising stars in the field and is designed to enhance the education of as well as foster collaboration among the participants. This will contribute to the training of the next generation of mathematicians and also help enhance the pre-eminent position of the US at the forefront of geometric function theory. In addition to plenary talks, the program includes short talks, a poster session, and an open problem session. The wide and varied array of conference participants will allow for exceptional exchanges of ideas between early-career and more established mathematicians. More information can be found on the conference website https://lsa.umich.edu/math/seminars/conference-on-advances-and-connections-of-modern-geometric-funct.html. Over the last few decades, the impact of geometric function theory is now seen in many fields including analysis on metric spaces, mappings of finite distortion, conformal geometry, nonlinear PDE, and geometric group theory. The presentations will focus on practical applications of techniques originated in geometric function theory. The mathematics discussed will address challenges within the related fields mentioned above, as well as the reciprocal influence of these areas on geometric function theory. This collaborative spirit aims to foster deeper exploration and innovation within the mathematical community to advance research in modern geometric function theory and related areas. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

The Medicare Hospice Benefit, which dictates hospice policy for most Americans, was designed based on the needs of people with cancer, a disease with a trajectory vastly different from that of heart failure (HF). Implicit in the Medicare Hospice Benefit is the assumption that people have the supports necessary to facilitate a home death. Yet, individuals with fewer financial and social resources, who experience the greatest HF morbidity and mortality, are less likely to use hospice and die at home than individuals with greater resources. Dr. Cross’s long-term career goals are 1) to use patient-centered mixed methods to identify and understand the end-of-life experiences of people with HF and 2) to develop interventions that address differences in end-of-life HF care outcomes through practice and policy change. This K01 project includes three specific aims. Aim 1 will use hierarchical multiple regression to characterize the influence of individual and hospital level factors on end-of-life HF care. Aim 2 will incorporate geographically bounded areas into hierarchical multiple regression to quantify the impact of neighborhood-based attributes on end-of-life HF care. Aim 3 will explore end-of-life HF needs and perceived opportunities to receive optimal care among adults with HF, their caregivers, and clinicians through semi-structured interviews. Dr. Cross will strengthen and address gaps in her experience through the following career development objectives: 1) acquire increased proficiency in mixed methods research, 2) develop expertise in advanced analytic methods for health outcomes research, 3) advance her understanding of the management of patients with advanced HF and the role of hospice and palliative care within the HF trajectory, and 4) acquire skills in designing, conducting, and evaluating socio-behavioral interventions. This proposal lays out a comprehensive career development plan consisting of expert mentorship, specialized coursework, and completion of a research project. Dr. Cross’s development during this four-year award will be guided by an interdisciplinary team of mentors at Emory University, led by Dio Kavalieratos, PhD, Associate Professor and Director of Research for the Division of Palliative Medicine; Neal Dickert, MD, PhD, the Thomas R. Williams Professor of Medicine in the Division of Cardiology; Shivani Patel, PhD, MPH, Associate Professor of Public Health in the Departments of Global Health and Epidemiology; and Modele Ogunniyi, MD, MPH, Professor of Medicine in the Division of Cardiology. This research training and career development plan will support Dr. Cross in achieving her goal of becoming an independent investigator in supportive cardiology and will inform the development of evidence-based solutions to improve end-of-life HF care.

NSF Awards · FY 2025 · 2025-09

This research project aims to prototype and evaluate an intelligent garment featuring an adaptive splint that clinicians can dynamically control to address the treatment goals of individuals with neurodevelopmental disabilities who engage in self-injurious behavior. This novel device will facilitate sensorimotor interaction between the adaptive splint and the individual. Additionally, the garment will communicate with therapists to enhance their understanding of the individual's responses to treatment decisions and to predict and analyze attempts at self-injurious behavior. Self-injurious behaviors in minimally verbal individuals with neurodevelopmental disorders can lead to significant physical, emotional, social, and economic challenges. Behavioral interventions currently represent the most established approach to managing self-injurious behaviors. Presently, interventions for severe cases involve individuals wearing rigid splints on their arms, which help mitigate injury risk while still allowing the behavior to occur. If successful, this research is anticipated to improve the quality of life for both patients and clinicians alike. The adaptive garment prototype will feature an active split that can adjust its mechanical stiffness in real time with a clinician-in-the-loop feedback mechanism. This research initiative has several key interdisciplinary objectives: 1) to assess the effectiveness of the first active splint designed for behavioral interventions, drawing on design and actuation principles from soft robotics, which is capable of withstanding self-injurious behaviors; 2) to address the challenge of accurately and automatically measuring the frequency, intensity, and duration of self-injurious behaviors in therapeutic settings, utilizing models developed from retrospective data gathered through ambulatory accelerometry, electrodermal activity, and photoplethysmography via a wearable biosensor, in conjunction with video data; 3) to analyze and evaluate the interactions between individuals and therapists during behavioral intervention sessions that incorporate the garment; and 4) to examine how the garment impacts therapists' decision-making processes. If successful, this research program will lay the foundation for healthcare garments capable of reasoning and modeling wearer behaviors to improve therapeutic 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.

NSF Awards · FY 2025 · 2025-09

This project uses machine learning to create a database of State of the State (SOTS) addresses from 1800 to 2016 and state-level agendas. The data collection involves collecting and cleaning the full set of speeches from governors over time. SOTS data are stored at publicly available data repositories and a website developed by the PIs. Methodologically, the project advances the study of unstructured data and the use of artificial intelligence and machine learning. The data support knowledge and scholarship related to public decision and provide a web resource for educators and journalists. This project extends the SOTS dataset that covers state-of-the-state addresses from 1800 to 2016. The PIs collect, process, and analyze SOTS speeches from years prior to 1960, using techniques developed to overcome poor quality documents implemented through software created by one of the PIs. The software applies machine learning to isolate, enhance, and extract text from hard-to-read documents, correcting document layout problems with a novel statistical approach before it runs optical character recognition (OCR). This results in a significantly higher level of accuracy than other current approaches. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-09

This award will support US-based graduate student, postdoctoral and early career investigator attendance at the RNA Localization and Local Translation conference, to be held June 30 to July 4, 2026. The meeting will be administered by the European Molecular Biology Organization and co-organized by Dorothy Lerit, Michael Kiebler, Matthew Taliaferro, and Edouard Bertrand. The format of the meeting is a combination of keynote presentations by leaders in the field, plus over 30 talks selected from submitted abstracts, 10 flash talks, and two poster sessions. Professional development programming is incorporated into the meeting agenda, designed to enhance interactions between trainees and established researchers. This meeting affords many opportunities (both formal and informal) for sharing recent research findings and exploring collaborations. This is a unique biannual meeting focusing on RNA localization and regulation that began in 1994. Recent advances on how the spatial and often developmentally-programmed localization of RNA impacts cell development and function will be highlighted in this conference. The meeting focuses on RNA transport, translation, stability and decay, and how cells regulate protein expression. The conference primarily highlights unpublished research findings and provides many experiences for young researchers to learn about the field and devise future avenues for research. The meeting will bring together scientists from around the world, and encourage career development of a new generation of researchers. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Elopement is an incredibly dangerous and prevalent behavior among individuals with autism spectrum disorder (ASD). While behavioral interventions are often effective at reducing elopement attempts, access to these services are limited, especially in areas with primarily rural or minority populations. An important resource for families, especially those with limited access to behavioral interventions, are safety toolkits. These are resources available online for parents and clinicians that include several strategies that may prevent some instances of elopement (e.g., locks on doors), improve the speed of finding a child who has eloped (e.g., identifying search teams), and reduce the potential harm following an elopement episode (e.g., teaching traffic safety). Safety toolkits have several advantages, primarily in their availability as a free resource that can be immediately provided to parents. However, results from a randomized clinical trial that incorporated safety toolkits for elopement suggest that parents of autistic children who elope may not consistently implement recommendations from these toolkits without clinician follow-up and support. Given this, it is important to modify and optimize these toolkits to improve ease of use. This project aims to use secondary data from a randomized clinical trial of a behavioral treatment of elopement to guide the development of a modified toolkit. Specifically, caregivers in the parent study completed detailed parent target problem narratives of their child’s elopement. We aim to use these narratives, along with additional participant information, to develop subcategories of elopement following analyses akin to past studies that have subtyped other topographies of challenging behavior (e.g., aggression). All caregivers in the parent study were also provided with safety toolkits, but groups differed in the amount of follow-up support provided by clinicians to complete the toolkit strategies. Thus, we aim to conduct additional analyses to determine which items from the toolkits were most likely to be implemented by parents on their own versus which were only implemented with the assistance of a clinician. These secondary analyses will be summarized and provided to a group of expert clinicians, researchers, and stakeholders (e.g., caregivers of autistic youth, autistic individuals, autism agency representatives) who will use the information to guide development of a modified toolkit that tailors recommendations to the type of elopement and service-delivery model. The end deliverable will include a modified toolkit that provides more tailored recommendations with the aim of improving usability.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Halogenation is a chemical reaction that is responsible for the introduction of a halogen atom including chlorine, bromine, iodine and fluorine (Cl, Br, I, F) into an organic compound. It has emerged as one of the most important reaction types for the selective synthesis of pharmaceuticals and biologically active compounds and for late- stage functionalization of drugs to enhance their therapeutic properties. Despite the importance of halogenation in drug development, current methods are largely reliant on reagents that are air- and moisture-senstive and/or unselective in the halogenation event, leading to the production of undesired halogenated byproducts. Enzymes are an attractive catalyst option for performing halogenation and halogenation-mediated reactions because of their unmatched selectivity and sustainability parameters. The overarching goal of my research group is to discover and develop halogenating enzymes for perfoming selective halogenation or halogenation-mediated reactions for chemical synthesis. Among the broad range of halogenase enzymes in nature, the vanadium- dependent haloperoxidase (VHPO) class of enzymes have been recognized as an attractive option for halogenation in chemical synthesis. These fascinating enzymes perform halogenation using inert halide salts and hydrogen peroxide as the terminal oxidant. Some additional notable features of VHPOs are their ease of access, tolerance to a broad range of solvents and temperatures and their ability to act on a wide range of substrate types. Over the next 5 years, the central goal of our research team is to expand the synthetic capabilities of this enzyme class in both halogenation-mediated and halogenation reactions for downstream application in the synthesis of biologically active compounds. In our first approach (Thrust A), we will use a concept referred to as enzymatic halide recycling to perform new biocatalytic oxidation and bond forming reactions. In this approach, a catalytic quantity halide salt is repeatedly oxidized by the enzyme to faciliate new bond formation using hydrogen peroxide as the terminal oxidant. In our second approach (Thrust B), we will develop a series of defunctionalative halogenation (replacing a functional group with a halogen) and halooxidation (addition of a halogen and an oxygen atom) reactions. Collectively, these approaches will provide a sustainable and selective catalyst platform for accessing intermediate and target compounds that are relevant to drug discovery and also dramatically expand the synthetic repertoire of halogenase enzymes for chemical synthesis.

NSF Awards · FY 2025 · 2025-09

NON-TECHNICAL SUMMARY: This award supports theoretical and computational research, and associated education to investigate the consequences of light interacting with materials and matter. While classical physics views empty space as truly empty, quantum mechanics reveals the vacuum as a sea of constantly fluctuating fields. These quantum fluctuations are essential to understanding how particles of light – photons – interact with matter. When light is spatially confined, as in optical cavities, these fluctuations become amplified, giving rise to strong light-matter interactions that can produce entirely new quantum phenomena. This project explores how such interactions can be harnessed to create exotic quantum states of matter with deeply entangled components. These states are not only scientifically novel but may also serve as architectures for robust quantum information. A key goal is to understand how vacuum fluctuations and nonlocal photon correlations stabilize highly entangled quantum systems capable of robustly storing and processing quantum bits of information. The research will investigate how these light-matter systems behave when driven far from equilibrium – revealing new dynamical regimes that challenge conventional ideas about how systems relax or thermalize – and explore efficient transport of energy and information through photon-matter hybrid quantum states. By integrating research with education and outreach, the project will extend its impact beyond the scientific community. Collaborating with high schools in the metro Atlanta area, it will bring quantum science into classrooms through hands-on activities and demonstrations. It will also launch “Emory Quantum Day,” a campus-wide event that invites students, teachers, and the public to engage with modern quantum research through talks and exhibits. Undergraduate students will receive training and mentorship in theoretical quantum science, preparing them to contribute to the Nation’s future scientific and technological workforce. TECHNICAL SUMMARY: This award supports theoretical and computational research, and associated education to investigate the consequences of light interacting with materials and matter. Understanding how to control and manipulate entanglement in many-body quantum systems is a frontier challenge in modern physics, with far-reaching implications for quantum information science and materials discovery. This award supports theoretical research on hybrid platforms where light and matter interact so strongly that fundamentally new quantum states emerge – transcending the properties of either component alone. The project investigates how electromagnetic vacuum fluctuations and confined light in optical cavities generate unconventional entanglement patterns in matter. A central thrust of this project is to uncover how vacuum fluctuations and non-local photon correlations imprinted in matter contribute to stabilizing long-range entangled phases beyond traditional quantum Hall systems, including time-reversal-invariant fractional topological insulators with spin-active excitations and photon-enabled non-Abelian orders in cavity-integrated superconducting networks. The research will also investigate how strong light-matter entanglement drives novel non-equilibrium and non-ergodic quantum dynamics, and will characterize new transport regimes arising from photon–exciton hybridization in optically active two-dimensional materials. Ultimately, the project aims to classify a new generation of light-matter hybrid materials with quantum functionalities that exceed those achievable by light or matter alone. In parallel, the project integrates research with education and outreach efforts to advance scientific literacy, inspire future scientists, and expand public engagement with quantum science. Through collaboration with public high schools in the metro Atlanta area, it will introduce classroom activities and hands-on demonstrations designed to spark curiosity about physics and expand access to high-quality STEM learning. The project will also establish “Emory Quantum Day,” a campus-wide outreach event that brings students, educators, and the public together to explore advances in quantum sciences through talks, exhibits, and interactive sessions. At the undergraduate level, the project will provide research training and mentorship, preparing students to contribute to the Nation’s scientific and technological enterprise. These efforts will help cultivate a quantum-aware workforce and connect frontier research with broader educational and societal impact. 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.