Emory University

NIH Research Projects · FY 2026 · 2026-06

ABSTRACT HIV remains a major public health challenge in Kenya, with untreated depression complicating HIV care and impacting treatment adherence and viral suppression. Despite Kenya's success in meeting international HIV control targets to date, diagnosis and treatment of depression among people living with HIV (PLH) remains insufficiently addressed. Given the well-established adverse impacts of depression on HIV care outcomes, improving depression care is critically important to maintaining Kenya’s laudable progress in addressing their HIV epidemic. The 2022 Kenyan HIV Prevention and Treatment guidelines recommend at least annual use of the Patient Health Questionnaire-9 (PHQ-9) for depression screening in HIV care settings, but only 52% of PLH in care had been screened in the last year according to national administrative data. Our long-term goal is to improve rates of equitable screening, referral, and treatment for depression among PLH in Kenya, thereby improving HIV care outcomes. The objective of this R36 application is to leverage implementation science approaches to evaluate the current utilization of PHQ-9 screening in HIV clinics in Kenya. This project aims to evaluate the utilization of PHQ-9 screening in Kenyan HIV clinics using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. This study will pursue three specific aims: (1) Estimate the prevalence of depression among PLH in Kenya and assess variations across key populations, clinic types, and geographic regions to inform targeted interventions. (2) Analyze the reach, effectiveness, and maintenance of PHQ-9 screening in government-funded HIV centers using electronic health record data, including evaluation of equity in screening based on demographic characteristics. (3) Conduct a qualitative evaluation of PHQ-9 implementation in three purposively selected HIV clinics in Kisumu, Kenya, exploring barriers and facilitators through in-depth interviews with purposively selected care providers. For aims 1 and 2, we will conduct quantitative analyses of nationally representative HIV program data. For aim 3, we will conduct qualitative, in-depth interviews with healthcare providers and staff at three selected HIV clinics in Kisumu, Kenya. This proposed research is highly significant because it aims to improve mental health integration into HIV care, enhance screening practices, and guide policy and program improvements, thereby advancing both mental health and HIV care outcomes in Kenya and potentially other African settings.

NIH Research Projects · FY 2026 · 2026-06

ABSTRACT Although tuberculosis (TB) has been curable and preventable for decades, TB remains the leading infectious disease cause of death worldwide. The global EndTB goal of <10 TB cases per 100,000 population and the US goal of TB elimination (<1 TB case per million) will not be achievable without the development of new prevention tools, such as an effective TB vaccine. However, the development of biomedical interventions to prevent TB infection has been hampered by a lack of understanding of host factors that mediate susceptibility and resistance to Mycobacterium tuberculosis (Mtb) infection following exposure. A hereditary basis for resistance to Mtb infection has long been postulated, but the biological pathways for resistance to Mtb infection remain unknown. Proteomics allows large scale measurement of protein production, degradation, and expression to characterize the functional roles of proteins in normal and disease-related molecular processes. Understanding the circulating proteomic profile can provide insights into the mechanisms of infection, immune response, and disease progression. However, no proteomic study has been conducted to identify disease-specific proteins, post-translational modifications, or signaling pathways that are associated with resistance to Mtb infection at a population level. In the proposed R21, we will conduct a hypothesis- generating, proteomic study of >5,300 proteins to identify predictors of resistance, among close contacts who remain uninfected, despite well-characterized exposure to active TB. We will leverage our funded TB GWAS R01 study (R01AI139406, MPI Gandhi/Sun) of 4,353 close and household contacts. In the parent R01 study, we identified 475 (12%) individuals with resistance to Mtb infection. Using a genome-wide association study (GWAS), we identified a novel genetic locus associated with resistance on chromosome 13, which has not previously been associated with any known immune mechanism of protection. The proposed R21 will utilize clinical and exposure data and plasma specimens from participants enrolled in the parent R01 study, to make this proteomic analysis highly feasible, and provide both targeted and untargeted insights into mechanisms associated with resistance. In Aim 1, we will identify and validate proteomic associations with resistance to Mtb infection by conducting a proteome-wide study of 5,300 proteins. In Aim 2, we will combine GWAS data from the parent R01 and proteins identified in Aim 1 to elucidate the causal relationships between proteomics and resistance using Mendelian Randomization. The findings of this R21 will provide preliminary data to facilitate a future, definitive investigation of proteomics and resistance to Mtb infection. A greater understanding of proteomics in Mtb infection will lead to novel insights for vaccine development and other biomedical interventions to prevent Mtb infection.

NIH Research Projects · FY 2026 · 2026-06

Abstract Increasing HIV preexposure prophylaxis (PrEP) coverage in the United States has impacted the HIV epidemic, with states that have higher levels of PrEP coverage experiencing greater reductions in HIV transmission. Yet PrEP scale-up to date remains well below the levels recommended by CDC. Our team recently documented the critical nature of telemedicine PrEP (telePrEP) – one in five PrEP users in the United States is receiving PrEP from the largest telePrEP provider, which provides services at no out-of-pocket cost to all users. We propose MISTR+, a project that will seek to establish an evidence base for telehealth and improve health outcomes for the over 100,000 users of this service by (1) developing a series of low-touch interventions based on existing evidence and new data analyses of telePrEP electronic records data, (2) testing interventions, and (3) enhancing our understanding of intervention performance through machine learning and cost-effectiveness analyses that will inform intervention prioritization. We will test interventions, such as message content, with a series of rapid randomized, controlled trials (also called A/B testing), seeking to improve health outcomes of PrEP care initiation, retention, and re-engagement. In addition to developing nuanced information regarding what components of interventions produce positive health effects, interventions without additional costs per user that improve health outcomes (such as messaging) will be scaled to all MISTR users for an immediate societal prevention benefit.

NIH Research Projects · FY 2026 · 2026-06

Project Summary Pancreatic cancer, characterized by aggressive behavior and poor survival, is hallmarked by desmoplastic stroma abundant in stromal cells, extracellular matrix, and neural invasion. A high level of intratumoral nerve density and the presence of cancer invaded nerves correlate with unfavorable prognosis, heightened risk of recurrence and metastasis. Dynamic interactions among cancer cells, nerves, and stromal cells establish a neuroinflammatory niche, promoting tumor growth, exacerbating perineural invasion and inflicting severe pain on cancer patients. The objective of this study is to develop new nanotherapeutic agents targeting tumor, stroma, and cancer nerve to overcome therapy resistance in pancreatic cancer while reducing neuropathic pain. We developed a tumor cell mimetic hyaluronic acid nanoparticle (HANP) drug delivery platform using a recombinant ATFmmp14 ligand containing the amino-terminal fragment (ATF) of uPA and MMP14 catalytic domain. We demonstrated that ATFmmp14 conjugated HANPs delivered 20-37% of the total carried drugs into stroma-rich pancreatic patient derived xenograft (PDX) tumors following systemic delivery. Intratumoral delivered ATFmmp14-HANP/drugs can penetrate through dense stroma to reach ductal tumor cells for drug delivery. Systemic administration of ATFmmp14-HANP carrying SN38 inhibited tumor growth for 83-97% and improved survival in the PDX tumor models. ATFmmp14-HANP/SN38 treated tumors also have significantly reduced neural invasion. To enhance therapeutic efficacy on drug resistant pancreatic cancer, we have produced novel ATFmmp14-HANPs carrying therapeutic agents that inhibit key neural signals and neuron-cancer interactions, including a â-adrenergic receptor (â-AR) inhibitor (Propranolol, Pro) that blocks sympathetic nervous signaling and a sensory nerve inhibitor (Gabapentin, GAB). Preliminary studies demonstrated their effects in vitro and therapeutic efficacy in the PDX models. Therefore, we hypothesize that biomimetic ATFmmp14-HANP mediated delivery of neural modulatory agents (Pro or GAB) and chemotherapy drug (SN38) induces strong therapeutic response in tumor cells, inhibits neural invasion, and reduces neuropathic pain. In the proposed research, we will optimize nanoformulations of ATFmmp14-HANP/Pro+SN38 (AM-HANP/PS) and ATFmmp14-HANPGAB/ SN38 (AM-HANP-G/S) in vitro using 3D co-cultures (Aim 1&2). The effects of AM-HANP/PS or AM-HANPG/ S on targeted delivery, tumor growth inhibition and cancer pain reduction will be evaluated in pancreatic PDX models (Aim 1&2). Changes in the density and activity of sympathetic and sensory nerves, neural invasion and â-AR activity of tumor cells will be investigated using histological, immunological, and molecular analyses (Aim 1&2). Finally, therapeutic response to AM-HANP/PS or AM-HANP-GS will be evaluated in the Kras/p53-driven mouse pancreatic cancer model to determine the effect on inhibiting tumor growth, reducing neural invasion, activating immune response (Aim 3). Success in the proposed study will develop novel targeted nanotherapeutic agents for the treatment of pancreatic cancer patients with therapy-resistant cancer and severe neuropathic pain. This research project will use pancreatic cancer PDX models in SCID mice and mouse tumor models to investigate therapeutic responses of targeted nanoparticles carrying dual drugs on tumor and stromal cells, and neural infiltrations. The objectives of the proposed research can only be achieved in animal tumor models for adequately determining targeted delivery, the effects of inhibition of tumor growth and neural invasion, activation of immune response, and evaluation of their effects on reduction of chronic cancer associated-pain.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY: Histone proteins are critical for the compaction and organization of newly synthesized genomes. Histone protein concentrations help regulate the timing of rapid cell divisions in the early animal embryo. Misregulation is developmentally lethal: histone overexpression leads to extra or asynchronous cell divisions, while reduced histone expression leads to cell cycle arrest. As embryos develop, cell division dramatically slows. This change in the cell cycle leads to radically differing demands for histone transcripts and variable rates of histone gene expression. Cells must quickly alter their histone expression dynamics to match their cycling needs. Unequal demand for histone transcripts is perpetuated later in development as diverse cell types acquire novel proliferative potentials. Because of the ubiquitous necessity of histone proteins, genomes often carry many copies of each histone that are nearly identical in sequence, which may be clustered or distributed. This creates a unique regulatory problem in differentiating cells because histone genes are indiscernible from each other. A longstanding, major assumption in the field is that histone genes are largely regulated in concert: all histone genes are expressed or silenced to the same degree. I aim to fill this fundamental knowledge gap by tracing histone transcripts to both gene and locus of origin to determine how identical histone genes are expressed throughout development to maintain proper proliferative potential. I will test my hypothesis in two specific aims: In Aim 1, I will test how clustering of histone genes affects expression by engineering a transgenic D. melanogaster that includes sequence variation in histone coding regions. This allows for the tracing of transcripts to their gene of origin. I will perform RNA sequencing to compare mRNA dynamics from individual histone genes through an embryonic time course as the cell cycle lengthens. These experiments will determine how the expression patterns of individual genes within a cluster change with dynamic cell division requirements. In Aim 2, I will test how separating histone genes between loci alters regulation by utilizing the natural genomes of Drosophila virilis and D. simulans/transgenic D. melanogaster hybrids, whose genomes carry two histone loci of different sizes (D. virilis) or similar sizes (hybrids). I will leverage natural histone coding sequence variations in both species to perform single nucleotide variant fluorescent in situ hybridization, visualizing locus-specific transcriptional patterns in differentiating neural cells. These experiments will define regulatory strategies that attenuate histone expression as cells differentiate and the cell cycle slows. Overall, these aims illustrate how identical sets of histone genes are differentially regulated during early animal development, which is crucial to our understanding of developmental cellular differentiation and proliferation. I designed these experiments, in collaboration with my sponsor and co-sponsor, to address critical knowledge gaps in our field, develop expertise in a broad array of techniques, and provide me with the training opportunities to become an independent researcher.

NIH Research Projects · FY 2026 · 2026-06

Project Summary Pre-pregnancy obesity (PPO) affects 29% of U.S. pregnant women, posing a significant public health challenge by impacting perinatal neurodevelopment and increasing risk for psychiatric disorders in offspring. While alterations in placental function are likely involved, current studies examine PPO, placenta, and brain parameters in isolation, leading to fragmented understanding. Moreover, there is a critical lack of longitudinal studies spanning different trimesters through the postnatal period, limiting prospects for timely intervention. To address these gaps, we propose recruiting 400 pregnant participants (200 BMI ≥30, 200 BMI 18.5-30) from Emory's obstetric network in Atlanta—a region with among the highest maternal obesity rates nationally. Participants will undergo three MRI assessments: second trimester (24-28 weeks, n=300), third trimester (32-36 weeks, n=240), and neonatal (1-2 months, n=210 expected to complete all three scans). Each <30-minute prenatal scan captures: (1) multimodal placental MRI (multi-echo T2* for oxygenation; IVIM for perfusion/diffusion); (2) multimodal fetal brain MRI (T2-weighted, resting-state, and diffusion-weighted imaging); and (3) maternal abdominal MRI for visceral adipose tissue quantification. The neonatal scan focuses solely on infant brain MRI. Maternal metabolic profiling includes pre-pregnancy BMI, gestational weight gain, first-trimester waist-hip ratio, and MRI-derived VAT. Neurobehavioral phenotyping will use the NIH Baby Toolbox at 6 and 12 months and ASQ:SE-2 at 6, 9, and 12 months. Our pilot data demonstrate that PPO associates with reduced maternal-side placental T2* (third trimester, sex-specific), reduced placental perfusion fraction f (second trimester), and altered fetal brain connectivity and white matter integrity. Building on these findings, we hypothesize that PPO compromises placental oxygenation and perfusion, which disrupts fetal brain development, leading to measurable neurobehavioral liabilities through 12 months. Aim 1 will determine whether PPO and central adiposity reduce placental oxygenation and microcirculation using T2* and IVIM metrics. Aim 2 will investigate how PPO shapes brain structure, function, and behavior from fetal period through 12 months, assessing attention, self-regulation, and social communication. Aim 3 will examine whether placental dysfunction mediates the PPO effect on brain and behavior through longitudinal mediation models. This comprehensive approach will elucidate the PPO-placenta-brain axis, informing targeted interventions to mitigate neurodevelopmental risks associated with maternal obesity.

NIH Research Projects · FY 2026 · 2026-06

Project Summary/Abstract Sickle cell disease (SCD) is characterized by a chronic, relatively stable anemia that is punctuated by acute drops in hemoglobin. These acute anemic events are accompanied by organ damage and clinical complications including stroke, acute chest syndrome, and vaso-occlusive episodes. Factors that drive exacerbations in anemia and mechanisms by which they contribute to acute inflammatory complications and increased mortality in patients with SCD are not understood. Chronic immune activation plays a central role in the pathophysiology of SCD. Tissue damage results in the release of intracellular contents, including mitochondrial and nuclear DNA, which contribute to overall inflammation. Cell-free DNA (cfDNA) levels are elevated in the plasma of SCD patients and are associated with vaso-occlusive episodes. Recent studies have described immune functions of red blood cells (RBCs), whereby they influence overall inflammatory status through scavenging of cytokines and expression of surface receptors. The nucleic-acid sensing receptor, Toll-like receptor 9 (TLR9) is present on RBCs and binds to circulating cfDNA in patients with infection, resulting in immune activation and anemia. This process has not been explored in the chronic inflammatory background of SCD patients. We propose that excessive levels of cfDNA from cellular damage and immune activation during vaso-occlusive complications drives acute drops in hemoglobin in SCD. Our central hypothesis is that cfDNA binding to RBC- TLR9 modulates RBC clearance and immune activation in SCD and thereby contributes to the severity of acute anemic events. Using clinical samples from patients with SCD in combination with murine models, and working at the cellular and molecular levels, we aim to 1) Determine the impact of RBC-TLR9 and cfDNA on RBC clearance in SCD, and 2) Examine the contribution of RBC-TLR9 engagement on immune dysregulation in these patients. Long term goals of this project include translating gained mechanistic insights into therapies that mitigate acute drops in hemoglobin and the associated inflammatory response in patients with SCD. Moreover, our findings may reveal predictive markers to enhance understanding of patients at the highest risk of experiencing severe acute anemic events, allowing tailored therapies and ultimately improving patient outcomes. The information gained will likely be applicable not only to SCD but also other inflammatory anemias.

NIH Research Projects · FY 2026 · 2026-06

Project Summary The convergence of the opioid crisis and HIV epidemic has created an unprecedented public health emergency, with approximately 10% of people living with HIV also co-infected with hepatitis B virus (HBV). While HIV/HBV co-infection already accelerates liver disease progression and increases mortality, the introduction of synthetic opioids like fentanyl has dramatically worsened outcomes through mechanisms that remain poorly understood. This proposal addresses a critical knowledge gap at the intersection of substance use disorder and HIV co- infections. The overarching goal of this project is to systematically investigate how fentanyl exposure fundamentally alters HIV/HBV co-infection dynamics at the molecular level and to identify targetable metabolic pathways for therapeutic intervention. We will leverage pioneering biomimetic cell culture models, including mouse-passed primary human hepatocytes (mpPHH) with 100% HBV infection rates and physiologically relevant cccDNA levels, combined with HIV-infected CD4+ T cells in innovative co-culture systems. Our project goals are to characterize fentanyl's impact on viral replication dynamics and identify metabolic pathways contributing to altered pathogenesis through comprehensive multi-omics analyses, and to investigate fentanyl-mediated drug- drug interactions with HIV/HBV antivirals using both 2D co-cultures and 3D liver organoid models, with validation in humanized mice harboring genetically modified human liver grafts. This application is highly relevant to HIV and substance use disorder research as it directly addresses the biological mechanisms underlying poor clinical outcomes in people who use drugs (PWUD) with HIV/HBV co-infection. By focusing on CYP3A4-mediated metabolism, the primary pathway for both fentanyl and many antivirals, we will uncover dangerous drug-drug interactions and altered therapeutic efficacy that currently compromise treatment success. Our findings will enable development of personalized therapeutic strategies that account for the unique metabolic challenges faced by PWUD, ultimately improving viral suppression rates and reducing liver disease progression in this vulnerable population. This paradigm-shifting approach treats substance use not as a behavioral comorbidity but as a central biological variable that fundamentally reshapes viral pathogenesis and treatment response.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY The present NIH R13 proposal reflects our request for support of a CF Data Science Workshop, to be held in Atlanta, GA, one day before the North American CF Conference begins there in October 2026. The purpose of the workshop is to stimulate the development of research tools for the application of data science approaches for the study of Cystic Fibrosis (CF) and related diseases. CF is a life-limiting, multi-system genetic disease where research progress heavily relies on access to large-scale, longitudinal, and heterogeneous patient data integrated with sophisticated analytical tools. The proposed Workshop is intended, primarily, to facilitate advances in the application of data science approaches toward disease, in general, starting with a focus on CF. We have a particular opportunity to take advantage of the congregation of CF investigators in Atlanta for the annual North American CF Conference (NACFC) to be held there on October 8-10, 2026; this is the largest annual congregation of researchers in the CF field, thus greatly increasing the likely attendance of this Workshop by relevant CF scientists who already were planning to attend the NACFC. The objective of the present proposal is to support a high-quality workshop that is relevant to the scientific mission of the NIH and to the public health, in a manner that accomplishes the exchange and dissemination of information related to the application of data science approaches to chronic diseases, including CF.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT Influenza A virus (IAV) poses a significant burden to both human and animal health. The spillover of IAV from animals to humans can furthermore result in influenza pandemics. Mallards and swine represent two important classes of species within influenza ecology. Mallards, like other wild aquatic birds, sustain IAV diversity within nature. Swine are intermediate hosts with susceptibility to both human and avian influenza viruses. Because of this susceptibility, IAV infection in swine can result in transfer of distinct IAV lineages with pandemic potential to humans. Although both swine and mallards are susceptible to IAV, the virus shows drastically different tropism in these hosts. These differences are likely to drive distinct population dynamics of IAV within each host. I hypothesize that the genetic composition of within-host viral populations will be shaped by the spatiotemporal dynamics of infection and that changes in viral population diversity over space and time will therefore show marked differences between swine and mallards. To test this hypothesis, swine and mallards will each be infected with a barcoded virus relevant to the host species: A/swine/North Carolina/A02245294/2019 (H3N2) virus (Sw/NC/19) or A/mallard/MN/10096/99 (H3N8) virus (Ma/MN/99). These viruses will carry a genetic barcode which allows tracking of many lineages within the viral population using next generation sequencing. In Aim 1, I will determine the spatial distribution and genetic composition of virus populations within swine and mallards following infection. Using the combination of extensive tissue sampling, barcoded viruses, and next generation sequencing I will be able to track IAV populations across the anatomy of the host. In Aim 2 I will determine how influenza virus populations change over time at a given anatomical site within swine and mallards. Through repeated sampling of the same anatomical site, I will be able to determine how IAV populations are shaped over time. These findings will advance understanding of IAV dynamics within distinct host species, yielding insight into the evolutionary processes that underly the emergence of IAV pandemics.

NIH Research Projects · FY 2026 · 2026-06

Premature ovarian insufficiency (POI) – defined as the loss of ovarian function before age 40 – is a leading cause of infertility and affects approximately 1% of women in the general population. The risk is significantly higher in girls and women with certain genetic conditions, including Turner syndrome (TS) and classic galactosemia (CG), where the majority will experience POI before adulthood and many even prior to puberty. Individuals with these conditions rank POI as one of the most devastating aspects of their diagnosis. Hormone- assisted oocyte retrieval is an established fertility preservation option, but it is only an option if follicles remain following spontaneous menarche. For prepubertal girls, ovarian tissue cryopreservation (OTC) is the only available method, but involves surgical removal of an ovary from a child who potentially might otherwise have achieved spontaneous menarche or natural conception. Clinicians currently lack validated biomarkers to predict which girls with TS or CG are at highest risk of POI prior to menarche, which is critical to choosing the best option for fertility preservation. The proposed study addresses this gap by testing the predictive value of prepubertal Anti-Müllerian Hormone (AMH) and Follicle Stimulating Hormone (FSH) for future ovarian function. AMH is widely used to estimate ovarian reserve in adult women, and FSH measured during the minipuberty of infancy may also have predictive value, but their utility in high-risk, prepubertal populations remains unclear. Aim 1 will test the predictive value of prepubertal AMH and FSH for spontaneous menarche and sustained menstrual cycling in girls with TS and CG from large national cohorts with hormonal data and clinical outcomes. Aim 2 will characterize longitudinal AMH and FSH trajectories and use latent class mixed modeling to identify distinct prepubertal hormone patterns in these populations. This study will be the first to evaluate the longitudinal utility of AMH and FSH as predictive biomarkers of future ovarian function in prepubertal girls with TS and CG—two rare, high-risk populations with limited fertility preservation options. By validating early biomarkers of follicular depletion, this project will directly inform clinical counseling for families navigating complex fertility decisions and support earlier, more personalized intervention planning. The results will establish foundational data for future development of multivariable predictive models incorporating clinical, hormonal, and genetic data to optimize reproductive health outcomes. Ultimately, this work will advance precision fertility care in pediatric populations and may serve as a model for risk stratification and fertility preservation decision-making in other conditions associated with early-onset POI.

NIH Research Projects · FY 2026 · 2026-06

New HIV infections continue and cannot be eradicated by current treatments due to a life-long reservoir of infected cells. This key obstacle to cure HIV consists of a reservoir of latently infected CD4+ T cells that persist despite long-term antiretroviral therapy (ART) and cause rebound of viremia if ART is interrupted. The R37 award AI157862 “Enhanced latency reversal and reservoir clearance in macaques” was funded in July 2021 with the overarching objective to obtain a deeper and broader understanding of the latency reversal induced by a SMAC mimetic (SMACm) and its potential to reduce persistent reservoirs using an innovative “kick and kill” approach. We have learned that treatment of SIV-infected, ART-suppressed macaques with the SMACm AZD5582, that activates the ncNF-kB signaling pathway, reactivates rebound competent latent reservoirs throughout the body. We also learned that the combination of AZD5582 and the BCL-2 inhibitor venetoclax reduced the intact SIV reservoir in peripheral blood and bone marrow but did not delay viral rebound after ART interruption. These findings highlight the intricate relationship between latency reversal, reservoir size, and viral rebound. We have three priority areas for the next phase of this R37 award that build on our body of work using venetoclax as well as broadly neutralizing antibodies (bNAbs), that have both antiviral and pro-immune effects. First, focus on reservoir establishment as an optimal time to intervene (rather than the maintenance phase). Second, focus on the antiviral immunity needed to complement venetoclax as a reservoir reducing intervention. And third, a deep dive into how the spatial landscape and immunovirologic features of infection are influenced by venetoclax. Our Central Hypothesis is that bNAb therapy will synergize with promotion of infected cell apoptosis through BCL-2 inhibition to limit reservoir formation. Using our expertise in conducting rigorous in vivo studies in nonhuman primates and immunovirologic multiomic analyses, we will test our hypothesis in three Specific Aims: 1) Define how venetoclax combined with bNAb therapy during early ART impacts decay of viremia, the intact reservoir, and the spatial landscape of infection; 2) Determine how venetoclax combined with bNAb therapy during early ART influences antiviral immune responses in a tissue-specific context; 3) Evaluate the virologic and immunologic impact of venetoclax and bNAb therapy given at start of ART versus at ART interruption. The experiments proposed will provide new evidence regarding the mechanisms of HIV/SIV reservoir establishment and how this process may be perturbed. Our experiments will evaluate safety and efficacy in a preclinical model. We hope that the results we generate will contribute to a cure for people living with HIV. RELEVANCE (See instructions): New HIV infections continue and cannot be eradicated by current treatments due to a life-long reservoir of infected cells. The goal of our research program is to identify targeted immunotherapies that reduce HIV reservoir formation when given early in infection with antiretroviral treatment. Our experiments will evaluate safety and efficacy in a preclinical model to inform approaches to cure HIV.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT Osteoporosis is a debilitating skeletal disease affecting over 50% of women and 25% of men over the age of 50, often resulting in painful and disabling fractures that significantly reduce quality of life and increase mortality. Achieving optimal peak bone mass and strength during early life is one of the most critical factors in reducing lifetime fracture risk. Cadmium (Cd) is a toxic heavy metal increasingly present in the environment due to industrial uses as a metal lubricant, in battery production, pigments, and plastics. Critically, Cd bioaccumulates in the body with a biological half-life of approximately 30 years, raising serious concerns about its effects during key developmental windows such as skeletal modeling in early life. This proposal aims to investigate the long- term skeletal consequences of Cd bioaccumulation during early skeletal growth and attainment of peak bone density, at doses that have previously been considered safe. We will assess effects of Cd on lumbar spine and femur during early skeletal development in mice up to time of peak bone density using advanced high resolution micro-computed tomography imaging, histomorphometry, evaluate biochemical markers of bone turnover and perform assays of bone strength and fracture resistance. This study will provide critical data on how environmentally relevant, chronic Cd exposures during development may compromise skeletal health. This work will inform public health policy and environmental safety standards, particularly as Cd exposure continues to rise globally. Moreover, it will highlight the vulnerability of developing skeletal systems to toxic environmental insults.

NIH Research Projects · FY 2026 · 2026-06

Project Summary A fundamental question in neuroscience is how complex movements are learned and produced to complete specific tasks. Motor skills are acquired and maintained through sensorimotor learning, a process through which motor output is modified in response to sensory feedback[1]. Many skilled behaviors, including speech, object manipulation, and tool-use, consist of distinct phases that can be adaptively re-ordered in real-time based on sensory feedback[2]. The nervous system must selectively coordinate muscle activity to perform multiple flexibly organized behaviors. Many functionally distinct behaviors rely on the same muscles for execution, furthering the need for controlled modulation of motor output. A critical gap exists in understanding how the nervous system coordinates the same muscles to perform distinct, flexibly organized behaviors. The overall objective of this project is to reveal how flexible and sequential movement is controlled and to quantify muscle activity across different movements and behaviors. Aim 1 will identify how patterns of muscle activity drive diverse sequential behaviors. Jaw kinematics and electromyography (EMG) activity from jaw muscles will be compared during phases of singing and eating. Aim 2 will reveal the neural substrates necessary for non-vocal learning. Novel seed-eating will be compared between control and LMAN-lesioned adult male Bengalese finches. Seed ingestion and changes in beak kinematics will be measured. This project will improve our understanding of behavioral representation and learning. Specifically, we will reveal whether specific behaviors require independent motor learning circuits, or a general circuit enables flexible performance of multiple complex behaviors. Insights from this work can inform a broader framework for multifunctional motor control. By identifying the organization of neural circuitry for distinct commands and characterizing the muscle activity underlying these behaviors, we will provide fundamental knowledge to guide rehabilitation strategies for comorbid disorders. The analogous circuitry and learning processes for vocal communication of humans and songbirds lends particular significance to neuromuscular disorders affecting facial muscles. Dysphagia, for example, is often treated with speech therapy, based on the shared musculature involved in speech and eating, but malnutrition and weight loss often persist[29]. A comprehensive understanding of how muscles function across different behaviors will support improvement of therapies aimed at restoring movement abilities. Particularly, if a shared motor program exists for a given muscle or muscle ensemble, a single treatment strategy could be designed to improve both speaking and swallowing.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Anti-drug antibodies against protein-based therapeutics can significantly impair treatment effectiveness and cause severe adverse events. Coagulation factor VIII (FVIII) is one of the most immunogenic therapies, with around 30% of severe hemophilia A (HA) patients developing neutralizing anti-FVIII antibodies (inhibitors), compared to 3-5% of severe hemophilia B (HB) patients with factor IX (FIX) deficiency. Factor replacement therapy is the main option for managing bleeding, but inhibitor development complicates treatment, and immune tolerance induction (ITI) is not always successful and carries risks. Patients with inhibitors are often excluded from gene therapy, limiting curative treatment options. Current research lacks sufficient understanding of what drives inhibitor development and how to predict response to ITI. As inhibitors are the terminal outcome of an upstream immune response, earlier markers of immune response to FVIII or FIX may be more sensitive predictors especially in an era where factor exposures are more protracted due to the increasing use of non- factor therapies. Further, as HA is more common than HB and the rate of inhibitors is higher, there is a critically unmet need in understanding the pathogenesis of antibodies to FIX which has limited immune tolerance approaches for these patients. Studies on FVIII immunogenicity have linked levels or genetic polymorphisms in T-helper cytokines with inhibitor development, but the downstream cellular consequences of these associations remain unclear. We have shown that B cell activating factor (BAFF), a cytokine implicated in autoimmune diseases, is associated with inhibitors in HA. BAFF levels are regulated by cis-genetic variants and influence B cell responses in autoimmune diseases. In HA mouse models, anti-BAFF therapy prevented FVIII inhibitors, but its ability to mediate tolerance to FIX is unknown. Our recent data suggest associations between BAFF and FIX antibody development, suggesting a more global role for BAFF in alloantibody responses to hemophilia therapeutics. This study aims to investigate the relationship between altered B/T-cell subsets, cytokine levels, and genetic variants, especially BAFF, in the development of FVIII and FIX antibodies. Aim 1 will focus on associating changes in cytokine expression, cellular profiles, and genetic variants with anti-FVIII IgG, using samples from HA patients with and without inhibitors. Aim 2 will explore the effects of proinflammatory cytokines and BAFF on FVIII-specific B cell development, using a novel B-cell tracking mouse model on a hemophilia A background. Aim 3 will investigate the impact of FIX dose response and BAFF on immune responses in HB, testing whether BAFF neutralization can prevent FIX IgG responses and the effect of FIX dose on B and T cell responses. This study represents the first exploration of BAFF’s general contribution to alloantibody responses to protein replacement therapy in hemophilia. It will provide valuable insights into the interactions between genetic variants, lymphocyte subsets, and cytokines in FVIII immunogenicity and could lead to new therapeutic approaches for FIX inhibitors in HB management.

NIH Research Projects · FY 2026 · 2026-06

Abstract: Antibiotic resistance is a crisis that has been ongoing for decades, with 1 million deaths each year being directly caused by antibiotic resistance and predicted to rise to 2 million by 2050. Regardless of the evident need to uncover pharmacological solutions to this crisis, there have been scarce developments made in discovering new antibiotics that evade mechanisms of resistance, such as β-lactamase inhibitors. A bacterial pathogen that is of the highest concern is carbapenem-resistant Acinetobacter baumannii (CRAB), a gram-negative bacterium. The CRAB strain of interest for this proposal is an OXA-23 overexpressing strain, to which OXA-23 is the most common β-lactamase in this bacterium. To address this issue, the Rather lab performed a high-throughput screen of 3000+ FDA-approved small molecule drugs against a hyper-permeable and efflux-deficient OXA-23 overexpressing strain of AB. From this screen, fendiline, a calcium channel blocker, with no reported bactericidal activity was identified to have potent activity (MIC = 8 µg/mL) against the efflux deficient strain with the induction of OXA-23 expression. However, within wild-type (WT) strains, bactericidal activity lowered (MIC = 128 µg/mL). Further studies showed that the addition of a membrane permeabilizer, such as PMBN and colistin, increased activity back to MIC’s ranging from 2-32 µg/mL in wild-type strains. Preliminary SAR studies have been conducted by synthesizing fendiline analogs that display 4-fold better potency and enantiomeric dependency in the WT strain. With the use of a diazirine photoaffinity probe, which covalently labels high-affinity protein targets upon irradiation, the mechanism of action (MOA) of fendiline was uncovered. The first goal of this proposal is to better understand the SAR of fendiline using the newly understand MOA to increase activity of the compounds in wild-type AB. To achieve this, regions of the fendiline scaffold have been highlighted that could lead to improvements in in drug accumulation and binding affinity. Within this goal, the hypothesis of the addition of a carboxylic acid to the fendiline scaffold to increase WT activity via increased drug accumulation and membrane permeability will be tested, as well as the addition of a primary ionizable amine. The second goal of this project is to test the synthesized analogs in clinically relevant strains of AB that are from various geographical and physiological sources. These small molecule drugs will be tested in combination with SPR741, an FDA-approved outer membrane permeabilizer, that is predicted to improve drug accumulation within the periplasm. This proposal will immensely aid my training as a medicinal chemist by providing me with hands-on training in drug discovery, as well as setting a synthetic foundation. In addition, this project aligns with my long-term career interests of working within the drug discovery field to repurpose and create new pharmaceuticals for the public.

NSF Awards · FY 2026 · 2026-06

This CAREER project will develop new ways to reshape living tissues for tissue engineering and regenerative medicine. Nature shapes organs and tissues by selectively removing cells in a process called apoptosis. This project will use spatially patterned light to induce apoptosis selectively to shape tissues. The high-resolution process will selectively remove cells while leaving neighboring cells intact. The team will test this approach in laboratory models of heart and liver tissue made from human induced pluripotent stem cells (iPSC). The goals will be to open channels for blood flow, model scar-like lesions, and study how immune cells clean up dying cells to support healing. The project will demonstrate how subtractive tissue engineering integrated with bioprinting can form a robust biomanufacturing platform. The project will create biohybrid fish robot kits and tissue-engineering modules to help students at Georgia schools see how biology and engineering come together in regenerative medicine. Graduate and undergraduate students will serve as mentors. The project will help connect local public schools, Georgia Tech, and Emory University to encourage students to enter the biomedical engineering workforce. This project will utilize the dual inhibition of Serum- and Glucocorticoid-Inducible Kinase 1 (SGK1) and c-Jun N-terminal kinase (JNK) to create a digital, light-dependent “switch” that toggles cells between survival (light off) and apoptosis (light on). Mechanistic studies will use pooled CRISPR screening and single-cell transcriptomics to map how this switch engages mitochondrial dysfunction, oxidative stress, and apoptotic signaling networks in engineered epithelial, cardiac, and hepatic tissues. The subtractive platform will be integrated with advanced bioprinting and digital micromirror–based light patterning to shape perfusable vascular channels and disease-relevant micro-lesions with features down to approximately 100 micrometers. Macrophage-mediated efferocytosis will then be leveraged for debris clearance and regenerative remodeling. Functional validation will assess contractility and electrophysiology in cardiac constructs, metabolic activity and drug responses in liver constructs, and longer-term integration and vascularization after implantation in immunocompetent mouse models. Together, this work will deliver a scalable toolkit for dynamic, high-resolution editing of complex tissues, enabling realistic disease models and regenerative strategies while informing inquiry-based curricula that connect living systems, photonics, and biofabrication tools for students at multiple educational levels. 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 · 2026-05

Vaccines are the most successful prophylactic measure against pathogens, and their protective capacity depends on the formation of long-lived immunological memory, e.g. memory T lymphocytes (TMEM). Coordination between B and T lymphocytes is required against intracellular pathogens to neutralize pathogens and eradicate infected cells, respectively, as recently highlighted with COVID19 vaccine responses. Individuals living with chronic infections were shown to exhibit inferior responses to subsequent infections and vaccination. Studies in animal models suggested the cause to be the inferior recall responses by the TMEM generated to acute stimuli in hosts with preexisting chronic infection (hereafter termed inflm-TMEM). However, epigenetic imprints of persistent inflammation on inflm-TMEM have not been examined, and interventions to restore efficient protective recall responses by inflm-TMEM are understudied. Previous studies and our preliminary data demonstrated arrested development of inflm-TMEM, especially the central memory subset (TCM). Previous transcriptional profiling and our chromatin-accessibility profiling revealed skewed transcriptional and epigenetic landscapes of antigen-specific inflm-TMEM compared to bona fide TMEM, with enrichment of signatures associated with inflammatory mediators including type I interferon (IFN-I) and interleukin-6 (IL-6), which signal downstream janus kinase 1/2 (JAK1/2). We hypothesize that JAK1/2 inhibition would recover normal TMEM differentiation in hosts with preexisting chronic infection. To investigate this, we will use the same mouse model utilized for our preliminary studies to examine the differentiation of antigen-specific T cells responding to acute infection in the presence of preexisting chronic infection with or without JAK1/2 inhibition (JAKi) treatment. We will dissect the profiles of inflm-TMEM using high- dimensional flowcytometry and combined scRNAseq/scATACseq (MultiOme) profiling. More importantly, we will investigate the functional impact of JAKi-treatment on enhanced pathogen clearance and protection upon rechallenge. Our team has expertise in immunology, mouse models, and MultiOme profiling tools. This puts us in a unique position to address our main objectives which are: (1) to examine the capacity of FDA-approved interventions (JAKi) to recover generation of efficient TMEM in hosts with preexisting chronic infection, and (2) to gain insights into the molecular mechanisms underlying the skewed differentiation of inflm-TMEM., and aspects recovered by JAKi treatment. These studies push the envelope of innovation where we will employ combined state-of-the-art high-dimension flowcytometry, functional assays, and MultiOme profiling, to decipher specific mechanisms associated with lower recall capacity of inflm-TMEM that is understudied to date. We will validate novel therapeutic approaches using FDA-approved medication(s) for enhancing TMEM formation in hosts with preexisting chronic infection. This is of high relevance for enhancing vaccine efficiency in people living with chronic viral infection, and can be extended to benefit other populations living with chronic diseases with underlying inflammation. Summary

NIH Research Projects · FY 2026 · 2026-05

The Emory Glycomics and Molecular Interactions Core (EGMIC) requests support for the acquisition of a Bruker timsTOF Ultra-2 mass spectrometry system, coupled with an Evosep LC, to provide Emory’s research community with transformative analytical capabilities for ultra-sensitive proteomics and glycomics. This instrument is essential for advancing NIH-funded research that requires analysis of proteins, lipids, and glycans from extremely limited sample inputs, including single cells, laser-capture micro dissected brain regions, and immunoprecipitated material, where current technologies fall short. For over a decade, EGMIC has been a leading provider of advanced biophysical and molecular characterization services, supporting over 60 NIH-funded projects. The core offers expertise and access to mass spectrometry-based glycomic profiling, intact protein mass analysis, and top-down proteomics using technologies such as ion mobility and electron capture dissociation. The requested Ultra-2 system will extend the core’s instrumentation portfolio to include next-generation, Trapped Ion Mobility Spectrometry (TIMS), enabling precise analysis of protein isomers, post- translational modifications, and low-abundance proteoforms at levels 100–1000 times more sensitive than currently possible at Emory. A team of expert mass spectrometrists and structural biologists will lead to the integration of this technology. Drs. Roberts, Song, and Lasanajak will oversee operation, user training, method development, and data analysis support. The technical team is already trained on Bruker workflows and has demonstrated feasibility through successful pilot studies using Ultra-2 demo systems. These studies include zeptomole-level detection of amyloid-beta isoforms and low-input phosphoproteomics from postmortem human brain tissue. The Ultra-2 will immediately benefit from over 11 Major and 8 Minor NIH-funded users spanning neuroscience, immunology, oncology, virology, and systems biology. Use cases include discovery of cell-type specific biomarkers in Alzheimer’s and Parkinson’s disease human brain tissues (Roberts, Seyfried, Faundez), immunopeptidomes for therapeutic antigen discovery (Ahmed), proximity labeling and single-cell proteomics in viral pathogenesis & neuroscience (Michailidis, Weinshenker, Tomalka), and low-input phosphoproteomics from sorted immune populations (Gordon, Lee, Li, Paiardini). The instrument will be housed in a fully equipped and dedicated room in the Whitehead Biomedical Research Building on the Emory Atlanta Campus. Institutional support includes long-term space allocation, technical personnel funding, coverage of the service contract for five years beyond the warranty, and an operating subsidy. The Ultra-2 is not currently available at Emory or anywhere in Georgia, and its acquisition will fill a critical gap in analytical sensitivity and throughput. Advanced training workshops, data processing pipelines, and collaborative support will ensure broad adoption and impact. This instrument will accelerate the productivity of NIH-funded investigators, promote high-impact publications, and support new grant applications centered on cutting-edge molecular profiling technologies.

NSF Awards · FY 2026 · 2026-05

The investigator studies problems in spectral theory, the mathematical theory that pertains to physical notions such as energy levels of quantum systems and vibration frequencies of mechanical systems. The research is motivated by universality, which is the appearance of certain common local statistical behaviors for different systems, and integrability, which is the existence of many conserved quantities in certain nonlinear systems used to describe their behavior over time. The project focuses on commonly studied one-dimensional systems, such as orthogonal polynomials and Schrödinger operators. One focus of this project is the study of spectral properties of large finite truncations of an infinite system, on a microscopic scale. These problems have immediate interpretations in terms of random matrix theory and one-dimensional quantum mechanics; moreover, mathematical methods developed on these systems have the potential to illuminate other mathematical models and physical applications. The project provides research training opportunities for graduate students and postdoctoral scholars. Asymptotic local zero distributions of orthogonal polynomials, as the degree goes to infinity, are described by scaling limits of Christoffel-Darboux kernels. Analogously, local eigenvalue distributions of truncations of some operators are described by scaling limits of corresponding reproducing kernels. A modern approach based on de Branges canonical systems gives optimal results for scaling limits in the fixed measure setting; one goal of this project is to develop this approach in the varying measure setting. Another goal is to describe new scaling behaviors beyond the standard universality classes, where instead of a scaling limit there may be a limit cycle or a one-sided characterization of allowed behavior; this is motivated by almost periodic operators in critical/supercritical regimes and ergodic operators with zero measure spectrum. The investigator also studies related questions in direct spectral theory, to develop techniques for fine control of spectral measures around a point in the spectrum, and sum rules with respect to essential spectra with infinitely many gaps, building upon recent applications of potential theory to differential operators. 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 · 2026-05

PROJECT SUMMARY Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive, late-onset neurodegenerative disorder affecting carriers of CGG premutation expansions (55–200 repeats) in the FMR1 gene. The condition is marked by tremor, gait ataxia, Parkinsonism, and cognitive decline, with neuropathological features such as intranuclear inclusions and Purkinje cell loss. While disease mechanisms such as toxic RNA gain-of-function and repeat- associated non-AUG (RAN) translation have been implicated in FXTAS pathogenesis, the post-transcriptional regulatory landscape, particularly the role of RNA modifications, remains poorly defined and largely unexplored in the context of FXTAS and neurodegeneration in general. Thus, the epitranscriptome represents a new dimension of regulation that could be critical in our understanding of FXTAS and neurodegenerative disease in general. This project investigates N6-methyladenosine (m6A), a highly prevalent RNA modification in the brain, in the context of FXTAS. m6A dynamically regulates RNA stability, translation, and localization, and is critical in many brain functions. Our long-term goals are to elucidate the role of m6A dysregulation in affecting key molecular pathways and neurodegeneration, thereby translating our results into clinically relevant strategies for the improved treatment of FXTAS and shared mechanisms of neurodegenerative diseases. Our exciting preliminary studies show (1) significant changes in m6A regulatory proteins and methylation patterns in FXTAS models, and (2) demonstrate that genetic disruption of the m6A pathway worsens CGG repeat-induced neurotoxicity in Drosophila. We hypothesize that m6A dysregulation plays a fundamental role in driving FXTAS pathogenesis by affecting key molecular and neuropathological changes. Aim 1 will define the m6A epitranscriptomic landscape in postmortem FXTAS and control human cortex tissue using m6A-CAM-seq (which provides single-nucleotide resolution m6A) and traditional m6A-seq. Changes in m6A will be integrated with changes in transcriptomic and proteomic data from the same samples to identify functionally important genes and pathways affected by m6A in FXTAS. Aim 2 will assess the functional impact of m6A pathway disruption in vivo by crossing m6A enzyme knockout mice with a CGG-repeat FXTAS mouse model and evaluating behavioral, neuropathological, and molecular phenotypes. By integrating our genomic, genetic and molecular findings will provide unique mechanistic insights on how m6A modifications could drive FXTAS pathogenesis, which have the potential for discovering new molecular targets with relevant clinical, translational, and therapeutic implications. This innovative study will be the first to define the role of m6A in FXTAS, offering new insights into disease mechanisms and potentially revealing new, widely applicable targets relevant to a broad class of neurodegenerative diseases.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Despite the effectiveness of antiretroviral therapies (ART) in reducing vertical transmission, maternal HIV infection and ART exposure during pregnancy is associated with immune dysregulation in mothers, along with inflammation and significant pathology in the placenta. Compounding these risks is the increasing prevalence of substance abuse among pregnant women and people living with HIV. Compared with the general population, HIV-positive women had higher use of marijuana (15% vs 7%) and cocaine/crack (17% vs 0.1%), and recent findings suggest that 6-18.3% of pregnant women report using illicit drugs throughout gestation. Despite this increase, little is known about the impact of comorbid substance use and HIV/ART on the placenta. In this study we seek to fill this critical knowledge gap by elucidating the mechanisms driving placental dysfunction in pregnant women living with HIV with comorbid substance use and examine how cocaine and/or cannabis use may exacerbate viral infectivity, inflammation, and ART efficacy at the maternal- fetal interface. We hypothesize cocaine and cannabis polysubstance use antagonize placental ART transport and metabolism through PXR signaling, which promotes HIV replication, inflammatory responses, and placental abnormalities associated with adverse maternal and fetal outcomes. We will address this by evaluating: pharmacologic mechanisms by which comorbid substance use and HIV alter ART placental efficacy (Aim 1), immunologic and virologic mechanisms underlying effects of comorbid substance use and HIV/ART on the placenta (Aim 2), and evaluate whether HIV, ART and/or comorbid substance use is associated with dysfunction and inflammation in placentae and maternal blood from HIV (+) and (-) pregnancies (Aim 3).

NSF Awards · FY 2026 · 2026-05

The project concerns questions in spectral theory, which is the mathematical theory that corresponds to physical notions such as energy levels of quantum systems and vibration frequencies of mechanical systems. One of the topics of this project is universality, which is the appearance of certain universal (or common) local statistical behaviors for different systems. The research is also motivated by integrability, which is the existence of many conserved quantities in certain nonlinear systems used to describe their behavior over time. The project focuses on Schrödinger operators, central to quantum mechanics, and related systems in one dimension; the mathematical methods developed have the potential to illuminate other mathematical models and physical applications such as electron conductivity in disordered materials and signal transmission using solitons. Several graduate students and a postdoc will be trained, and conference organization as well as writing of a monograph on reflectionless operators is planned. One focus of this project is the application of de Branges canonical systems to universality limits for orthogonal polynomials and related systems. A new approach co-authored by the PI reformulates the question in terms of a limit of canonical systems and uses that to obtain a very general criterion for bulk universality; substantial extensions of this approach to other universality phenomena will be studied. Another focus of the project will be the development of inverse spectral theory for reflectionless Schrödinger operators for Dirichlet-regular Widom spectra without the “direct Cauchy theorem” property; the structure of the isospectral torus in this regime will have immediate consequences for the Korteweg-de Vries equation with almost periodic initial data. Finally, of interest will be new research directions made possible by the recent development of Stahl-Totik regularity for Schrödinger operators, such as the study of sum rules for Schrödinger operators with arbitrary essential spectra. 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 · 2026-05

PROJECT SUMMARY The desire and ability to appropriately seek out rewards is crucial to the survival of most species. Several psychiatric disorders, including major depressive disorder and substance use disorder, are characterized by dysfunctional reward seeking. Identifying neural circuit mechanisms that support reward seeking behaviors will ultimately lead to new treatments for these disorders. One region that has previously been implicated in reward seeking is the lateral septum (LS). However, the mechanism by which the LS modulates reward seeking behavior is unknown. One potential mechanism is through the connection between the LS and ventral tegmental area (VTA). Dopamine neurons in the VTA encode a reward prediction error (RPE) to represent the difference between the expected and actual reward received. This RPE signal determines whether a reward is worth seeking or not, with positive RPE values driving learning reward associations and negative RPE signals driving extinction. There have been multiple hypotheses as to the origin of the RPE signal in VTA dopamine neurons, but whether the signal is locally generated or largely inherited from elsewhere in the brain remains debated. This raises the possibility that upstream regions could significantly contribute to or shape RPE in the VTA, such as the LS. The LS directly innervates the VTA and has been shown to be reward responsive, which suitably positions it as a possible candidate to modulate reward-related behaviors by influencing the RPE signal. This proposal aims to identify whether the LS modulates reward seeking via its projection to the VTA, and specifically how the LS contributes to the generation and modulation of the RPE signal in VTA dopamine neurons. In Aim 1, I will perform cellular resolution calcium imaging of the LS-VTA population while the animal engages with a series of operant assays designed to elicit an error signal. I predict that LS-VTA neurons, like the non-specific LS neurons, have a differential response to rewarded trials and unrewarded trials when the expected reward is omitted. In Aim 2, I will implement projection-specific, closed-loop optogenetic inhibition of LS-VTA neurons while simultaneously performing population-level calcium imaging of dopamine neuron activity to examine the causal role of the LS-VTA population in shaping the VTA RPE signal and in extinction of a learned behavior. These results will determine the extent to which LS-VTA neurons causally contribute both to the RPE signal and reward seeking behavior. Furthermore, the findings of this proposal could aid in identifying novel mechanisms to target in the treatment of several psychiatric disorders and substance use disorders.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract Neuropsychiatric disorders often emerge during childhood and adolescence, and many involve maladaptive learning and memory. Persistent memories of salient positive or negative events can contribute to the onset and maintenance of disorders like addiction and anxiety; yet we lack a mechanistic account of how affective experiences drive selective memory prioritization throughout development. Dopaminergic and noradrenergic projections to the hippocampus have been implicated in long-term memory for emotion-related events and research in nonhuman animal models suggests that dopamine and norepinephrine systems may follow different developmental trajectories. Whether a developmental asymmetry is also present in humans and how it may impact emotion-related learning and memory processes that render youth vulnerable to neuropsychiatric disorders is unknown. The proposed research aims to establish a mechanistic account of how emotional experiences drive selective memory prioritization over human development. We will investigate neuromodulatory system function and its relations to emotional memory over development using behavioral, psychophysiological, neuroimaging, and computational approaches. Aim 1 examines how affect induced by outcomes in a classic probabilistic reinforcement learning task influences memory and neuromodulatory-linked function from childhood to adulthood. Aim 2 assesses how naturalistic affect during emotional video watching relates to memory and brain function. Aim 3 characterizes age-related change in catecholamine function longitudinally, using neuromelanin-sensitive MRI as proxy, and relations with everyday emotional memory. This research has the potential to: 1) establish affective contributions to memory selectivity and persistence in controlled experimental, naturalistic experiential, and everyday memory studies; 2) determine relations between multiple non-invasive proxy measures of noradrenergic and dopaminergic system function and emotion-related memory across development; 3) provide a multimodal, cross-sectional, and longitudinal characterization of neuromodulatory-linked function; 4) delineate neurocognitive phenotypes that may relate to risk for psychopathology and inform the development of early interventions.