Emory University

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Despite the advent of new diagnostics and treatments, tuberculosis (TB) remains a leading cause of overall mortality worldwide. There is an urgent need to better understand the host immune response to Mycobacterium tuberculosis (Mtb) and its role in causing lung damage and lung health morbidity as well as to train the next generation of TB scientists focused on patient-oriented research. The overarching goal of this K24 is to provide support for Dr. Russell Kempker to 1) have the protected time needed to successfully mentor early-stage investigators in TB patient-oriented research, 2) receive training in host immunology and bioinformatics as well as in team science, mentorship, and leadership and 3) to carry out innovative TB translational research on the host immune response to Mtb. Dr. Kempker has mentored >60 U.S. and international trainees in TB patient-oriented research and has leadership positions in numerous TB research capacity building programs including serving as the Co-Director of the NIH NIAID supported Emory/Georgia TB Research Advancement Center (TRAC) Developmental Core and MPI and Associate Program Director of two Fogarty International Center D43 Global Infectious Diseases TB Research Training Programs in the countries of Ethiopia and Georgia, respectively. The proposed research will leverage a long standing (>20 years) collaboration with the National Center for Tuberculosis and Lung Diseases in Tbilisi, Georgia including leveraging an ongoing NIAID R01 study (Contact PI, Kempker; R01AI173946) to conduct the proposed research and to provide mentored research opportunities. This K24 would utilize a unique cohort of persons with pulmonary TB undergoing adjunctive surgical resection to support new studies including 1) evaluating the impact of surgical removal of Mtb diseased lung on decreasing systemic inflammation and 2) utilizing enhanced spatial transcriptomics methods to evaluate the host immune response associated with various types of lung granulomas at a single cell level. Findings from this newly proposed research are expected to provide critical insights that can inform strategies for developing novel host directed therapies. Emory University provides an excellent environment for achieving the training goals for this K24 proposal and through it various schools and international partners for the recruitment of a diverse, strong pool of early-stage investigators. Overall, this proposal would directly address key research priorities in the NIAID TB strategic research agenda and provide Dr. Kempker the time, training, and skills to effectively mentoring the next generation of impactful TB scientists in patient oriented clinical and translational research. The long-term goal of the proposed activities in this K24 proposal are focused on improving the lives of persons inflicted with and suffering from TB and to provide meaningful contribution in the fight to end TB.

NSF Awards · FY 2025 · 2025-08

This project concerns a theoretical study which lies at the interface between different disciplines in science and engineering: nonlinear wave formation and fluids (soliton theory), certain probabilistic models (random matrices), and statistical mechanics (interacting particle systems). All the models of interest are foundational instances of integrable systems. Integrable systems are a special class of dynamical systems, describing a large array of physical models and characterized by a rich mathematical structure: many physical observables are conserved as the system evolves, and there exist techniques which in principle allow one to derive explicit, exact solutions for any initial data and precisely track their behavior. In certain settings, integrable systems display remarkable universal patterns, meaning that their solutions become independent on the initial data and, in some cases, on the governing equations, even in the presence of randomness. Analyzing universality properties of a system -or of a class of systems- allows to better understand the physical structure of the model(s) and to predict its ’expected’ behavior in applications and experiments. This project focuses on the study of asymptotic behaviors and critical phenomena for the aforementioned integrable models, and the emergence of universality properties. It aims to resolve open questions in these fields, based on classical tools and new approaches developed by the investigator. The project has significant applications in several physics models of current interest: growth phenomena (e.g. crystals, cancer cells), polymers, optical fibers, superconductors (e.g. Bose-Einstein condensate) and fluids (most notably, rogue waves and turbulence). In particular, one of the main objects of study in this project is the analysis of properties of special types of solutions, the so-called soliton gasses, whose existence in nature is supported by recent experimental evidence. The research agenda is organized into the following parallel directions of research. (1) Investigate asymptotic behavior and universal profiles of dispersive integrable partial differential equations in the presence of randomness: in particular, random soliton ensembles and soliton gasses. The research activity includes describing and classifying the wave patterns and coherent structures emerging as the dynamic of the random solutions evolves. (2) Analyze universality properties of statistical quantities of determinantal point processes and novel random matrix ensembles within certain asymptotic regimes, and their geometrical interpretation. The study involves using and further developing tools from complex and asymptotic analysis. The main strategy is the reformulation of each problem in terms of a particular boundary value problem, the so-called Riemann-Hilbert (RH) problem. The next concurrent steps are (a) establishing a geometrical connection between the RH problem, and Painlevé-type equations and isomonodromic tau functions, via a linear system of ordinary differential equations (Lax Pair), as well as (b) performing RH analysis with steepest descent methods. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT The alarming increase in antibiotic-resistant bacterial infections is a looming public health crisis. Gram-negative bacteria, including Escherichia coli and Pseudomonas aeruginosa, are leading causes of mortality attributed to antibiotic resistant infections. These bacteria build an outer membrane (OM) around their cell that acts as a shield, blocking the entry of many antibiotics and conferring potent intrinsic antibiotic resistance. Key to the OM’s barrier function is the packing of lipopolysaccharide (LPS) molecules into the surface-exposed outer leaflet of the OM bilayer. Phospholipids (PLs) then make up the OM inner leaflet. An LPS deficit in the OM allows PLs to mislocalize to the surface (to fill the void) and this weakens the OM. OM lipid asymmetry is critical for Gram- negative survival, virulence, and antibiotic resistance. Accordingly, bacteria employ active measures to maintain lipid asymmetry. We uncovered evidence for a novel inter-membrane lipid signaling mechanism by which E. coli can sense LPS deficiency in the OM and trigger increased LPS synthesis inside the cell so that OM lipid asymmetry can be restored. Signaling originates from an OM phospholipase (PldA) that degrades mislocalized PLs; lipid products from this reaction are internalized and notify the cell of the LPS deficiency in the OM. Our preliminary data suggest that PldA plays a key homeostatic role. Deleting pldA is lethal in mutant strains with slow transport of LPS to the OM. Moreover, PldA activity can potently resist antibiotic inhibition of LPS synthesis. Recent novel antibiotic discovery efforts have focused on disrupting LPS synthesis and transport to the OM. Our data forewarn that PldA may enable resistance to such drugs in the pre-clinical pipeline. However, our data also offer hope that interfering with PldA lipid signaling may potentiate the action of these emerging novel antibiotics. We aim to test the role of PldA in protecting E. coli against LPS synthesis and transport defects induced genetically or with antibiotic inhibitors. Our goal is to characterize the PldA lipid signaling pathway and unravel the steps leading to increased LPS production. We also aim to explore the conservation of inter-membrane lipid signaling by examining the newly discovered OM phospholipase of P. aeruginosa and assessing if it too can help counteract LPS deficits in the OM. Our study will establish a new inter-membrane lipid signaling paradigm in two important pathogens and will reveal new insights into how OM lipid asymmetry is continuously sensed and, if broken, rapidly repaired so that integrity of the OM antibiotic barrier can be continuously preserved.

NIH Research Projects · FY 2026 · 2025-08

The development of new synthetic methods has the potential to transform how pharmaceutical drugs are made and even what types of compounds will be designed as potential targets. Particularly important in the current era is the development of new strategies to access chiral scaffolds as it is generally recognized that there are has been an overreliance on the use of planar scaffolds for drug candidates. Enantioselective C-H functionalization is the central focus of this proposal. It represents an exciting new approach but a major challenge has been how to control site-selectivity in substrates containing multiple C-H bonds. The Davies group pioneered the rhodium-catalyzed chemistry of donor/acceptor carbene intermediates and found that these carbenes are exceptionally effective as selective C-H functionalization. In order to maximize their synthetic potential, Davies designed chiral catalysts of different shapes and sizes to control the three dimensional shape of the products and which C-H bond will be functionalized. His first generation catalyst was effective at reacting at activated C-H bonds. His second generation catalysts were sterically demanding and could distinguish between primary, secondary and tertiary C-H bonds at unactivated site. The third generation catalysts described in this proposal are bowl-shaped catalysts and are capable of subtle site selectivity between very similar C-H bonds. The secondary structure of the bowl plays a critical role in the selectivity. The program over the next five years will evaluate four series of bowl-shaped catalysts with a range of challenging substrates. In addition, the systems will be optimized so that it can operate under extremely low catalyst loadings. Many of the targets are related to compounds of pharmaceutical interest and the Davies group will work closely with companies to ensure the new methodology is impactful in drug discovery and large scale process chemistry.

NSF Awards · FY 2025 · 2025-08

Technical Summary: Liquid droplet coacervate formation through phase separation is driven by the positive entropy of backbone desolvation allowing for intermolecular enthalpic side-chain complementarity to dominate secondary nucleation events. Importantly, this hardwiring into environmental conditions serves as a molecular “Lamarckian-like” analog computer, providing specific functional assemblies templated from the initial coacervate. To define how environmental conditions and molecular templates organize each nucleation step, and to characterize the range of potential emerging functions in these hierarchical formations, we combine the expertise and perspectives provided by our labs’ systems chemistry approaches to build cooperative communication networks between different material phases. Our objectives will be achieved through 3 aims focused on creating biomaterial forms guided by the evolved achievements of bacterial cell information exchange: pili attachments (or more generally fimbriae) for nucleic acid exchange, small molecule reaction-diffusion networks, and extended nanowire energy transfer between condensates. These studies will provide the first strategies for creating self-assembling informational coacervates of cooperative and functionally synergistic synthetic materials that complement and expand the properties of living systems. Non-technical Summary Intrinsically Disordered (ID) synthetic materials have revolutionized the construction of transparent and moldable materials that are now used for so many societal applications. In contrast, Nature’s polypeptides have evolved novel functions ranging from scaffolding to locomotion, from material transport and energy acquisition to catalysis, signaling, and organismal defense, all based on a precisely folded three-dimensional protein structure. While backbone dynamics, side chain electrostatics, hydrophobics, van der Waals packing, and desolvation all contribute to protein folding energetics, these forces depend on media dielectrics, pH, temperature, external surfaces, and phase transitions, making environmental adaptability critical.1,2 Indeed proteins evolved intrinsically disordered regions (IDRs) that function as adaptable interfaces for mutualistic co-assemble, and on an even larger scale, liquid-liquid phase separated coacervates, known as biomolecular condensates (BMC) or membraneless organelles.3,4 BMCs appear responsible for processing environmental information, and most recently, a heptad repeat sequence within the glutamine-rich region (QRR) of the ID Whi3 protein was shown to be necessary and sufficient as a rheostat temperature control knob that controls both nuclear division and polarized growth in the fungus Ashbya gossypii. Within its compact genome of roughly 4,600 genes, this dynamic BMC provides Lamarckian-like evolutionary adaptation connecting to the digital genome, raising critical questions as to how general conformational dynamics might be processed as specific analog outputs. As we continue to learn the rules for controlling BMCs to function in order transitions, we have the potential to construct BMC peptide assemblies that access alternate critical functional assemblies for new life processes, including polymer translation and electron transfer chains for energy acquisition, and are poised to define other cooperative functions able to expand the functional adaptability of living systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-08

SUMMARY Tumor suppressor genes represent a major class of oncogenic “drivers” and offer robust window for therapeutic intervention. However, direct targeting loss-of-function tumor suppressor genes remains challenging, because that majority of tumor suppressors do not have enzymatic activity and exert their normal function through protein- protein interaction (PPI). Noteworthy, a unique class of tumor suppressor mutations are missense mutations encoding single amino acid substitutions that impair the normal PPI. These tumor suppressor mutations are defined as “loss-of-interaction” mutation. We aim to directly target the “loss-of-interaction” tumor suppressor mutations through discovery of small molecule PPI inducers to restore their anticancer functions. SMAD4 is such a tumor suppressor with “loss-of-interaction” mutations in cancer that disrupt its normal PPI with SMAD3. Using SMAD4 as a proof-of-concept study, we propose to utilize our newly developed TR-FRET SMAD4-SMAD3 PPI screening platform to reveal novel small molecule mutant SMAD4-PPI inducer (MuSMADid) that can induce the mutant SMAD4 PPI with SMAD3 and restore the pathway and cellular response to the tumor suppressive TGF-b signaling. Preliminary studies showed that the SMAD4-SMAD3 TR-FRET assay is robust and scalable in 1536-well uHTS format and is sensitive to monitor the SMAD4-SMAD3 PPI dynamic at single amino acid resolution. From a bioactive chemical library, Ro-31-8220, a bisindolylmaleimide derivative, was identified as potential MuSMADid that induced the mutant SMAD4 PPI with SMAD3 and restored the responsiveness of SMAD4 mutant colon cancer cells to the TGF-b anti-proliferation signaling. Identification of Ro-31-8220 as a potential MuSMADid provides strong evidence for direct targeting “loss-of-interaction” SMAD4 mutations. Together, this preliminary data supports our central premise that novel chemical probes can be discovered as potential MuSMADid by leveraging the established uHTS TR-FRET assay to screen structurally diverse chemical libraries. Based on the stages of discovery research, our proposal will focus on Aim 1 “Primary Screen Implementation” to identify MuSMADid hits with new chemical scaffolds, followed by verification with orthogonal PPI assays, and on Aim 2 “Functional Validation” to prioritize a list of validated novel small molecule anti-tumor MuSMADid for future hit-to-lead optimization phase. We will use the uHTS TR-FRET platform to rapidly identify primary hits and validated hits followed by characterization of their PPI induction and cellular activities in restoring the TGF-b tumor suppressive signaling. Accomplishing the goals of the proposed study is anticipated to generate a list of prioritized and confirmed small molecule MuSMADid compounds that show potent biochemical and biological activities in inducing the mutant SMAD4-SMAD3 PPI and restoring the TGF-b anti-proliferation signaling pathways. Top ranked anti-tumor MuSMADid with the strongest structural and functional evidence will be used as chemical probes to study the mutant SMAD4-dependent cancer biology and as candidates for future hit-to-lead studies towards the development of novel small molecule MuSMADid drug for precision oncology.

NIH Research Projects · FY 2025 · 2025-08

Anxiety and related disorders are common and impairing; in particular, avoidance is a highly detrimental component of anxiety that is poorly understood. To better understand and treat avoidance, a theory of avoidance that can account for experimental findings and translate across species is needed. This application proposes to use an interdisciplinary approach to combine neural and behavioral data to validate a novel computational model of avoidance, to test differences in avoidance behavior in people with clinically impairing anxiety and avoidance using this model, and to test whether model-predicted behavior is correlated with and has a causal influence on real-world avoidance behavior. The expected outcome of the proposed research is a novel approach to modify avoidance via a computational model-based operationalization of normative and maladaptive avoidance, opening avenues for translational human and non-human studies and treatment development. This expected outcome consistent with Goals 1 and 3 of NIMH’s Strategic Plan (specifically: 1.1.B: “Applying novel behavioral assays of [cognitive, affective, and social] domains that are causally linked to specific mechanisms at multiple units of analysis [e.g., genetic, molecular, cellular, circuit, physiological, behavioral, systems].”; 1.1.C: “Advancing novel assays to develop biomarkers of disease and for therapeutic discovery.”; 3.1.A: “Developing promising preventive and treatment intervention strategies that target specific molecular, cellular, neural circuit, or psychological mechanisms driving core domains of cognitive, behavioral, and affective function that are disrupted in mental illnesses, including those that cut across diagnostic categories.”; and 3.1.B: “Developing and validating quantitative behavioral and neurophysiological measures of target engagement in humans and animals as translational assays linked to functional domains disrupted in and across mental illnesses.”).

NIH Research Projects · FY 2025 · 2025-08

__________________________________________________________________________________ Abstract Due to intracranial vascular malformations, such as aneurysm, or stenosis, thrombosis and embolism, cerebrovascular disease (CVD) may manifest as ischemic/hemorrhagic stroke. The CVD ranks 5th in major causes of death and disability in the US and has claimed 160,264 lives in 2020, highlighting more investment in basic and clinical research to address the unmet needs for CVD prevention, diagnosis, prognosis and therapeutic intervention. As a minimum invasive procedure, the intra-arterial digital subtraction angiography (IA-DSA) provides hemodynamic information on the fly for intervention, enabling critical decision-making in percutaneous angiography guided procedures. Thus far, IA-DSA has been the gold-standard for CVD diagnosis and therapeutical interventions, though a few new techniques, e.g., CT/MRI angiography, are finding their clinical utilities. However, an intravenous DSA (IV-DSA) is still clinically desirable in recognition of the risk of complications associated with IA-DSA (Challenge I). Also, there exist motion artifacts (Challenge II) induced by vascular pulsation or the patient’s involuntary motion and nephropathy (Challenge III) induced by small, iodinated contrast agent molecules that are cleared from the body via renal excretion. Recently, X-ray phase-sensitive imaging (PSI) has emerged as a novel modality and is reaching human scale for clinical applications. The dark-field (D-F) contrast generated by microstructures in X-ray PSI can be substantially larger than the conventional attenuation contrast that has been used for imaging since X-ray’s discovery. Super-paramagnetic iron oxide nanorods have been proposed and implemented for theranostic applications, including T2-weighted MRI by shortening the time of spin-lattice relaxation. To overcome the above three mentioned clinical challenges in IA-DSA, we propose to investigate the feasibility of instantaneous DSA (iDSA), which is a synergetic combination of X-ray D-F imaging and SPIO nanorods, for intravenous CVD screening, diagnosis and therapeutic intervention with sufficient contrast sensitivity and no motion artifacts. Towards the long-term goal of establishing the iDSA as a standalone modality, we specify the following two Aims in the proposed project: (1) Optimization of SPIO nanorod’s dimension to maximize the D-F signal for iDSA via simulation study, (2a) Phantom study to optimize the imaging method and demonstrate the relation between D-F signal and iron concentration in SPIO nanorods, and (2b) Animal study to optimize the imaging method and assess its potential for iDSA with no motion artifacts.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Black or African American men experience the highest lung cancer incidence (60.6 per 100,000 people) and mortality rates (45.7 per 100,000 people) compared to any other racial/ethnic group of both men and women and African Americans are much less likely to undergo lung cancer screening compared to their White counterparts. Faith-based settings have proven to be an effective implementation setting for promoting cancer screenings among African Americans, but the ability of faith-based settings to serve as a setting to promote lung cancer screening is underexplored. To address these gaps, the trainee (Ms. Anderson) will collect data related to the readiness of African American faith communities in Georgia to promote lung cancer screening. Guided by the PRECEDE-PROCEED model, the specific aims are to (1) explore barriers and facilitators to lung cancer screening through interviews with African-American smokers in Georgia with special attention to the potential role of the church in lung cancer screening promotion through interviews; (2) conduct a scoping review that examines core elements of existing faith-based cancer screening programs to identify possible program components for a faith-based lung cancer screening promotion intervention; and, (3) assess organizational readiness for implementing promising program components in a future faith-based lung cancer screening promotion program among ministry leaders using a church readiness survey. The expected outcome will be data related to determinants of lung cancer screening among African Americans and the readiness among African American churches to implement lung cancer screening program components for a faith-based lung cancer screening intervention. This knowledge can inform the development of faith-based lung cancer screening promotion interventions that prioritize African Americans. Additionally, this work will support the training of Ms. Anderson, who is committed to becoming an NIH-funded independent investigator in cancer prevention and control, health equity, and implementation science. Ms. Anderson’s three-year training plan includes: (1) formally develop methodological skills and expand knowledge in implementation science and intervention development in the context of cancer prevention and control, (2) develop knowledge of community-engaged research and gain experience collaborating with African American faith communities, and (3) develop skills in mixed-methods approaches for intervention development, including measurement and survey development and qualitative research. The team of mentors, Dr. Kegler (Primary Sponsor), Dr. Epps (Co-sponsor), Dr. Guan (Collaborator), Dr. Morshed (Collaborator), and Dr. Higgins (Expert Advisor) will provide oversight, guidance, and mentorship throughout the course of the fellowship period in the topic areas of cancer prevention, implementation science, and mixed methods. Ms. Anderson will leverage resources within the doctoral program, Rollins School of Public Health, and Emory University. The candidate, mentorship team, and the environment are extremely well situated to achieve the proposed research and training aims.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest forms of cancer, with a dismal 5-year survival rate of only 13%. Despite advances in cancer immunotherapy, the efficacy of adoptive cellular therapies (ACT), including chimeric antigen receptor (CAR) T cell therapy, in PDAC is limited due to the dense desmoplastic stroma and immunosuppressive tumor microenvironment (TME). This project aims to develop and explore novel approaches to enhance the effectiveness of ACT for PDAC. The F99 phase (Aim 1) focuses on assessing the efficacy of mesothelin-directed CD26+CD4+ CAR T cells in murine PDAC models. CD26+CD4+ T cells have shown favorable stem-memory phenotypes and polyfunctional cytokine secretion capabilities. We hypothesize that CD26 on CAR T cells plays an active role in reshaping the TME through its enzymatic activity, which functionally alters immunosuppressive peptides. Our approach involves using congenic markers to distinguish between donor and host cells, allowing for detailed immune profiling via flow cytometry. We will assess tumor growth over time using luciferase-expressing PDAC cells and bioluminescence imaging. To elucidate the importance of CD26 enzymatic activity, we will employ systemic inhibition using sitagliptin and evaluate its impact on CAR T cell efficacy, persistence, and memory phenotypes. Additionally, we will investigate the potential synergistic effects of co-infusing CD26+CD4+ CAR T cells with CD8+ T cells to determine whether multifaceted T cell-mediated interactions enhance cellular therapy efficacy. The K00 phase (Aim 2) builds upon my predoctoral work in ACT development to characterize the impact of the microbiome on ACT outcomes in PDAC. Recent evidence suggests that the gut microbiome significantly influences the efficacy of cancer immunotherapies; I therefore seek to identify specific microbial signatures associated with improved responses to ACT. I will employ 16S rRNA sequencing and metagenomic analysis to characterize the gut microbiome composition in PDAC mouse models undergoing different adoptive cell therapies. I will also investigate the efficacy of ACT in response to different microbiomes, manipulated with antibiotics or by addition of defined microbial consortia into germ-free mice. Mechanisms by which the microbiome influences immune cell function will be interrogated both in vitro and in vivo. Based on these findings, I aim to develop novel microbiome- modulating strategies, such as targeted prebiotics or probiotics or novel engineered ACT strategies, to enhance the efficacy of adoptive cell therapies in PDAC. This research has the potential to significantly advance our understanding of adoptive cell therapies for PDAC and other solid tumors. By unraveling the intricacies of CD26- mediated immunomodulation (F99) and exploring the role of the microbiome in ACT treatment outcomes (K00), we aim to develop more effective strategies for overcoming the challenges posed by the PDAC tumor microenvironment. Ultimately, this work could lead to the development of novel, more potent adoptive cell therapies in pancreatic cancer, offering new hope for patients facing this devastating disease.

NIH Research Projects · FY 2025 · 2025-08

SUMMARY Dengue is an emerging global public health threat. Decades of extensive research undertaken primarily in dengue-endemic regions has resulted in the prevailing consensus that secondary infections and antibody- dependent enhancement (ADE) are pivotal in the pathogenesis of severe dengue disease. While previous research showed severe outcomes in naïve populations, our understanding of the mechanisms underpinning the pathogenesis of the severe disease during primary dengue infections, and how it diverges from secondary infections, remains limited. Bridging this knowledge gap is vital, given that dengue is spreading to new areas with substantial naïve population, compounded by lack of vaccines that can generate balanced immune response or distinct clinical management protocols for primary versus secondary dengue. Hence, the specific aims outlined below will provide comprehensive studies in India, where we find substantial burden of severe disease by primary infections, to concurrently scrutinize the disease spectrum in primary and secondary dengue, to elucidate pathogenesis. Aim 1, Determine the differences in innate immune responses during severe primary and secondary dengue infection. Aim 2, Evaluate differences in the magnitude, function, and post-translational modification of dengue-specific antibodies during severe primary and secondary dengue infection. Aim 3, Determine how dengue specific CD8+ and CD4+ T cell responses differ between severe primary and secondary dengue infection. The proposed studies encompass in-depth analyses of innate, inflammatory, antibody, and T- cell responses, alongside virological aspects, and their intricate interplay. Leveraging state-of-the-art tools and technologies such as viral inclusive s\cRNA seq, Fc glycosylation, and human monoclonals, the research will be primarily conducted in India utilizing samples from patient cohorts there. The joint ICGEB-Emory Vaccine Center laboratory in New Delhi, that we developed over several years to enhance human immunology research capacity, stands as an invaluable and unique resource for this endeavor.

NIH Research Projects · FY 2025 · 2025-08

PROJECT ABSTRACT In daily life, we use both hands to complete a wide variety of tasks as we navigate the world. Buttoning a shirt, preparing food, and driving a car rely on the ability to coordinate the movement of both hands freely and flexibly in pursuit of a goal. When people with motor disorders like Parkinson’s Disease (PD) lose their capacity to coordinate bimanual movement, these daily tasks become challenging with great detriment to their self-sufficiency and quality of life. Deficits in bimanual coordination—the structured, simultaneous movement of both hands—present early in the progression of PD and are resistant to classic modes of treatment. It is thought that a network of brain regions including the primary motor cortex and the supplementary motor area works together to coordinate the movement of both hands. Yet how populations of neurons in these brain areas organize their activity to achieve bimanual coordination and how these patterns degrade in PD remain unclear. To answer these questions, I will investigate the organization of activity patterns across neurons underlying the movement of both forelimbs in freely behaving healthy mice (Aim 1) and the MitoPark mouse model of PD-like pathology (Aim 2). The MitoPark model is a genetic model of PD that effectively captures the progressive onset of motor symptoms in PD through the selective disruption of mitochondrial function in dopaminergic neurons. To quantify whole-body motor coordination, I will use a combination of 3D tracking, wireless in vivo electrophysiology, and latent variable modeling. To encourage complex, naturalistic movement, I have designed a novel behavioral assay for bimanual coordination in which mice explore and climb in a transparent 3D environment that resembles their natural burrow structure. In Aim 1, I will track the 3D movement of healthy mice in daily sessions over the course of three weeks while wirelessly recording their neural activity in primary motor cortex (MOp) and secondary motor cortex (MOs). With canonical correlation analysis (CCA), a linear method for simultaneous dimensionality reduction, I will identify latent patterns of neural activity that covary with the movement of each forelimb. I hypothesize that these patterns occupy distinct subspaces of the population activity in MOp to enable precise, individuated forelimb control while occupying overlapping subspaces in MOs to facilitate coordinated movement. In Aim 2, I will use 3D tracking and wireless electrophysiology to capture the movement and neural activity of three cohorts of MitoPark mice at different stages of PD-like pathology. I hypothesize that, as deficits to bimanual coordination increase in severity with MitoPark progression, patterns of MOs activity underlying left and right limb movement will become more distinct—a neural population-level mechanism of motor dysfunction that could be targeted by future therapies relying on shifting neural dynamics toward a healthy state.

NIH Research Projects · FY 2025 · 2025-08

Cachexia is a common and lethal syndrome affecting up to 80% of patients with advanced cancer, responsible for approximately 30% of all cancer-related deaths. Despite being a significant factor that worsens patient outcomes, cachexia remains one of the most under-recognized and undertreated complications in cancer care. It results in severe muscle wasting, weight loss, inflammation, and profound fatigue, significantly reducing patients' quality of life and response to treatment. In head and neck squamous cell carcinoma (HNSCC), cachexia affects 40-50% of patients, leading to a median survival of just 13 months, which is only one-fifth of the survival time seen in non-cachexic patients. Cachexia remains poorly understood, and there is currently no approved treatment that effectively reverses this condition. Current management strategies, such as nutritional support and exercise, are largely ineffective and hope only to halt the condition, not reverse it. The effects of patient outcomes and lack of treatment options highlight the urgent need for a deeper understanding of the early biological mechanisms of cachexia to identify opportunities for timely intervention. Recent preclinical studies indicate that cachexia is driven by early systemic dysfunctions involving tightly interconnected metabolic, immune, and inflammatory pathways. These complex interactions create a vicious cycle that accelerates disease progression, highlighting the need for a comprehensive approach to understanding the systemic nature of cachexia. To address the shortcomings of prior human cachexia research, which focused mainly on isolated pathways, we propose an integrated multiomics approach to comprehensively explore these systemic mechanisms in HNSCC patients. By investigating plasma metabolomics, DNA methylation of circulating white blood cells, and inflammatory cytokines, we aim to identify key biomarkers and mechanisms driving weight loss, cachexia progression, and survival. Leveraging an existing cohort of over 200 HNSCC patients with comprehensive pretreatment and longitudinal data, we propose four specific aims: Aim 1 will compare correlations between immunometabolic markers in cachexic and non-cachexic patients; Aim 2 will assess associations between plasma metabolomics, DNA methylation, and weight loss; Aim 3 will develop an integrated immunometabolic network map linking biomarkers to cachexia symptoms; and Aim 4 will evaluate associations between biomarkers and survival outcomes. This research is highly feasible due to the availability of an established cohort with extensive pretreatment omics data and longitudinal patient outcomes. By uncovering the key mechanisms underlying cachexia and their systemic interplay, this study will provide crucial insights that are currently missing in human cachexia research. The findings could lead to targeted biomarkers and interventions, ultimately improving early detection, treatment, and quality of life for cancer patients. The significance of this research lies in its potential to revolutionize our understanding of cachexia as a systemic disorder and to provide a path toward effective interventions for this devastating condition.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Elopement is a prevalent and dangerous behavior for children with autism spectrum disorder (ASD).1, 2 Fortunately, treatments based in applied behavior analysis (ABA) can effectively reduce elopement.3-6 However, most parents of children who elope report receiving either no professional help or support that is likely not comprehensive or ongoing.7 Thus, there is a significant research-to-practice gap where children are not receiving the evidence-based strategies that exist for elopement. Community-based ABA services, provided by Board Certified Behavior Analysts (BCBAs), are ideal settings to address this gap as 40% of children with ASD receive ABA8 and the number of BCBAs has risen dramatically in recent years.9 Although BCBAs are trained in the behavioral knowledge underlying evidence-based strategies for elopement, they often do not receive hands-on training in assessing and treating elopement specifically (e.g., functional analyses)10 and may lack guidance for parent training,11 which is central to addressing elopement that occurs in home or community contexts. To help address the research-to-practice gap, our group developed a manualized parent-mediated Function Based Elopement Treatment (FBET) based on the past literature of ABA treatments for elopement. FBET impacts elopement through the mechanism of reinforcing and increasing appropriate behaviors that allow the child to access the functional reinforcer for elopement through more appropriate means.6 The intervention is time-limited, designed for non-specialized settings, and intended for use by BCBAs without specialized training. FBET demonstrated feasibility in a pilot randomized controlled trial (RCT ; N=24)6 and has positive results from a recently completed efficacy RCT (N=76; manuscript under review). To date, FBET has been delivered by BCBAs in a specialized, university-affiliated center with training and supervision fromexperts. There is a critical need to expand access by deploying FBET in community-based ABA clinics where the treatment can be more easily accessed. In partnership with 3 community ABA organizations, we propose a pilot, cluster randomized trial to evaluate the feasibility and preliminary effectiveness of FBET compared to treatment as usual (TAU) in these settings and evaluate inner and outer context factors related to implementation grounded in the EPIS (Exploration-Preparation-Implementation-Sustainability) model.12-14 Results will set the foundation for a R01 hybrid implementation-effectiveness RCT of FBET targeting the factors found to impact implementation in the current trial. Primary aims involve evaluating the feasibility of the pilot effectiveness RCT; evaluating preliminary effectiveness outcomes and analyzing the mechanism of action of FBET; and using mixed methods to evaluate factors associated with implementation in a community-based ABA setting. This line of research has strong potential to improve access to care for this dangerous behavior.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY Endometriosis is defined as ectopic endometrial-like tissue (lesions) and affects ~200 million women worldwide. Despite this, little progress has been made over the past 20 years in screening, detection, prognosis, and treatment. The primary symptom of endometriosis is debilitating pain, which profoundly affects quality of life. On average, women experience symptoms for approximately 10 years before being properly diagnosed. Standard treatments, including drugs or surgery, often fail to provide long-term pain relief. Thus, there is an urgent, unmet need to develop improved diagnostic and targeted therapeutic strategies for women suffering from endometriosis. Our central hypothesis is that impaired reactive aldehyde detoxification by ALDH2 underlies endometriosis-associated pain, and that the increased prevalence of the ALDH2*2 mutation among Asian women at least in part explains their increased prevalence of severe symptoms. Supportive of our premise, preliminary data in women with peritoneal endometriosis and pelvic pain show that endometrial ALDH2 activity is decreased, and this is associated with decreased ALDH2 expression and increased 4-HNE adduct formation, indicative of impaired reactive aldehyde detoxification. Further, in these women, endometrial 4-HNE adduct formation correlates with the presence of pelvic pain. Our preliminary data in ALDH2*2 knock-in mice with reduced ALDH2 activity reveal that abdominal pain-associated behaviors are exacerbated in a mouse model of peritoneal endometriosis and increasing ALDH2 activity with an enzyme activator alleviates abdominal pain-associated behaviors. Further, abdominal pain-associated behavior correlates with endometrial 4-HNE adduct formation. Guided by our strong preliminary data, we will further test our hypothesis by: 1) Determining the role of reactive aldehyde detoxification by ALDH2 in endometriosis- associated pain in a mouse model of deep endometriosis; and 2) Determining the role of reactive aldehyde detoxification by ALDH2 in endometriosis-associated pelvic pain in Asian women with wildtype and mutant ALDH2 and peritoneal endometriosis. The contribution of this proposed research is significant because it will address an unmet need for women with endometriosis pain by developing effective treatment and a biomarker to reduce diagnostic delay.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Muscle spindles provide sensory information critical for our balance and movement, yet their firing during active conditions remains poorly understood. This lack of understanding of muscle spindle function in voluntary conditions creates both scientific and clinical barriers to understanding the role of muscle spindles in healthy and impaired control of balance and movement. While the efferent drives to the gamma motor neurons (gamma drive) that innervate the muscle spindle are known to modulate the sensory signals from the muscle spindle according to the internal state (including attention, emotion, and task-goal), much of the studies are done using passive imposed movements. We propose a novel approach combining a computational biophysical model of muscle spindles with direct recordings from human leg muscle spindles using microneurography and muscle fascicles using ultrasound during voluntary isolated-joint and standing balance tasks. PI Ting and Co-I Simha have recently developed a computational model of muscle spindle that simulates the intrafusal crossbridge dynamics, allowing it to be generalized to a variety of movement conditions. The model predicts that the muscle spindle firing follows muscle fascicle length changes during passively imposed movements, including an initial burst at the beginning of the first stretch. Collaborator Bent is one of the handful of people in the world who can obtain microneurography measurements from human lower limbs and has recently published on the relationship between muscle fascicle length and muscle spindle firing in the human leg muscles in response to imposed sinusoidal movements during seated rest conditions. In Aim 1, we propose to measure muscle spindle firing in response to similar sinusoidal movements performed voluntarily and to use our model to understand the observed muscle spindle firing in the context of differing gamma drives. In Aim 2, we will extend our model to understand muscle spindle firing during natural and robotically-assisted postural sway. We will use the expertise of Collaborator Blouin, who has designed a unique robotic device that can decouple body part movements during human standing balance to identify sensorimotor control mechanisms. This unique combination of recent developments in computational modelling and robotic technology with the delicate and increasingly rare microneurography method allows us to understand muscle spindle function in the lower limbs during voluntary behavior in humans. The only data from human muscle spindles during voluntary movement are from many decades ago when technological limitations prevented measurements of muscle fascicle kinematics, application of decoupled body part movements during standing balance, and using computational models to infer the role of gamma drive, all combined in one experiment. The results from this proposal will significantly advance our basic understanding of human sensorimotor control of balance and movement, as well as provide a mechanistic framework for understanding neuromotor impairments such as spasticity that may arise from the dysregulation of gamma drive in chronic motor impairments in conditions such as cerebral palsy, stroke or spinal cord injury.

NSF Awards · FY 2025 · 2025-08

Graph Neural Networks (GNNs) are a powerful class of artificial intelligence models that help analyze complex relationships within data, from understanding how our brains function to predicting molecular interactions or identifying financial anomalies. While these models have shown remarkable promise, their widespread application in the real world faces significant hurdles: they often struggle to process extremely large datasets, adapt to unseen data, and maintain reliability when faced with intentional disruptions or faulty information. This project aims to overcome these limitations by focusing directly on the data itself, rather than solely on refining the GNN models. By making graph data more compact, cleaner, and better aligned with learning objectives, this project will enable more efficient, accurate, and robust AI systems across critical domains such as healthcare, finance, and national security. The project will address core challenges of GNNs related to data scale, distribution, and quality through three research tasks. The first task will tackle scalability by identifying key structural properties necessary for effective learning and developing graph condensation methods that significantly reduce data size while automatically preserving critical information. The second task will investigate how distribution shifts relate to graph properties and will introduce new data augmentation and test-time adaptation strategies to enhance generalization under out-of-distribution conditions. The third task will focus on data quality by creating unsupervised graph purification techniques to remove adversarial perturbations and by designing detection mechanisms to identify and mitigate various types of attacks. This project will include comprehensive evaluations using publicly available datasets and real-world applications, supported by collaborations with academic institutions and industry partners. The project outcomes will complement existing model-centric approaches and promote more efficient, robust, and generalizable GNN solutions across domains such as finance, neuroscience, and cybersecurity. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Anti-factor VIII (FVIII) alloantibodies, known as inhibitors, develop in 20-30% of patients with severe hemophilia A following therapy with FVIII infusion. This, in turn, makes bleeding difficult to control and prevent, resulting in increased morbidity and mortality, increased cost of care and decreased quality of life. Despite the negative consequences of inhibitor formation, no prophylactic therapy is currently available to predict or prevent inhibitor development. This largely stems from a fundamental lack of understanding regarding key immune pathways that initiate this process. In order to effectively understand risk factors that may predict the likelihood of inhibitor development and then prevent this process in at-risk patients, our long-term goal is to identify the immunologic mechanisms that initiate and then orchestrate inhibitor formation, in order to predict and then prevent the development of anti-FVIII alloantibodies in patients with hemophilia A. This is in line with a key priority identified by the NHLBI to identify central immune targets that may be used to prevent inhibitor formation. Addressing these pertinent clinical problems, our data in a pre-clinical model shows that both marginal zone B cells (MZ B cells) and CD4 T cells are required for FVIII inhibitor formation. Interestingly, FVIII fails to induce CD4 T cell proliferation or IgG antibody production following a single FVIII exposure. Instead, we found that ant-FVIII IgM, which forms following the first exposure to FVIII and increases with subsequent exposures, facilitates IgG antibody formation and CD4 T cell proliferation. Our central hypothesis moving forward is that upon exposure to FVIII, MZ B cells generate a polyclonal anti-FVIII IgM response, leading to immune complex formation, enhanced presentation of antigen by dendritic cells, and CD4 T cell activation. Using a pre-clinical model, we first aim to elucidate the immune populations responsible for anti-FVIII IgM production, with the hypothesis that MZ B cells and dendritic cells play a central role. We will next examine the impact of anti-FVIII IgM on FVIII localization and uptake by antigen presenting cells in the spleen. Moreover, laboratory protocols for isolation of polyclonal and monoclonal anti-FVIII IgM antibodies will be further developed, allowing evaluation of the influence of antibody epitope specificity and clonality on the immune events influencing IgM- driven CD4 T cell proliferation. Completion of the outlined research will provide vital preliminary data for the successful submission of an independent R01 application, which will focus on elucidating specific mechanisms underlying IgM-driven CD4 T cell proliferation in FVIII inhibitor formation. These studies possess the capacity to not only provide new insight into key aspects of inhibitor formation, but may also provide an important framework to develop rational approaches to prophylactically prevent inhibitor development in patients with hemophilia A. Thus, completion of the outlined research will facilitate successful advancement to a career as an independent physician scientist, combining the care of pediatric hematology patients with continued advancements in the field.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY We propose to acquire an ultra high-performance liquid chromatograph coupled with a SCIEX triple quadrupole 7500 tandem mass spectrometer (SCIEX 7500 LC-MS/MS) to be housed in the Targeted Analysis Core (TAC) in the Rollins School of Public Health at Emory University. The TAC provides analytical laboratory services for multi-media characterization and quantification of environmental contaminants and clinical biomarkers to several Emory research centers. The proposed instrument is state-of-the-art and delivers the highest level of speed, performance, and sensitivity currently available. Acquisition of this instrument will transform the sample processing capacity of the core with high sensitivity and robust quantification and allow effective assessment of exposures to a variety of well-known and emerging contaminants and biomarkers in exposure and epidemiological studies ongoing at Emory. NIH-funded Emory research centers will benefit immediately from the new features of the instrument. Researchers from these centers will make use of this instrument to enable a wide range of basic and biomedical research studies aimed at better understanding of the effects of environmental exposures on human health. While this instrument will be mainly used by the major user group, we expect it to impact many other researchers as well. The instrument will be supported by the TAC team with exceptional expertise in analytical chemistry and in providing training and support for high quality environmental exposure assessment.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT This K99 Career Pathway to Independence in Blood Science Award details a five-year training program to advance Dr. Bhavya Doshi’s career goal of becoming an independent translational physician-scientist in coagulation. The proposed application combines approaches using tissue culture and animal models with investigations using patient samples to address the current limitations in the understanding of the immune response to factor VIII (FVIII). Dr. Doshi’s career development and training objectives are geared to foster this research proposal and her overall career goal of understanding basic mechanisms that drive disease to develop targeted treatment and prevention strategies. During the award period, Dr. Doshi will engage with a robust team of scientists in hemostasis and immunology to build her immunologic and translational research skills, learn genomic skills necessary for her future career aspirations, and continue to develop her expertise in coagulation and inhibitors. Under the guidance of her mentors, Dr. Rodney Camire and Dr. Michael Milone, these training objectives will be met by a combination of didactic course work and workshops, participation in seminar series, hands-on research experience, and mentoring by her advisory committee. Her advisory committee is composed of world-renowned scientists with extensive mentoring experience and diverse and complementary scientific expertise. They are all versed in bringing basic research findings to the bedside. Hemophilia A (HA) is caused by a mutation in the F8 gene leading to dysfunction or deficiency of coagulation FVIII. The development of neutralizing antibodies (“inhibitors”) to FVIII is the leading cause of morbidity and mortality in patients with HA. Dr. Doshi’s preliminary studies in HA patients and mice are the first to support that the cytokine B cell activating factor (BAFF) is potentially a biomarker and/or regulator of the FVIII immune response. This proposal seeks to probe basic mechanisms in FVIII-specific B cell generation and how BAFF contributes to this humoral response in order to leverage these findings for therapeutic application. Aim 1 seeks to determine the location, kinetics, and types of B cell responses to FVIII in mice by using a novel method to identify FVIII-specific B cells and subsequently determine what happens to this compartment with immunomodulatory strategies, including anti-BAFF. As BAFF is both systemically and locally produced by fibroblast cells and hematopoietically-derived immune cells, respectively, Aim 2 investigates the source of BAFF and its effect on the T cell response to FVIII. Finally, Aim 3 assesses whether genetic drivers of cytokine levels for BAFF or T helper cytokines drive phenotypic changes in T and B cell subsets that lead to inhibitor generation and/or persistence in HA patients. Together, these studies will inform the immune compartments that are critical to the FVIII immune response and establish the preclinical data to translate anti-BAFF therapy to the clinics. The research and career objectives in this proposal will bolster Dr. Doshi’s research repertoire to enable her transition to an independent physician scientist focused on blood disorders, specifically hemophilia.

NIH Research Projects · FY 2025 · 2025-07

PROJECT ABSTRACT Infections due to carbapenemase-producing organisms (CPOs) are associated with high mortality rates due to extensive antibiotic resistance, and carbapenemase genes can be transferred between bacteria leading to out- breaks. Therefore, CPO identification has significant implications for antibiotic selection and use of infection control practices in healthcare facilities. No antibiotic susceptibility test profile accurately identifies CPO. Yet, existing methods for CPO detection, including phenotypic, molecular, and lateral flow assays, are not performed by most clinical microbiology laboratories due test complexity, prolonged workflows, subjective results, reagent instability, and high cost. Phenotypic tests have many key features necessary for a general CPO screen, yet logistical barriers still prevent their widespread adoption. The objective of the current proposal is to evaluate the potential impact of rapid CPO detection using a form-factor optimized phenotypic test paired with machine learn- ing algorithms to distinguish carbapenemase gene families at the time of GNB identification. Our central hypoth- esis is that a rapid, low-cost phenotypic test will increase CPO detection, decrease time-to-identification of a CPO infection, and facilitate timely initiation of effective antibiotics and isolation practices. Rapid CPO detection will be achieved with a phenotypic test optimized by our group (the mCNP) and ported into a structurally-pro- grammed sticker microfluidic to perform four discrete reactions in a single channel (the µCNP). These assays provide objective carbapenemase detection in ~20 minutes and will be used to achieve the objectives of this proposal, as laid out in three aims. 1) Distinguish carbapenemase class and gene family using machine learning. This aim is based on the capacity of machine learning to identify subtle changes over time in the colorimetric mCNP test and provide objective, automated results to the carbapenemase class and gene-family level. 2) Eval- uate rapid phenotypic detection of CPO in the µCNP, which will provide reproducible and stable carbapenemase detection in a low-cost, scalable sticker microfluidic that replicates mCNP performance. And 3) Compare rapid carbapenemase detection to standard-of-care testing by leveraging active protocols for collection of clinical cul- tures and ongoing studies of CPO carriage and healthcare environmental contamination. Rapid CPO testing will increase overall CPO detection and decrease time to identification from GNB-positive cultures and surveillance rectal swabs. Expected results include the demonstration of the utility of the µCNP as an accessible phenotypic carbapenemase test for appropriate antibiotic selection and rapid identification of CPO-colonized individuals for timely contact isolation. We envisage an important positive impact as our platform will provide equitable access to carbapenemase testing, improve patient outcomes, and prevent CPO outbreaks in healthcare networks.

NIH Research Projects · FY 2025 · 2025-07

Representing ~3% of the U.S. population, high-risk, non-elderly Medicare beneficiaries account for ~25% of overdose deaths and hospitalizations related to prescription opioids. Among this population, opioid-related harms are concentrated in the 20-25% who are prescribed long- term opioid therapy, primarily for chronic pain. We will first examine effects of a recent, important policy intervention – Medicare Part D opioid safety edits – on an understudied cohort of high-risk, non-elderly beneficiaries who are prescribed long-term, high-dose opioid therapy (Aim 1). Effective January 1, 2019, Medicare Part D plans are required to incorporate a set of enhanced safety edits into their drug utilization review systems. The most salient is a “care coordination edit” alerting pharmacists when daily doses of opioid prescriptions exceed 90 morphine milligram equivalence. The new Medicare Part D opioid safety policy is intended to identify overprescribing through pharmacist-prescriber consultation without directly restricting patient access (intended beneficial effect). It may also encourage the initiation of buprenorphine for opioid use treatment in lieu of high-dose opioid regimes (beneficial spillover effect). However, the possible misinterpretation of the 90-MME threshold as a “hard stop”, coupled with administrative burdens, may prompt rapid dose reduction and abrupt discontinuation (unintended detrimental effect). Furthermore, some key subgroups may be less likely to benefit from the Medicare Part D opioid safety policy and more susceptible to unintended harms (Aim 2). The Medicare Part D opioid safety policy initially evolved against the backdrop of the public health emergency declared in 2020. To minimize potential disruptions to health care, the federal government made temporary changes to the Medicare telehealth and opioid regulations, which may have facilitated beneficial effects of the Medicare Part D opioid safety policy and alleviated detrimental policy effects (Aim 3). We will use 2017-22 Medicare claims data and a quasi-experimental research designs to accomplish our Aims. We will assess appropriate opioid tapering (intended beneficial effect), inappropriate opioid tapering (unintended detrimental effect), buprenorphine initiation (beneficial spillover effect), and opioid-related adverse events in emergency department and inpatient settings (downstream effect). We aim to: 1. Examine effects of the first-year, pre-public health emergency implementation of the Part D opioid safety policy on high-risk, non-elderly beneficiaries who are prescribed long-term, high-dose opioid therapy; 2. Compare how key subgroups were differentially affected by the Medicare policy effects; 3. Extend Aims 1 and 2 to the pre- and post-public health emergency periods to elucidate the interaction of the Medicare Part D opioid safety policy with flexibilities provided during the 2020 public health emergency and beyond. Our findings will enable policymakers to develop nuanced policies and practices tailored to the high-risk, non-elderly population and key subgroups.

NIH Research Projects · FY 2025 · 2025-07

Interferon-induced transmembrane proteins (IFITMs) inhibit fusion of diverse enveloped viruses with host cells through a poorly understood mechanism. At least two modes of restriction have been described for IFITMs – protection from incoming viruses when expressed in target cells and reduction of infectivity of progeny virions upon incorporation into the viral membrane (dubbed “negative imprinting”). According to the currently accepted “tough membrane” model, IFITMs block viral fusion by increasing the negative curvature, lipid order and bending modulus of cell membranes and, thereby, arresting fusion at a hemifusion stage. However, our pilot results challenge this model by revealing that, whereas IFITM expression in cells increases the lipid order of intracellular compartments, the membrane of HIV-1 particles produced by IFITM-expressing cells has lower lipid order and membrane tension. Another critical new finding is that IFITM mutants that lack antiviral activity when expressed in target cells incorporate into and negatively imprint progeny virions. These results highlight key differences between the effects of IFITMs on cellular vs viral membranes and warrant further investigation. Our central hypothesis is that IFITMs inhibit viral entry through a multifaceted mechanism that involves: (a) rigidification of cell membranes at the sites of virus entry that arrests fusion at a hemifusion stage; and (b) “negative imprinting” of virions through reducing the order and tension of viral membrane and/or disrupting its nanoscale organization. To test this hypothesis, we propose the following Specific Aims. Specific Aim 1 will focus on ultrastructural basis for IFITM-mediated inhibition of viral fusion with endosomes, using correlative light-electron microscopy, electron tomography, and immunogold EM to elucidate the primary mechanism of the influenza A virus restriction by IFITM3 and the mechanism of fusion rescue by cyclosporine A treatment. Specific Aim 2 will define the determinants of stability of IFITM-arrested hemifusion intermediate through experimental manipulations that alter the propensity of arrested hemifusion to progress to full fusion. Specific Aim 3 will identify the IFITM residues that are critical for negative imprinting of virions, which are distinct from residues regulating the protection of target cells from infection; this will be accomplished by constructing and testing chimeras between active and inactive IFITM orthologs. Specific Aim 4 will delineate the effects of IFITMs on viral membrane in the context of negative imprinting of virions, which we hypothesize to occur through disruption of nanoscale organization of viral membrane and/or reduction of viral membrane tension. Successful completion of these Specific Aims will provide critical paradigm-shifting insights into the mechanism(s) of antiviral activity of IFITMs expressed in target cells and incorporated into progeny virions.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY In 1973, an industrial accident resulted in the shipping of a brominated flame-retardant chemical instead of a nutritional supplement to farms across Michigan. The mix-up led to the widespread contamination of the Michigan food supply, exposing an estimated nine million Michiganders to polybrominated biphenyl (PBB). In response to the disaster, the Michigan Department of Health and Human Services (MDHHS) created the Michigan Long-term PBB Registry. The study was created to examine the adverse health effects associated with exposure to PBB. One of the primary concerns of the exposed community was whether exposure to PBB would increase their risk of cancer. Fifty years after the PBB disaster, the affected community still does not have an acceptable answer to this question; although, preliminary evidence points to an increased risk of several cancer types. Dr. Michele Marcus and her team at Emory University have formed a strong academic- community partnership which now seeks to provide the affected community with some answers regarding their cancer risk. The Michigan PBB Registry includes over 7,500 ever-active participants and now includes children and grandchildren of those who ate the contaminated food. The PBB disaster provides a unique opportunity for scientific inquiry, while also addressing a pressing community concern. Since PBB had a defined exposure window, there is a possibility to study the harmful effects of an endocrine disrupting chemical during specific lifestages (i.e. adulthood, childhood, in utero). Additionally, while PBB is no longer produced in the United States (US), it has a similar chemical structure to other commonly used brominated flame retardants and shares many concerning properties with other contemporary chemicals (i.e. lipophilic, long half-life, resistant to environmental degradation). Our study seeks to understand the potential association between serum PBB levels and cancer incidence and mortality. We have linked the Michigan PBB Registry to the National Death Index to obtain mortality data and are in the process of linking to two state cancer registries to obtain cancer incidence and mortality data. We will utilize standardized incidence and mortality ratios to first understand if there is a higher burden of cancer in the Michigan PBB Registry compared to the general US population. Next, we will utilize longitudinal and survival models to examine the association between serum PBB levels (measured at several timepoints) and cancer incidence/mortality and time to these events, respectively. We will also examine these models stratified by lifestage at exposure. Our proposal also includes a review of our biorepository, that includes over 35,000 additional stored samples, to identify samples taken before and after cancer diagnoses to set up future nested case-control studies to examine underlying biological mechanisms. It is our hope that this study contributes not only to our understanding of the role of endocrine disrupting chemicals in cancer but provides much needed information to the affected community which can utilize this information to make informed healthcare decisions with their providers about cancer screening.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY Regular infusion of replacement factor VIII (FVIII) is the gold standard of care to prevent bleeding in most patients with hemophilia A (HA). Because HA patients have absent or altered FVIII, normal FVIII constitutes a foreign antigen. Accordingly, HA patients treated with FVIII can develop anti-FVIII antibodies that can neutralize the pro- coagulant activity of FVIII and/or shorten its circulatory lifespan. Antibodies against FVIII can thus render FVIII treatment ineffective, making patients prone to bleeding as well as increasing their risk of morbidity and mortality. However, only a subset of patients with HA become immunized to FVIII. The exact mechanisms driving immunity to FVIII remain poorly understood, though there is evidence suggesting that multiple B cell pathways of antibody production may be involved. What regulates whether a patient will form anti-FVIII antibodies and the pathway by which these antibodies will develop remains unclear. In the current application, we demonstrate that immunity to FVIII is regulated by recipient genetics in a tractable mouse model, providing a sensitive system to elucidate genetic regulators of the immune response to FVIII. The current application proposes to use a specific outbred population of mice (Diversity Outbred (DO) mice) that was generated by multi-generational breeding of 8 inbred parental strains. As DO mice are highly variant and have undergone extensive recombination, the use of DO mice greatly increases the likelihood of identifying key genetic traits regulating the immune response to FVIII. Quantitative trait loci (QTL) analysis will be carried out using several important phenotypes found within the B cell and antibody response to FVIII. In addition, as the genomics platform used can distinguish contributions from each of the 8 inbred parental strains used to generate the DO mice, and the complete genomic sequence of each strain is known, the resulting study will be able to narrow down variants in coding regions, regulatory elements, or areas predicted to affect transcript splicing. The capacity of this approach to identify genetic risk factors is shown in preliminary data through which the same team of investigators on the current application successfully mapped genes associated with immune responses to a distinct antigen (other than FVIII) but for which there are also genetic regulators of antibody responses in mice. In aggregate, identification of genes regulating the B cell response and ability to generate an antibody response to FVIII using this approach would both provide specific targets for the development of novel therapeutics to prevent an immune response to FVIII, as well as having the immediate benefit of providing a clinical test to help predict, a priori, which patients are more likely to make anti-FVIII antibodies and/or benefit from immune tolerance induction. Lastly, FVIII produced following gene therapy has the potential to induce the formation of antibodies against FVIII that can limit (or eliminate) the benefits of gene therapy. Thus, the proposed study has relevance not only to maintaining FVIII as a lifesaving therapy as part of current treatments for HA, but also to the developing field of gene therapy that promises to be a cure for HA and for which anti-FVIII antibodies can be a serious impediment.