University Of Wisconsin-Madison

NIH Research Projects · FY 2026 · 2026-05

SUMMARY Cell-cell communication is essential for coordinating complex biological processes, and extracellular vesicles (EVs) have emerged as critical mediators of intercellular signaling. This project focuses on a unique class of large EVs called midbody remnants (MBRs), which are released during cell division. MBRs represent a novel mode of intercellular communication with potential implications in various physiological and pathological contexts. The overarching goal is to elucidate the mechanisms by which MBRs facilitate the transfer of information between cells. Specific goals over the next five years are to: 1) investigate how the informational content of MBRs varies in different biological contexts by identifying and characterizing conserved and unique molecular cargo (RNAs, small RNAs, and cell surface proteins) of MBRs from different cell types, including cancer, stem, and differentiated cells, and 2) elucidating the mechanisms by which recipient cells recognize and internalize MBRs. In addition, 3) we will investigate the potential hijacking of the MBR pathway by viruses for transmission, by examining viral RNA localization, factors required for viral RNA targeting to MBRs, and the ability of virus-infected MBRs to induce infections. Lastly, we will begin to: 4) investigate the role of MBRs in neurodevelopment and neurodevelopmental disorders, like autism spectrum disorder, by profiling changes in MBR informational content during neural progenitor cell differentiation and mechanistically testing genes necessary for cell fate and proliferative function that we find altered or loss in diseased states. The research design involves isolating MBRs from diverse cell types, performing transcriptomic and cell surface proteomic analyses, functional perturbation studies, live-cell imaging, and utilizing cellular and biochemical tools. This interdisciplinary approach will provide mechanistic insights from the genome- wide scale to sub-micron resolution. The findings from this project have significant implications for public health, as they could unravel the roles of MBRs in cell proliferation, RNA signaling, and EV biology, which are crucial in cancer, stem cell biology, and diseases associated with aberrant cell division and proliferation. Furthermore, understanding MBR function may identify novel therapeutic targets and establish MBRs as potential delivery vehicles for treating various diseases.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Chronic inflammation is a detrimental status, preventing efficient wound healing. In chronic inflammation, neutrophils remain active at the wound site after the acute inflammation period, continuing to recruit other immune cells and potentially exacerbating the wound condition. One approach for inflammation resolution is to promote neutrophil reverse migration, a path that some neutrophils take in regular wound healing processes. While signals and triggers have been identified for reverse migration, the underlying molecular regulation remains elusive. This study aims to decipher the molecular status of neutrophils during wound healing, with a long-term goal to identify determinants that promote neutrophil reverse migration. Our recent work has shown that there are four neutrophil subpopulations in zebrafish either in normal development or in burn wound healing conditions. The K99 Phase of this study will focus on identifying key subpopulations among them that are involved in reverse migration, tracking the dynamics of their molecular profiles, and examining the necessity and sufficiency of candidate subpopulations or factors in the process. By connecting molecular scale changes to the migration behavior, this part of the study will provide insight into developing novel strategies to achieve controlled neutrophil clearance for inflammation resolution. In this phase, I will receive training and develop skills in applying quantitative imaging on zebrafish models to visualize cellular behaviors. This training will prepare me to become an independent investigator who develops strategies to promote wound healing by integrating genetic and genomic approaches to study the role of innate immune cells in wound healing and regeneration. The R00 Phase of this study focuses on the role of opsin and phototransduction pathway in regulating neutrophil behavior, which is a wound-healing related molecular signature identified from my current work. By applying quantitative imaging skills on genetic models, I will assess the impact of light on neutrophil function, exploring the connection from physical interactions to molecular regulation in the control of neutrophil behaviors. In addition to scientific progression, this proposal also provides a detailed plan to facilitate my transition to independency. Aside from receiving training for imaging-related research skills, I will improve my communication, teaching and mentoring, and leadership skills through formal and informal interaction with my advisory committee, attending and presenting at conferences, mentoring students, and participating in leadership skill workshops. The proposed study will be conducted under the mentorship of Dr. Anna Huttenlocher and the support of my advisory committee. The Huttenlocher lab in the Department of Medical Microbiology and Immunology at University of Wisconsin-Madison provides an ideal environment for me to develop both research and non-research-related skills, supporting me in achieving research independency.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Matthew Blum, MD, MHS is an Assistant Professor of Medicine in the Division of Nephrology at the University of Wisconsin School of Medicine and Public Health. He seeks a Mentored Clinical Scientist Research Career Development Award from the National Institute of Diabetes and Digestive and Kidney Diseases to gain the expertise and experience necessary to develop an independent career as a physician-investigator studying the epidemiology of environmental exposures and chronic kidney disease. Fine particulate matter exposure is a ubiquitous air pollutant linked to over 3 million annual cases of chronic kidney disease. Addressing this challenge necessitates a deeper understanding of the underlying mechanisms by which particulate matter contributes to chronic kidney disease. The current proposal, under the mentorship of Drs. Brad Astor and Morgan Grams, proposes an investigation to discover the molecular signatures of real-world fine particulate matter exposure and elucidate their role in the development of chronic kidney disease using precision medicine tools. The specific aims of the proposed research are 1) identify epigenomic, proteomic, and metabolomic hallmarks of fine particulate matter exposure, 2) test associations of DNA methylation, proteins, and metabolites of interest with chronic kidney disease and death, and 3) evaluate the extent to which portable air cleaner use modifies metabolic hallmarks of fine particulate matter. The research will examine data from two complementary studies, the Atherosclerosis Risk in Communities study, a longstanding prospective cohort of adults across four U.S. communities, and AirPressureNYC, a clinical trial testing the blood pressure lowering effects of indoor air filtration among New York City residents. The results of this research will deepen our understanding of the molecular pathways associated with particulate matter exposure, which is critical for identifying at-risk individuals and developing therapeutic targets to mitigate the effects of air pollution on chronic kidney disease and other chronic diseases. The research effort will be accompanied by a comprehensive career development plan to develop the necessary skillset to carry out this research and establish research independence. The customized academic curriculum will be implemented in a robust academic environment with strong institutional support. Short-term goals include developing expertise in precision medicine tools, advanced epidemiology methods, and air quality modeling. The long-term career goal is to develop an independent research program investigating the environmental epidemiology of chronic kidney disease in an effort to reduce the morbidity and mortality of kidney diseases related to environmental exposures.

NIH Research Projects · FY 2026 · 2026-05

Abstract Invasive fungal infection by Aspergillus species, most commonly by Aspergillus fumigatus, remains one of the leading causes of mortality in immunocompromised patients undergoing solid organ or HSC transplantation because antifungal agents currently used in clinics are poorly effective in treating Aspergillus infection in patients with impaired immunity and neutropenia due to drug toxicities, drug-drug interactions, and the emergence of drug-resistant strains. Neutrophils provide the first line of defense against fungal infection. They effectively kill fungi by fungicidal oxidative bursts, presentation of fungal antigens to T cells, and by increasing fungal clearance by folding their hyphae and decreasing the spreading of infection with extracellular traps (NETs). However, the efficacy of neutrophil transfusions for A. fumigatus has been limited. Therefore, enhancing the antifungal properties of neutrophils is essential for advancing adoptive neutrophil transfer for treating Aspergillus infections. In this application, we aim to develop a novel therapeutic approach to effectively target A. fumigatus infections using induced pluripotent stem cell (iPSC)-derived neutrophils (iNeutrophils) armed with anti-Aspergillus CARs. The major goal of the R21 phase is to provide proof of principle that iNeutrophils equipped with anti-Aspergillus CARs possess superior fungicidal properties. In Aim 1, we will identify the single-chain variable fragment (scFv) that is most effective in iPSC-derived neutrophils for targeting A. fumigatus. In Aim 2, we will characterize the anti-fungal potential of anti-A. fumigatus CAR-iNeutrophils in vitro. If the R21 milestones are achieved, we will advance the development of CAR-iNeutrophil therapies into the R33 phase by enhancing their antifungal potential and demonstrating their efficacy and safety in vivo. In Aim 3, we will identify the most effective CAR configuration and genetic modifications that enhance the fungicidal properties of iNeutrophils. In Aim 4, we will assess the efficacy and toxicity of CAR-iNeutrophils in vivo using zebrafish larvae and invasive pulmonary Aspergillosis mouse models. Overall, generating CAR-iNeutrophils that directly target fungal species will enable the development of a new class of antifungal therapies. These therapies will employ the adoptive transfer of readily available neutrophils with enhanced antifungal functions to treat life-threatening drug-resistant A. fumigatus infections in patients with neutropenia or dysfunctional neutrophils.

NSF Awards · FY 2026 · 2026-05

This Faculty Early Career Development Program (CAREER) award supports the investigation of a new hybrid nanomanufacturing platform to build quantum information devices with high precision and reliability. The project advances the national interest by promoting the progress of science for in-space manufacturing and quantum computing and strengthening the United States' leadership in next-generation space systems and quantum technologies. The work will lay the groundwork for scalable production of qubit arrays, enabling more powerful and energy-efficient computation and measurement. The research also prepares technologies suitable for future space-based manufacturing, where microgravity can improve material uniformity in quantum devices. The educational plan integrates research with hands-on learning through an immersive virtual reality teaching platform. The virtual reality enabled training will increase participation and open pathways for learners, especially those who typically do not have access to hardware or testing facilities, to participate in advanced manufacturing and quantum technology education. The objective of this CAREER project is to establish a laser-assisted hybrid nanomanufacturing system that unifies three capabilities: electrically driven micro- and nano-scale printing of functional materials; coaxial femtosecond laser sintering to form dense, functional, and patterned three dimensional features; and dual-angle laser diffraction sensing for in situ quality monitoring and feedback control. The research will (1) model and measure coupled electric fields, droplet formation, and material transport during printing; (2) establish predictive models for laser-induced melting, neck growth, and microstructure evolution that govern device functionality; (3) design and implement the laser diffraction based sensing and control framework to enable nanoscale digital holographic microscopy; and (4) demonstrate optically addressable qubit arrays fabricated with the integrated platform. The project will also pilot scaffold-assisted growth strategies to program desired twist angles in stacked two-dimensional materials and integrate the resulting structures into device architectures. By addressing interactions among electric fields, fluid dynamics, and ultrafast laser energy deposition, the project is expected to deliver a scale-up pathway for fabricating high-quality qubit arrays and quantum devices and to provide a blueprint for adaptable production in microgravity environments. The resulting models, sensing methods, and process controls are anticipated to generalize across other additive manufacturing processes where precise patterning, defect mitigation, and closed-loop control are essential. 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 Speech fine structure (FS) information consists of frequency modulation cues that are vital for perceiving speech in the presence of noise. However, there is a lack of speech-based tests that can inform the processing of FS in a variety of population. Further, very little is known about how FS in speech is neurophysiologically encoded in different individuals, due to which there is also a lack of tools to objectively evaluate the neural coding of FS and effectively remediate FS processing in a variety of conditions that affect speech perception. In this study, we propose a novel and easy to use speech-based psychoacoustic and non-invasive electrophysiological (multichannel EEG) tools for assessing the perception and neural encoding of FS information in the presence of noise individuals with typical hearing and individuals with hearing loss. In Aim1, we leverage the phenomenon of temporal integration of FS in speech to parametrically assess the importance of FS information for speech perception in different types and levels of noise. Unlike non-speech stimuli, the methods developed in the study will use ecologically valid speech stimuli such that the results are generalizable to speech perception in real- world listening situations, and have the potential to characterize inter-individual differences and are applicable to wider range of hearing losses. In Aim 2, we will evaluate the the neural signatures of speech FS processing by parametrically increasing FS information in sentences. The neural signatures here will be quantified as the encoding of the speech envelope embedded on carriers with differing amount of FS, thus providing a proxy for FS processing. Our approach in retaining the envelope and modifying the FS information circumvents the problem of recovered envelopes in assessing speech FS processing. This will provide empirical evidence for the importance of FS for speech perception in noise and the metrics developed in this project will be useful to develop subjective and objective assessment tools and speech processing strategies in cochlear implants and individualizing of hearing aid fine-tuning to maximize listening outcomes. The study will further serve as the basis for further research designed to develop clinically viable psychoacoustic and electrophysiological protocols that can be easily realized in a limited test time to assay FS processing.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Autonomic dysfunction remains underdiagnosed and misunderstood but is a significant healthcare burden that affects millions of people in the United States. Autonomic disturbances are present in 40% of neurodegenerative diseases like Parkinson’s disease, Alzheimer’s disease, and other dementias and is often coupled with higher markers of cerebrovascular pathology. In this context, cerebrovascular health and autonomic function may be linked, but the connection is unknown. Additionally, little is understood about the contribution of autonomic dysfunction in tandem with drivers of cerebrovascular pathology on vascular contributions to cognitive impairment and dementia (VCID). The overarching objective of this proposal is to elucidate the link between drivers of cerebrovascular pathology and autonomic dysfunction and identify the impact on VCID biomarkers. Our preliminary data demonstrate that elevated cerebral pulsatility is associated with greater VCID biomarkers (e.g. white matter hyperintensities, WMH) in cognitively normal adults, and our published data demonstrate that adults with lower cardiovascular responses to physiological stressors are associated with greater WMH in healthy adults. Therefore, the central hypothesis is that disrupted cerebral hemodynamics will associate with impaired autonomic function, and together these contribute to greater VCID biomarkers. To test this hypothesis, I will use state-of-the-art magnetic resonance imaging (MRI) and the novel 4D flow MRI technique to measure cerebral hemodynamics (e.g., cerebral pulsatility and cerebral blood flow, CBF) in collaboration with experts in the field of MRI (e.g., Dr. Wieben, Co-sponsor). Additionally, I will use gold-standard techniques to directly measure autonomic function (e.g., sympathetic nerve activity, SNA; baroreflex sensitivity, BRS; and cardiovascular responses). Lastly, I will assess VCID neuroimaging biomarkers (e.g. WMH and cerebrovascular reactivity, CVR), and evaluate the associations between cerebral hemodynamics or autonomic function and these VCID biomarkers. Aim 1 will examine cerebral hemodynamics in middle-aged adults with and without symptoms of autonomic dysfunction. Aim 2 will determine the impact of cerebral hemodynamics and autonomic function on VCID biomarkers in middle-aged adults with and without symptoms of autonomic dysfunction. Collectively, these data will determine the link between cerebral hemodynamic and autonomic function and their contributions to brain health. The proposed work, in conjunction with the comprehensive training plan, will assist in the development of a scientific niche in the field and ensure success through the transition from a predoctoral trainee to a postdoctoral fellowship position. In addition, outcomes from this project will have broader implications for how to prevent or treat autonomic dysfunction that could also benefit brain health.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Adeno-Associated Virus type 2 (AAV2) is a single-stranded DNA virus in the Parvovirus family that is modified to serve as a platform for recombinant AAV2 gene therapy vectors (rAAV). AAV2 depends on a coinfecting “helper” virus (such as Adenovirus, Herpesvirus, and Papillomavirus) or exogenous DNA damage, to replicate in host cells. In the absence of a helper virus, non-replicative AAV2 genome recombine to form circular extrachromosomal episomes that persists long-term in the nucleus. During both replicative and non-replicative infection, AAV2 genomes localize to cellular sites containing DNA Damage Response (DDR) proteins. However, since the mechanism driving AAV localization and episome formation remain poorly understood, this poses a barrier to improving rAAV vectors for gene therapy. My preliminary work discovered that non-replicative AAV2 infection induces a replication stress response dependent on PARP1 signaling (Poly- ADP ribose polymerase 1). Additionally, PARP1 associates with the AAV2 genome by cooperatively binding with the pioneering transcription factor KLF4 (Krüppel-like factor 4) on the viral P5 promoter. Inhibition of PARP1 signaling or mutating the KLF4 binding site reduces AAV2 gene expression. Based on these findings, I hypothesize that both global and local PARP1 signals regulate the localization and recombination of AAV2 genomes in the host nucleus, driving efficient episome formation and gene expression. To test this hypothesis, I propose the following specific aims: Aim 1: To investigate how AAV2 genomes initially localize to cellular DDR sites, I will examine the role of PARP1 binding by using chemical inhibitors to globally modulate PARP1 activity and mutant viruses to locally disrupt PARP1-AAV2 interactions. By monitoring changes in AAV2 genome localization, I will elucidate the stepwise process driving this critical event. This aim is necessary to clarify how PARP1- mediated recruitment to DDR sites initiates viral genome processing, directly contributing to the understanding of episome formation. Aim 2: To define the molecular basis of AAV2 genome rearrangements that form extrachromosomal concatemers, I will identify the genomic sites where nicking occurs to trigger local recombination. Using PARP1 inhibitors, I will assess how blocking PARP1 signaling affects the formation of recombination junctions and the subsequent assembly of rAAV transgenes into large vectors. This aim is essential for understanding how AAV2 genome recombination underpins the formation of efficient gene therapy vectors. Together, these studies will provide unprecedented insights into the biology of AAV2’s non- replicative cycle, which remains largely unexplored. Elucidating the mechanisms regulating AAV2 localization and recombination will inform the development of more potent rAAV gene therapy vectors. A deeper understanding of AAV2's rearrangement and persistence mechanisms is critical for designing vectors capable of carrying large transgenes, a crucial step for advancing gene therapy application.

NSF Awards · FY 2026 · 2026-04

This award supports participation of 45 graduate students, postdocs, and early-career researchers at the 2026 Workshop on Recent Developments in Electronic Structure Theory, which is held June 22 through June 25, 2026, at the University of Wisconsin - Madison. This is a hybrid meeting with approximately 120 in-person attendees and up to 210 attendees total including the virtual component. The workshop facilitates the exchange of ideas between junior and senior researchers in electronic structure theory and serves as an opportunity for creating new collaborations. The workshop program focuses on the latest developments in electronic structure theory and computational materials science, exposing opportunities and new directions. The emerging area of incorporating the use quantum computers in electronic structure simulations to engage challenges in the field is among the workshop topics. Quantum computers may make possible accurate simulation of materials that with interesting properties that emerge from electrons that interact strongly with each other. This requires new algorithms and theoretical approaches stimulating workshop discussion. The simulation techniques covered by the workshop are used across a variety of fields including physics, chemistry, and materials science, both in academia and in industry. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2026 · 2026-04

This project will advance the understanding of causes and implications of recent extreme sea ice variability in the Antarctic through development of a research and logistical partnership with New Zealand. We focus on the Ross Sea as an area of strategic interest for the US and New Zealand, a major locus of recent variability, and as a key area of significance to global ocean circulation and intact ecosystem food webs, motivating the establishment of the Ross Sea Marine Protected Area (MPA). Understanding drivers of sea ice variability and its implications for this large and remote region requires integration across a range of approaches. This pilot study will integrate deployment and testing of advanced observing technology, modelling, and satellite remote sensing to assess capabilities and strategies for a broader integrated program to understand the drivers and implications of the recent rapid sea ice decline in the Ross Sea. This program seeks to advance capability in key areas, building a strategic collaboration between the United States Antarctic Program and the New Zealand Antarctic Research Program and other international partners, in alignment with the “Antarctica InSync” initiative, supporting coordinated, sustainable research in one of the world’s most logistically challenging environments. This will foster increased collaboration and shared logistics support, and further enhance US leadership in the Antarctic. Insights from this work will help improve predictions of how the Southern Ocean and sea ice both respond to and influence global environmental change. Antarctic sea ice extent has exhibited extreme recent variability, with a modest long term increase culminating in 2015, followed by a dramatic decline in 2016 and record lows in both summer and winter in 2023, although with significant variability over the past decade. These changes in sea ice extent are likely closely related to changes in thickness. The causes of this recent variability and its implications have been identified as a key theme for the international research effort “Antarctica InSync”. This collaborative RAPID project will (1) evaluate advanced and emerging technology that can contribute to an observational network capable of capturing key processes across the Ross Sea, (2) improve and evaluate both satellite and model products with in situ observations, and (3) develop a combined modelling, satellite, and in situ observational strategy to understand these processes. This is centered on capability development through evaluation of techniques in the McMurdo region, leveraging existing programs and logistics. This capability can then be exploited in future projects through widespread deployment of in situ observations, integrated with a refined modelling and satellite observation strategy to address the complex coupled role of various atmosphere-ice-ocean processes in driving sea ice variability. 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 · 2026-04

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) results from insulin insufficiency owing to near complete destruction of insulin- producing pancreatic β-cells by an autoimmune process. Over the last decade, the active participation of pancreatic β-cells in their own autoimmune destruction and the impact of aberrant stress responses to T1D disease progression have gained considerable attention. Pharmacologic agents targeting β-cell stress responses have shown promise in clinical trials, underscoring the potential for targeting β-cell stress in diabetes. Senescence is a β-cell stress adaptation program that has recently emerged as a key contributor to T1D pathogenesis. Senescence involves a cell-cycle arrest that prevents the replication of damaged cells and activation of a secretory program that promotes their clearance by the immune system. However, failure of immune surveillance leads to the accumulation of senescent cells, leading to chronic inflammation and tissue dysfunction. Our work has identified context-dependent heterogeneity of β-cell senescence, with different cellular stressors initiating distinct senescence programs with divergent effects on T1D progression. Senescent β-cells that normally accumulate in the non-obese diabetic (NOD) mouse model of T1D promote islet inflammation and disease progression. In contrast, NOD β-cells deficient for the unfolded protein response (UPR) exhibit an alternative senescence program marked by a secretome that promotes immune clearance and is protective against diabetes. Importantly, we have shown that β-cells exhibiting features of both senescence programs accumulate during T1D pathogenesis in humans. These intriguing findings highlight a serious knowledge gap regarding the nature and extent of β-cell senescence heterogeneity. As our discoveries show that distinct subsets of protective and pathogenic senescent β-cells exist in T1D, there is an urgent need to define the compendium of β-cell senescence programs and identify their underlying causes. We hypothesize that β-cell senescence exhibits molecular and phenotypic heterogeneity in a context-dependent manner based on the nature of the initiating stressor and subsequent temporal progression. In this proposal we will (1) define the molecular and epigenetic heterogeneity of senescent β-cells in primary human islets, and (2) track the temporal progression and stability of each senescence program. We will use cutting-edge techniques including single cell multiomics as well as proteomics of cell surfaces and secretomes. Leveraging the comprehensive molecular maps of β-cell senescence heterogeneity generated in this proposal, we will mine publicly available datasets of islets from T1D and autoantibody-positive samples to define the extent of β-cell senescence heterogeneity during the pathogenesis of human diabetes. Overall, these studies will support the development of targeted interventions to maximize the beneficial effects of β-cell senescence programs while mitigating the pathological effects of maladaptive β-cell senescence programs in T1D.

NIH Research Projects · FY 2026 · 2026-04

Protective mRNA Vaccines Against Tuberculosis. Summary. Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), remains a significant global health challenge, affecting approximately one-third of the world’s population and resulting in nearly 1.4 million deaths annually. The existing vaccine, M. bovis BCG (BCG), offers variable protection, with efficacy ranging from 0% to 80%. Our previous research has identified several innovative platform technologies aimed at enhancing vaccine development for major infections impacting both human and animal health. Notably, we have developed unique nano-adjuvant systems (NAS) that have demonstrated effectiveness against respiratory infections, including coronavirus and M. avium. In this project, we will utilize our expertise in tuberculosis vaccine development and nanoparticle vaccine platforms to assess the protective efficacy of a novel combination vaccine against TB. Our approach incorporates cutting-edge mRNA vaccine technology delivered via QuilA-DOTAP (QTAP), a novel lipid nanoparticle delivery adjuvant that ensures stable mRNA transcript delivery at various temperatures suitable for use in TB- endemic regions. Preliminary analyses of QTAP-adjuvanted combination mRNA vaccine encoding three mycobacterial antigens (Ag85B, Hsp70, and EsxH), referred to as QRNA, have shown robust protective immunity in mouse models challenged with both low and high doses of the virulent M. tb Erdman strain. In this project, we plan to First; examine the safety and immunogenicity of QRNA vaccines in variable murine models using both immune-compromised (Rag1-/-) and immune-competent (C3HeB/FeJ) murine models. Second; analyze the protective role of QRNA vaccine as a homologous or heterologous vaccine primed with BCG against challenge with M. tb Erdman (lineage 4, laboratory strain) or HN878 (lineage 2, hypervirulent clinical strain). Finally, we will assess protective immunity of QRNA vaccines in guinea pigs to identify vaccine-induced immune correlates of protection elicited by the mRNA vaccine candidates in guinea pigs, a TB model that mimic human infection. Once achieved, results from those aims will enhance our understanding of RNA-based immunization against TB. Future projects will further dissect the generated immunity in non-human primates, a more relevant model for human TB.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Understanding novel mechanisms by which animal viruses enter cells, evade immunity, and cause disease has scientific and public health importance. Arteriviruses are an understudied family of RNA viruses (related to coronaviruses) that infect a wide variety of mammals. The host and viral factors that determine arterivirus disease, persistence, and cross-species transmission remain unknown and unpredictable. This lack of understanding has implications for predicting/thwarting arterivirus emergence in humans, as some arteriviruses have been shown to infect human cells. Macrophages are exclusively infected by most arteriviruses, but the subpopulation(s) of macrophages that support arterivirus replication remain poorly defined. The process by which arteriviruses enter cells is highly novel and also poorly understood. Each virion displays an unusually large set of surface glycoproteins (7-11 depending on the virus) that are unlike any known viral fusion machinery. The macrophage-specific molecule CD163 is a required arterivirus receptor, yet CD163 by itself is insufficient to mediate arterivirus entry. We recently identified the neonatal Fc receptor (FcRn) as an important entry factor that arteriviruses use together with CD163 to gain entry into cells. Aim 1 of this project builds upon this discovery to define the molecular details of the arterivirus:FcRn interaction. In Aim 1a, we will map the site(s) on FcRn that are critical for arterivirus engagement by creating chimeric FcRn molecules that incorporate features of arterivirus-permissive and -resistant FcRn orthologs, with the goal of defining the domains, motifs, and residues involved in arterivirus/FcRn interactions. In Aim 1b, we will generate chimeric arteriviruses that contain combinations of glycoproteins from different arteriviruses, seeking to define the viral glycoproteins, domains, motifs, and residues involved in FcRn engagement. In Aim 1c, we will continue to develop our understanding of the host factors required for arterivirus entry by performing screens to identify additional host factors that are functionally redundant with FcRn for the viral entry process. In Aim 2, we will use the murine arterivirus (lactate dehydrogenase-elevating virus, LDV), which causes life-long viremia in adult mice, to understand several aspects of arterivirus infection in vivo. In Aim 2a, we will use a nanoluciferase-expressing LDV to perform body-wide imaging and identify the tissues that support LDV infection over time. In Aim 2b, we will hone in key tissues and identify the macrophage populations within these tissues that support LDV infection and determine how persistent arterivirus infection impacts recovery of target cell populations. Finally, in Aim 2c we will use FcRn-knockout mice to determine whether arteriviruses hijack FcRn’s physiologic role in placental biology, potentially explaining the high efficiency with which arteriviruses transmit vertically. This project will provide insights into novel mechanisms of viral entry, macrophage infection and dysfunction, viral persistence, and vertical transmission through the study of the neglected “pre-emergent” family of mammalian viruses, the arteriviruses.

NSF Awards · FY 2026 · 2026-04

Non-technical description: This project brings together researchers from USA and Germany to develop a new class of optical materials that can control light in unusual and highly customizable ways. These semiconductor materials, which we refer to as tunable anisotropic chalcogenides for optics have the potential to enable faster light-based communication systems, improved sensors, mixed reality displays, photon routers for quantum computing, and advanced tools for laser-based manufacturing. The team discover new materials by combining theory, computer simulations, and materials informatics, followed by the formation of single crystals and thin films using state-of-the-art synthesis techniques. The project includes extensive training for the next generation of materials scientists and engineers, international exchange opportunities for students, and community building activities such as an online photonics research forum. It includes a coordinated student exchange with the DFG partner, collaboration with Air Force Research Laboratory, and activities that cultivate entrepreneurship across the participating institutions. Technical description: The proposed research will create a new class of low-loss optical materials called tunable anisotropic chalcogenides for optics that have large optical anisotropy with controlled spatial variations and, in select cases, dynamically tunable anisotropy across the visible to mid-infrared spectral ranges. The team use first-principles density functional theory and materials informatics to identify promising low dimensional chalcogenides containing transition metal cations, followed by synthesis via vapor transport crystal growth and pulsed laser deposition. Structural and optical properties are probed using X-ray, neutron, and electron-based methods along with optical spectroscopies capable of quantifying linear and circular anisotropy. Alloying and ion bombardment are employed to systematically tune the anisotropy. The integrated closed feedback loop supports iterative optimization within a high dimensional materials space, thereby expediting the rapid discovery and developments of TACOs. The project is expected to lead to an open-access database with physical properties of optically anisotropic crystals. 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 · 2026-04

PROJECT SUMMARY Sleep spindle deficits are a promising biomarker and therapeutic target for schizophrenia spectrum disor- der (SSD), as they reflect underlying dysfunction in thalamocortical circuits. However, current non-invasive neuromodulation techniques lack the depth and precision to directly target deep brain structures like the thala- mus, where sleep spindles are generated. Temporal interference transcranial electric stimulation (TI-TES) of- fers a novel approach to selectively stimulate deep brain regions, such as the thalamus, while minimizing elec- tric fields elsewhere. Additionally, TI-TES permits simultaneous stimulation and high-density EEG (hdEEG) ac- quisition during sleep, a combination pioneered by the research team. Supported by preliminary data, the over- all objective of this project is to demonstrate that TI-TES can effectively target thalamic circuits and enhance sleep spindle activity in healthy subjects during non-rapid eye movement (NREM) sleep. Specifically, this pro- ject aims to 1) identify the optimal TI-TES parameters (frequency, location) for enhancing spindle frequency activity (SFA), and 2) determine the differential effects of thalamic TI-TES on fast and slow spindle subtypes, slow waves, and SO-spindle coupling. The central hypothesis is that slow and fast spindle subtypes can be selectively enhanced by modulating the location and frequency of thalamic TI-TES. The rationale for this pro- ject is that focal thalamic stimulation could restore normal spindle activity in SSD patients in a personalized manner, potentially improving thalamocortical connectivity and addressing broader neurobiological deficits. To achieve these aims, personalized, multipolar TI-TES combined with hdEEG will be applied to healthy subjects during the N2 sleep stages of a 90 min afternoon nap. Each participant will undergo bilateral thalamic stimulation at three target locations (broad thalamic, anterior, posterior) across separate nap sessions in a ran- domized, counterbalanced crossover design. Within each session, randomized stimulation frequencies will range from 8-16 Hz, along with a SHAM condition. Under Aim 1, increases in 8-16 Hz spectral power will serve as the primary metric for identifying the most effective stimulation parameters. Under Aim 2, detailed analyses of the recorded hdEEG data will explore the number, density, amplitude, duration, and topography of slow and fast spindles, as well as slow waves, and SO-spindle coupling. Individual spindles and slow waves will be iden- tified using automated detection algorithms. This research is highly innovative as it represents the first use of TI-TES to enhance sleep spindle activity, and, based on available literature, the first attempt to directly elicit spindles through thalamic stimulation in humans. The proposed research is significant because it is expected to provide strong scientific justification for future clinical trials of non-invasive neuromodulation therapies aimed at restoring normal spindle activity and alleviating thalamocortical dysfunction in patients with SSD, where cur- rent treatments remain inadequate.

NIH Research Projects · FY 2026 · 2026-04

Abstract This R35 Maximizing Investigators’ Research Award (MIRA) proposal aims to develop computational systems to address critical challenges in single-cell and spatial transcriptomics experiments. Single-cell and spatial transcriptomics experiments allow us to measure genome-wide gene expression in tens of thousands of individual cells (e.g. from blood, healthy tissue, tumors, or other diseased tissue) or across thousands of tissue spots. As a result, they have emerged as revolutionary tools that allow us to address scientific and clinical questions that were elusive just a few years ago. Computation has likewise been transformed by developments in artificial intelligence (AI). In spite of incredible advances, our ability to obtain genomic measurements continues to outpace our ability to derive useful information from them. This MIRA proposal addresses some of the most critical challenges that are currently limiting the pace at which the scientific community can turn valuable data from high-throughput genomic experiments into meaningful results. In particular, we plan to develop powerful and efficient computational methods to improve the downstream analysis of data from single-cell and spatial transcriptomics experiments. To reduce barriers for non-experts, the methods we develop will be implemented in accessible, interactive software that exploits the power of AI foundation models. Comprehensive benchmarking frameworks will also be developed so that our models and others can be appropriately evaluated. The proposed methods, software, and benchmarking frameworks are required to improve the use of AI single-cell foundation models in genomics, to maximize the information obtained from powerful single-cell and spatial transcriptomics experiments, and to enable biologists and/or clinicians to perform complex analyses without expertise in programming or data science.

NSF Awards · FY 2026 · 2026-04

This NSF CAREER project aims to create new ways to control complex systems using data. Modern technologies such as autonomous vehicles, intelligent robots, advanced energy systems, and smart infrastructure must make decisions in real time while operating in uncertain and rapidly changing environments. Traditional control methods rely on detailed mathematical models of how a system behaves, but building such models is often difficult, expensive, or even impossible for today’s highly complex systems. This project will bring transformative change by developing a new scientific foundation that allows engineers to design reliable control strategies directly from measured data, without requiring precise models. This will be achieved by creating mathematical tools that use time-series measurements to understand system behavior and guide decision-making. The intellectual merit of the project includes advancing the theoretical foundations of data-driven control, addressing fundamental open questions in modelling, analysis, and control design for complex dynamical systems, and developing methods that learn and adapt in real time while providing guarantees on performance and safety. The broader impacts of the project include improving the reliability and safety of next-generation autonomous technologies and integrating research results into education and outreach activities that prepare students and the broader community for a data-driven technological future. Despite growing interest in data-driven control, ensuring robustness under uncertainty and enabling real-time adaptation remain fundamental open challenges. Many existing approaches rely on fixed offline data or uncertainty models that are incompatible with control design, preventing their safe deployment in real-world environments. This project overcomes these limitations by adopting a behavioral systems framework, where the system is defined directly by its trajectories rather than intermediate parametric models. This unifying behavior-based perspective drives three coordinated research efforts. The first develops principled uncertainty modelling and robust control methods directly from data, ensuring rigorous safety and performance guarantees. The second incorporates streaming data into the behavioral framework to create adaptive algorithms capable of continuous learning and adaptation in complex, changing environments. The third validates this theory through high-fidelity simulations and robotics experiments. Together, these research efforts establish a unified, reliable foundation for the data-driven control of complex 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 2026 · 2026-04

Total Parenteral Nutrition (TPN) is a lifesaving clinical therapy that provides intravenous nutrition when patients are unable to feed enterally. Unfortunately, prolonged TPN is associated with serious complications, especially in children, including parenteral nutrition associated liver disease (PNALD) with features of steatosis, cholestasis, fibrosis, and eventual organ failure. A critical barrier in the field is that the etiology of PNALD is poorly defined and current treatments remain focused on alleviating acute symptoms rather than targeting the underlying pathophysiology. These challenges are especially problematic in pediatric populations where no mouse model has been available to examine PNALD complications for rapid translational research and potential intervention. To address this gap, recently developed a pediatric TPN model that supports metabolism for up to 9 days. Leveraging this, our preliminary data shows acute hepatic inflammation following TPN driven by macrophages, followed by subsequent infiltration of myeloid derived suppressor cells, leading to suppression of bile salt export proteins and cholestasis in most animals. These changes were associated with microbiome signatures, such as elevated intestinal Enterococcus or intrahepatic Salmonella, that correlates with hepatic cytokine expression. When antibiotics are administered, as a clinically relevant intervention, hepatic inflammation and infiltrating myeloid cell patterns are diminished, yet metabolic genes involved in fat synthesis become elevated, leading to steatosis risk. These findings suggests that immunological responses to intestinal microbes and their metabolites drive diverse phenotypic metabolic disease outcomes through myeloid cell augmentation in early life under TPN. Furthermore, in a search for missing enteral components that might help improve hepatic outcomes and growth, we identified that milk derived extracellular vesicles, which are rich in immune augmenting miRNA, such as Let- 7, effectively blocks hepatic immune responses and small intestinal tight junction proteins when provided intravenously with TPN in the absence of antibiotics. Finally, ultrasonication of bEV ameliorates their benefit in vivo and in vitro. Therefore, the use of microRNA will be explored as a therapeutic. This proposal will be the first to utilize a pediatric mouse model of TPN to systematically and rigorously define the time-course of PNALD, identify the causal mechanisms of divergent disease course, and exploring a promising therapeutic that may assist with the prevention and treatment of PNALD.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Chemoradiation (CRT) to the head and neck for cancer treatment exposes normal tissues to radiation, which has many devastating effects and often results in difficulty with speech and swallowing. Acute effect of radiation-induced peripheral neuropathy (RIPN) includes transient electrophysiological and biochemical changes combined with altered vascular permeability followed by demyelination. RIPN of either motor or sensory nerves in the head and neck could cause major disruption to the deglutition process including reduced tongue force and reflexive airway protection. Pharmaceutical interventions such as glibenclamide (GLC) have been shown to reduce inflammatory cytokines such as tumor necrosis factor (TNFα) and interleukin 6 (IL-6), decrease oxidative stress, increased neurotrophic factors, and increase the myelin sheath in response to peripheral nerve injury. However, controlled research examining these putative benefits of GLC for the treatment of RIPN in the oral motor cavity has not been performed and optimal treatment modalities or timelines have not been established. Our hypothesis is CRT delivered to the base of the tongue creates neuroinflammation in the PNS and CNS and that GLC therapy with the early implementation of tongue exercise can mitigate the neurogenic source of dysphagia and improve swallow-related physiologic outcomes. To examine these clinically-relevant issues, we will use a rat model to test tongue exercise and GLC treatment for the remediation of chemoradiation-induced muscle damage. The proposed research has two specific aims: 1): To test the hypothesis that treatment with GLC and tongue exercise will improve functional measures of deglutition in a rat animal model of head and neck CRT. 2): To test the hypothesis that the use of a GLC and tongue exercise will mitigate inflammation of the PNS and CNS following CRT. This work is innovative and significant because the mechanisms by which GLC treatment combined with tongue exercise can prevent or treat the effects of chemoradiation-induced speech and swallowing dysfunction is unexplored. Our animal model and treatment are analogs to treatments used in human patients and follow the Institute of Medicine guidelines for increasing translation. Further, this work is highly significant in providing a basis for understanding the mechanisms underlying the potential of therapeutic interventions for chemoradiation-induced dysphagia. Translation of findings will assist with increasing the effectiveness of treatments for chemoradiation-induced tongue muscle impairments that are so prevalent in patients with head and neck cancer.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Neural stem cells (NSCs) in the brain generate newborn neurons throughout life, providing an endogenous stem cell pool that can be harnessed to improve cognitive function during aging and neurodegenerative disease. Thus, understanding how adult neurogenesis is regulated may provide new targets and opportunities for therapeutic upregulation in these conditions. Intermediate filament (IF) proteins such as nestin and glial fibrillary acidic protein (GFAP) have been invaluable as markers for NSCs, increasing our understanding of the different cell states and cell types of the neurogenic niche. The IF protein vimentin is also expressed in NSCs, but due to variability in antibody quality and the lack of reporter mouse lines, very little is known about when and where it is expressed in the neurogenesis cascade. Recently, my lab has demonstrated many unique aspects of vimentin’s function and regulation in adult hippocampal NSCs in vitro. We found that vimentin mRNA is stabilized during quiescence, yet translationally repressed through an RNA-binding protein interaction with vimentin mRNA’s 3’UTR. As qNSCs activate, repression is removed, resulting in a rapid increase in vimentin protein. Additionally, as qNSCs activate, they traffic accumulated proteins that need to be degraded to the centrosome to form an aggresome. Vimentin collapses around the aggresome, forming a vimentin cage, bringing with it interacting proteins such as proteasomes. During cell division, the aggresome, vimentin cage, and associated proteins are asymmetrically segregated into one daughter cell. The daughter which inherits these cargoes has a decreased proliferation rate, whereas the non-inheriting daughter has a normal proliferation rate, resulting in a rejuvenative asymmetry between daughter cells. Vimentin is also required for efficient quiescence exit both in vitro and in vivo, further suggesting that vimentin’s role in NSCs is not only as a potential marker, but also as a key component to intrinsic mechanisms of quiescence exit. However, most of these findings were largely performed in vitro, thus we do not know if this process is conserved in the adult brain, nor how this asymmetric inheritance would affect the outcome of daughter cells in the neurogenic niche itself. To address these open questions, we created a novel transgenic mouse with endogenous vimentin fused to linker-mScarlet. We will characterize vimentin-mScarlet expression at the mRNA and protein level in cells of the hippocampus, and through prospective sorting followed by cell behavior analyses, we will reveal when and where vimentin mRNA and protein are expressed in the hippocampus. Importantly, we will also perform chronic in vivo imaging in cranial windows in these mice to visualize vimentin-mScarlet protein during quiescence exit and its asymmetric segregation during divisions, following the consequence of this inheritance in vivo. These studies will not only provide an important novel tool to the scientific community, but also reveal new knowledge on NSC subpopulation dynamics, answering critical questions about how NSCs rejuvenate their niche.

NIH Research Projects · FY 2026 · 2026-03

The discovery of novel drug targets and the optimization of treatment regimens remain critical challenges in addressing diseases with unmet medical needs. Despite substantial progress in genetic and multi-omics research, existing methodologies often lack generalizability across diverse populations and fail to capture the complex, potentially non-linear relationships underlying drug responses. Specifically, most human genetics- facilitated drug target discovery efforts using Mendelian randomization (MR) rely on genetic resources from populations of predominantly European ancestry, potentially exacerbating health and healthcare disparities that affect underrepresented populations. Additionally, the dose-dependent and combinatorial effects of drug targets remain poorly understood, hampering the development of tailored treatments and precision medicine approaches. Several methodological challenges persist in achieving reliable drug target discovery and treatment optimization. For instance, confounding due to linkage disequilibrium (LD) undermines the validity of MR analyses, particularly in diverse populations with varying genetic architectures. Moreover, the absence of robust causal inference frameworks for populations with pre-existing health conditions complicates drug target discovery. In addition, biases in existing non-linear MR approaches hinder accurate evaluation of dose-response relationships, especially for therapeutic targets with saturation kinetics or other non-linear effects. To address these challenges, this program will develop and implement advanced statistical genetics tools over the next five years. From a theoretical perspective, we will focus on improving the robustness of MR to LD-induced confounding, ensuring more reliable causal inferences across diverse populations. We will design novel MR methodologies incorporating structural equation models for drug target discovery tailored to individuals with pre- existing health conditions, providing actionable insights for patient-specific therapies. Additionally, we will refine non-linear MR approaches to address known biases, thereby enabling more accurate and clinically relevant dose-response analyses. With these innovations, this program will also deliver transformative applications. We will conduct systematic drug target discovery by incorporating multi-omics and genetic resources from populations of diverse genetic ancestries, as well as populations with different combinations of pre-existing health conditions. We will elucidate the dose-dependent effects of the identified drug targets to optimize therapeutic dosing regimens for clinical application. Furthermore, we will extend the factorial MR framework to explore the effects of combined therapies, identifying potential synergistic interactions and supporting the development of precision treatment strategies. By integrating applied and theoretical advances, this program seeks to establish a robust, generalizable framework for identifying and optimizing drug targets. Ultimately, our goal is to bridge the gap between genetic discoveries and their clinical translation, advancing personalized medicine to improve health outcomes for diverse populations in the United States and worldwide.

NIH Research Projects · FY 2026 · 2026-02

Project Summary/ Abstract An immediate manifestation of stroke is the altered expression of coding and noncoding (ncRNA) genes including microRNAs (miRNAs), which play a crucial role in regulating post-stroke brain damage and recovery. The miRNAs typically suppress target mRNA translation, and their stability is controlled by multiple factors, including biogenesis, degradation, and interactions with other RNAs such as long ncRNAs (lncRNAs). However, the mechanisms driving miRNA degradation after stroke remain poorly understood, limiting their therapeutic potential. Emerging evidence highlights Target-Directed miRNA Degradation (TDMD) as a key pathway regulating miRNA stability. Unlike conventional miRNA activity, where miRNAs suppress target mRNAs, TDMD enables target RNAs to induce miRNA degradation when they exhibit extended complementarity beyond the miRNA seed sequence. However, its role in stroke pathogenesis remains largely unexplored. Understanding whether TDMD contributes to miRNA depletion in the post-stroke brain could open new avenues for targeted gene regulation and therapeutic intervention. Our research highlighted that miRNA miR-7 is significantly downregulated in its mature form following stroke, despite its biogenesis remaining unaffected. This results in the induction of its primary target, α-synuclein (α-Syn), which exacerbates ischemic brain injury. Since the underlying cause of miR-7 degradation remains unclear, we hypothesize that TDMD is a critical mechanism for regulating miRNA levels in the post-stroke brain. Using bioinformatic analysis we noted that brain-enriched lncRNA Cyrano can preferentially bind miR-7 with extended complementarity beyond the seed sequence. Our preliminary studies showed significant induction of Cyrano in the post-stroke brain. Preliminary studies further showed that Cyrano deletion leads to increased miR-7 levels in the ischemic brain, confirming the lncRNA- miRNA relationship and miR-7 degradation likely through TDMD. TDMD requires ZSWIM8, a ubiquitin ligase, to expose miRNA for degradation. Our preliminary studies showed increased ZSWIM8 expression in the post- stroke brain, while siRNA targeting ZSWIM8 reduced ischemic brain injury, providing further evidence of TDMD activation. Building on preliminary evidence, we will therefore investigate TDMD as a key molecular mechanism driving post-transcriptional miRNA degradation in the post-stroke brain. We will pursue two aims to decipher the involvement of TDMD. In Aim 1, we will test that TDMD regulates miRNA miR-7 levels and post-stroke secondary brain damage whereas in Aim 2, we will test that TDMD requires ZSWIM8 for miR-7 depletion in the post-stroke brain. The overall goal is to uncover the prevalence and impact of TDMD in regulating miRNA levels and function after stroke. The long-term goal is to prioritize the development of newer therapies to improve post-stroke functional outcomes and facilitate recovery.

NSF Awards · FY 2026 · 2026-02

Mathematical optimization is the process of maximizing a performance or quality indicator by identifying the best possible value among the set of all feasible options. Optimization problems arise in virtually all human endeavors related to decision making including engineering, economics, sustainability, healthcare, and manufacturing. Instances of such optimization problems are particularly challenging to solve whenever evaluating performance and/or testing for feasibility requires an expensive simulation or experiment whose results may be corrupted by random errors. Bayesian optimization (BO) is a class of machine learning-based optimization algorithms that has recently been shown to achieve state-of-the-art performance in several important applications from this problem class such as in deep machine learning, validation of expensive simulators, and material and drug design. However, traditional BO methods treat the mathematical functions that model performance and feasibility as black boxes with unknown structure, which sets a fundamental limit on their computational efficiency. This observation is the key motivation for this research project, which looks to overcome these efficiency barriers via the development of new algorithms that exploit known problem structures within the Bayesian framework. These novel capabilities will be applied to three unsolved problems currently impacting society: (1) identifying unknown mechanisms in cellular decision-making processes for biomanufacturing; (2) discovery of new sustainable and economical lithium-ion battery electrode materials; and (3) real-time energy minimization in industrial heating, ventilation, and air conditioning (HVAC) systems. In addition, the project looks to tightly integrate research and educational activities through the development of interactive workshops and games related to decision science, which will be made accessible to the public. Through collaboration with local educators, planned outreach activities also will provide K-12 students from underrepresented communities with opportunities to learn about decision science. The proposed optimization methodology is inspired by the principle of grey-box modeling, which states that one should avoid learning what is already known when applying machine learning methods. The investigator conjectures a significant reduction in experimental and/or computational effort can be obtained in practice over traditional Bayesian optimization (BO) methods by properly leveraging prior (or domain) knowledge, which is almost always available in practice. Since prior knowledge can come in many diverse forms, the proposed research will focus on some of the most common and important examples. The three specific research aims are: (1) optimizing with hybrid physics-based and data-driven models given noisy and incomplete datasets; (2) optimizing with constrained multi-fidelity models that fuse data from a collection of heterogeneous sources of variable accuracy and cost; and (3) scaling to high-dimensional and sparse data problems through the incorporation of non-myopic and graph-structured formulations. The proposed research aims to promote convergence of statistics, machine learning, optimization, and process systems engineering. More broadly, the improved methods developed as a part of this research project will allow practitioners to solve a wide range of grey-box optimization problems with greater speed and accuracy. Planned outreach activities include educating K-12 students about decision-making under uncertainty via interactive workshops and games, incorporating new data-driven optimization material into the chemical engineering curriculum, and organizing cross-disciplinary professional workshops on the potential significance and impacts of cutting-edge BO technology. 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 · 2026-02

PROJECT SUMMARY/ABSTRACT Yellow fever (YF) is a serious mosquito-borne disease (~80,000 deaths annually) endemic to Africa and South America that is poised for emergence/re-emergence on a global scale. YF is caused by the yellow fever virus (YFV), which replicates primarily in the liver where it causes significant damage and organ dysfunction. Although treatment of YF is limited to supportive care, a highly effective live-attenuated YF vaccine (known as “17D”) was created in the 1930s. 17D differs from its parental strain, “Asibi,” by only 22 amino acids; however, the mutations responsible for the attenuation of 17D remain unknown. A major barrier to understanding 17D attenuation and YF pathogenesis is the lack of an immunocompetent small animal model that faithfully recapitulates important aspects of human YF disease. In collaboration with physicians and pathologists in Brazil, we have shown that infection of hamsters with hamster-adapted YFV-Asibi recapitulates human YF extremely accurately. Using this model, we have begun to tackle the most pressing questions in the YFV field. We developed a highly flexible reverse genetics system for YFV that enabled us to create large panels of hamster-adapted (HA)-17D/Asibi chimeric viruses. Using disease in the hamster as our primary readout, we identified two mutations in17D’s NS2B gene that, when introduced into HA-Asibi, completely abolish YF disease but have a relatively small impact on viral replication. It is well established that YFV-Asibi and YFV-17D evoke significantly different antiviral type I interferon (IFN) response, with YFV-17D inducing significantly more IFN than YFV-Asibi. Therefore, in Aim 1, we will first study the relationship between these two NS2B mutations, IFN induction, viral replication, and attenuation. We will determine the molecular basis for differential IFN responses between YFV-Asibi and YFV-17D. And finally, we will identify and characterize the innate immune factors that are antagonized by virulent, but not attenuated, YFV. Using the hamster model and specimens collected from YF patients in Brazil, we recently discovered that gastrointestinal (GI) damage plays a central role in the development of YF intoxication by allowing gut bacteria to opportunistically spread within the virus-ravaged host. Thus, intoxication is a septic-shock-like syndrome. There is now an urgent need to understand the drivers of GI damage in YF. Our preliminary studies have shown that YFV does not infect cells in the GI tract. Therefore, in Aim 2, we will seek to understand how YFV infection causes severe GI damage. First, we will determine the anatomical distribution of GI damage in the hamster model. Next, we will determine the anatomic distribution of vascular damage in YF. And finally, we will determine if the viral toxin NS1 is responsible for causing YFV-mediated GI damage. This project integrates viral genetics, antiviral immunity, and recent insights into YF intoxication into a new unified mechanism of YFV pathogenesis. This research has real-world implications for improving vaccine safety/efficacy and developing interventions aimed at reducing the morbidity and mortality of YF.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT The PACE (proteobacterial antiseptic efflux) family of transporters was only discovered about 10 years ago through functional genomics studies in Acinetobacter baumannii identifying genes upregulated in response to chlorhexidine exposure. Short chain diamines such as putrescine and cadaverine have been identified as likely native substrates for these transporters, which are conserved with the core genome. Since then, several homologs have been profiled, revealing that most (but not all) PACE transporters confer resistance to chlorhexidine, and about half confer resistance to short chain diamines. However, the full substrate profile and native substrate of PACE transporters that do not transport short chain diamines are not known. Mutagenesis and in vitro transport assays have identified a glutamate residue in the first transmembrane helix as important for proton coupling, but the substrate binding site(s) has not been identified. Transport is electrogenic, but the H+/substrate stoichiometry and transport mechanism is not yet determined. The sequence indicates that the PACE transporters likely have 4 transmembrane helices, but native mass spectrometry in detergent and native PAGE in solubilized membranes suggest different degrees of oligomerization and there is no experimentally determined three dimensional structure. The PACE transporters are only slightly larger than the more well- studied SMR (small multidrug resistance) transporters, which also have 4 transmembrane helices and a functionally critical glutamate in transmembrane helix 1. Based on this similarity, we tested the ability of two PACE transporters from different clades, PA2880 and AceI, to confer resistance to known SMR substrates. We identified additional substrates and observed that PA2880 confers resistance to some substrates but enhances susceptibility to others. Our lab has previously characterized the transport mechanism of the SMR transporters, which have similar functional promiscuity, and the proposed work adapts the methods we have developed to study the PACE transporters. Here we combine resistance/susceptibility assays in bacteria to more broadly characterize the substrate profile of AceI and PA2880 (Aim 1), cross-linking to determine topology in vitro and in the bacterial membrane (Aim 2), and in vitro liposomal transport assays (Aim 2) and NMR studies (Aim 3) to, identify key residues in proton- and substrate- binding and determine the mechanism by which these transporters confer susceptibility rather than resistance to some substrates.