University Of Arizona

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY TElomerase Reverse Transcriptase (TERT) is rate limiting in maintenance of telomere length by telomerase and also has telomere independent functions such as regulating cell growth. We showed TERT promoter mutations (mutTERT) occur in ~70% of Bladder Cancers (BC), most commonly at -146bp and −124bp which generate an identical 11 bp sequence that is recognized by a common upstream signaling mechanism. These mutations drive TERT overexpression, maintain BC growth and are associated with poor BC patient prognosis. These data led us to develop a panel of innovative assays specifically designed to identify, through a chemical library screening approach, small molecules that reduce TERT expression from mutTERT but not wtTERT. Discovery of such compounds is a first step in attaining our overall goal of developing a drug that is selectively toxic for BC cells, while having minimal toxicity on normal stem cells, which require TERT for self-renewal. Preliminary Data: Using CRISPR, we constructed BC cells expressing HiBiT or EGFP reporters downstream of mutant or wt TERT promoters. We validated these assays by showing that siRNA-mediated depletion of GABPA, a regulator of mutant promoter expression, selectively reduced mutTERT as monitored by HiBiT or EGFP. We deployed our mutTERT-HiBiT assay in an High-Throughput Screen (HTS) pilot screen of 605 kinase inhibitors and found 23 hits that reduced mutTERT-HiBiT. Among these were inhibitors to known drivers of TERT expression such as Aurora Kinase A, as well as inhibitors that were mutTERT selective, all of which targeted mTOR. This data leads us to the Hypothesis that small molecules that specifically suppress TERT expression driven by a mutant promoter can be identified by a phenotypic screen. Three Specific Aims test this hypothesis. In Aim 1, an HTS screen of a 350K chemical library will be conducted using a mutTERT-HiBiT reporter assay to identify compounds that decrease TERT expression driven off the mutant promoter at 16hrs. Hits will then be confirmed, and counter screened to remove those with unwanted activities. In Aim 2, priority hits will be purchased, reconfirmed in the primary assay and their selectivity to effect mutant over wt TERT evaluated head to head deploying EGFP reporter assays in BC cells and by allele-specific qPCR. An iterative analog-by-catalog (ABC) approach will be used to establish nascent structure-activity relationship of hit scaffolds and improve potency and selectivity. In Aim 3, the best hit from each scaffold that meet a set of rigorous potency and selectivity criteria will be selected as a probe and characterized in multiple assays to map their activity on downstream effects of TERT. These assays use a panel of BC and non-BC cell lines with and w/o TERT promoter mutations to determine the probes’ effects on: 1) downstream TERT-related gene transcription via evaluation of our TERT Expression Signature (TES); 2) telomere length quantitation; 3) Telomerase-dependent and independent TERT functions including cell growth. Future Directions: We set the stage for novel drugs targeting cancer specific, mutTERT driven, telomerase activity in patients with BC or other TERT-driven malignancies.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Over 95% of ALS patients exhibit cytoplasmic mislocalization and aggregation of the nuclear RNA-binding protein, TDP-43. These aggregates often contain N-terminal or C- terminal truncated isoforms of TDP-43 along with full length TDP-43 (flTDP-43). It is unclear if these aggregates are the direct cause of cell death, though reducing cytoplasmic TDP-43 or its isoforms in disease models improves cell viability. Recently, our lab uncovered a macroautophagy-independent endolysosomal mechanism that requires the E3 ubiquitin ligase, Rsp5/NEDD4, the ubiquitin segregase chaperone, Cdc48/VCP, and ESCRT machinery to facilitate trafficking of TDP-43 into multivesicular bodies (MVBs). However, many mechanistic steps in this process remain unclear including how this pathway relates to a previously defined means of endolysosomal cytoplasmic protein degradation known as endosomal microautophagy (eMI). Using biochemical, genetic, and microscopy-based approaches, I will determine the specific interactions, modifications, and cellular conditions under which TDP-43 is targeted to MVBs in human and neuronal-cell models. These experiments will uncover new mechanistic detail regarding TDP-43 endolysosomal degradation and eMI. I will also investigate the degradation mechanism of three TDP-43 isoforms: sTDP-43, TDP-35, and TDP-25. TDP-43 isoforms have distinct half-lives from flTDP-43 which suggests isoform-specific degradation pathways may exist. Targeted degradation of disease-specific TDP-43 isoforms may have greater efficacy in disease treatment, while preserving functional flTDP-43 species thus avoiding loss of function phenotypes. Using our unbiased genome- wide dot blot screening platform in yeast and candidate-based approaches based on our current work, we will elucidate the clearance mechanisms of all major TDP-43 isoforms. Collectively, this study will uncover new mechanistic detail regarding TDP-43 endolysosomal degradation, reveal broader insight into cytoplasmic proteostasis mechanisms, and advance the search for novel therapeutic targets for ALS and other TDP-43 proteinopathies.

NSF Awards · FY 2025 · 2025-08

As the occurrence and severity of wildfires increases across the United States, post-wildfire debris flows and flooding represent an increasing threat to communities. This work focuses on using ground vibrations, produced by debris flows and floods and recorded by seismic instrumentation, to better understand the conditions that trigger flows from within recently burned areas. Using this approach will allow the investigators to monitor a burned area with higher spatial resolution than traditional monitoring equipment, allowing them to record and characterize small-scale changes in flows and the rainfall conditions that trigger them. By monitoring for years following the fire, this work will also allow them to assess how post-wildfire flow hazards evolve with time. This work will improve models of debris flow and flood triggering, which will allow for better assessment of post-wildfire risks to communities downstream from burned areas. Better understanding these hazards and triggering thresholds will lead to improved models of landscape evolution and more-accurate early warning for downstream communities. This project will lead to a better understanding of debris flow processes and will enhance tools to study them using seismic data. Leveraging recent advances in seismic instrumentation will allow the investigators to generate in-situ observations of post-wildfire debris flows using a network of nodal seismometers installed in a recently burned area. Specifically, the investigators will test the following hypotheses: a) debris flow initiation locations will migrate downstream over time as the landscape recovers, b) the timing and location of debris-flow initiation can be predicted using a slope-dependent dimensionless discharge threshold, and c) debris flow surge magnitude and frequency are influenced by drainage area, rainfall intensity, and sediment supply. Using data from ~100 seismic instruments, validated with additional instrumentation, the team will produce a comprehensive catalog of post-wildfire debris flows within the study area, including the location and timing of initiation, velocity, and changes in grain size as they move downslope. These data, which will provide a more spatially and temporally complete picture of the lifecycle of post-wildfire debris flows relative to traditional monitoring methods, will enable the investigators to better understand the behavior of these flows. Results will advance fundamental understandings of debris flow processes and the ability to extract information about environmental phenomena from seismic data. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-08

Understanding and predicting air quality and how chemicals move and change in the atmosphere is important for protecting public health, supporting agriculture and energy systems, improving weather forecasts, and shaping environmental policies. To do this effectively, advanced computer models are needed that can connect atmospheric and chemical processes from local to global scales, while also making it easier for scientists to test new ideas, compare results, and work together. This project develops CheMPAS-A, a new atmospheric chemistry modeling system that incorporates additional chemistry features into a modern global weather model, the Model for Prediction Across Scales-Atmosphere (MPAS-A), and provides a seamless framework for simulating atmospheric chemistry from global to local scales. A key part of CheMPAS-A is a flexible, easy-to-use coding system that helps researchers quickly explore, test, and improve how atmospheric chemistry is represented, making science faster and more collaborative. By encouraging shared development, utilizing up-to-date software practices, and helping to train future scientists, CheMPAS-A transforms individual research into tools and knowledge that benefit both science and society. This project tackles two critical cyberinfrastructure challenges in atmospheric chemistry modeling: (1) creating stable, portable, high-performance, and user-friendly modeling software, and (2) developing an efficient, sustainable framework for integrating new scientific processes and algorithms. The project augments MPAS-A with a stable and functional chemistry capability by integrating the Multi-Scale Infrastructure for Chemistry and Aerosols (MUSICA) library. An innovative scripting capability called QUACS or Quick Updates to Aerosol and Chemistry Systems for Next Generation Multi-Scale Models enables the integration of custom parameterizations through a high-level, open-source, and globally used scripting language. QUACS empowers domain specialists and students to innovate. Enhanced configuration options and pre- and post-processing tools further improve flexibility and accessibility without compromising core stability. The outcome of this work is designed to accelerate scientific advancements and sustain scientific innovation in atmospheric chemistry modeling. This award by the Office of Advanced Cyberinfrastructure is jointly supported by the Division of Atmospheric and Geospace Sciences and the Division of Research, Innovation, Synergies, and Education in the Directorate for Geosciences. 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 Proteins carry out the majority of cellular functions and are essential for cellular activities. Most proteins must fold into the correct shape to fulfill their functions and need to endure constantly changing conditions within the cell. However, proteins cannot accomplish this on their own; they rely heavily on chaperones. Different chaperones fulfill various functions to ensure proteostasis. Here, we focus on Hsp60 and Hsp10, which assist in protein folding and prevent protein aggregation. Protein misfolding is implicated in many severe diseases such as Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, cystic fibrosis, and Huntington's disease. Despite decades of research, there is a fundamental gap in understanding the molecular mechanisms underlying the protective role of chaperones. This proposal will address four key questions: 1. How does ATP induce a simultaneous conformational change in all subunits of Hsp60? ATP can bind to each subunit of the heptameric or tetradecameric Hsp60 inducing an enormous conformational change. It is a cooperative process, but how the different subunits communicate with each other remains unknown. Understanding this allosteric mechanism is key to comprehending the kinetic cycle of Hsp60, which involves native substrate binding, encapsulation, and release of the folded substrate. 2. How do substrates interact with a chaperone? Is there a common binding motif? What is the timescale? A given chaperone can interact with many different client proteins. This study aims to determine if there is a common binding motif for substrates when interacting with the chaperone. This will provide detailed molecular principles of how substrates interact with chaperones, and this knowledge is valuable to provide insights into the chaperone's selectivity and its ability to handle various types of substrates. 3. What is the purpose of the tails of Hsp60? Several chaperones have unstructured flanking regions that are essential for their function. However, due to their flexible nature, these regions are not easily accessible to most biochemical methods. Solution-state NMR can provide visualization of how these regions interact with substrates, unraveling their contribution to substrate binding and encapsulation. 4. What is the role of the co-chaperone, Hsp10? Hsp10 has been overlooked for many decades, thought to be merely the helper of Hsp60. Recent studies reveal that Hsp10, in the absence of Hsp60, assists in protein folding and inhibits protein aggregation. Studies, how Hsp10 in the absence of Hsp60 interacts with substrates will help understand how Hsp10 contributes to proteostasis. The combination of all these studies will shed light on fundamental questions about the mechanisms that chaperones and co-chaperones use to efficiently fold proteins into their functional forms and prevent aggregation. A process which crucial to maintaining protein homeostasis, which is vital for life.

NIH Research Projects · FY 2025 · 2025-08

Abstract Non-melanoma skin cancer (NMSC) represents a major public health burden. Cutaneous exposure to solar ultraviolet (sUV) radiation is a causative factor in NMSC, and inflammatory dysregulation is a key mechanism underlying detrimental effects of acute and chronic UV exposure. The identification of relevant and targetable immune checkpoints such as PD1/PD-L1 is changing clinical outcomes of cancer patients. However, leveraging immune checkpoint modulation for cancer prevention remains mostly unexplored. Recent data from our laboratory has shown that PD-L1 is upregulated in epidermal keratinocytes after acute and chronic UV stimulation in human skin, and may therefore serve as a target for skin cancer immunoprevention (i.e., strategies harnessing tumorigenesis-directed innate or adaptive mechanisms of immune surveillance). However, the possibility that other stress-induced immune checkpoint proteins are also upregulated in the skin due to UV exposure and are therefore viable targets for immunoprevention of NMSC has not been explored. In this CIP- Net UG3/UH3 project we will pursue the novel hypothesis that overexpression of select UV-responsive immune checkpoint proteins early in the progression from normal skin to NMSC can promote an immune suppressive microenvironment and can be targeted to prevent photocarcinogenesis. In order to test this hypothesis, the UG3 phase (Aim 1) will use matched human samples of sun-protected skin, sun-damaged skin, actinic keratoses (AK), cutaneous squamous cell carcinomas (cSCC) and basal cell carcinomas (BCC) for transcriptomic profiling and immunohistochemistry analysis in order to identify novel immune checkpoint proteins that are upregulated early in the skin carcinogenesis process. The UH3 phase (Aim 2) of this study will confirm that these human targets are also upregulated early in mouse skin tumorigenic progression, can affect cellular responses to UV stress in keratinocytes in culture, and can influence cutaneous responses to UV and photocarcinogensis in a transgenic mouse model. Multiplex IHC will also be utilized to verify the top candidates using a translationally- relevant platform. The milestones associated with the UG3 phase are 1) Define 2-3 immune checkpoint proteins that are upregulated in keratinocytes of sun-damaged skin or AK as well as overexpressed in cSCC tumor cells (keratinocytic origin), and 2) Confirm these targets at the protein level using immunohistochemistry. The milestones associated with the UH3 phase are 1) validating immune checkpoint protein candidates to be UV responsive in mouse skin, 2) determining UV-inducible signaling/phenotypic responses to keratinocytic knockout (genetic deletion) of these immune checkpoint proteins in vitro and in vivo, 3) screen compound libraries to discover and characterize small molecules targeting these immune checkpoints, and 4) validating our previous IHC findings using clinically-relevant multiplex staining of the human samples. The proposed research will serve to identify novel molecular immune biomarkers for NMSC that will allow us to intervene at earlier stages of skin carcinogenesis to reduce the morbidity and mortality of cSCC.

NSF Awards · FY 2025 · 2025-08

Black holes are at the forefront of current mysteries in both astrophysics and fundamental physics. Ubiquitous in the universe, they serve as an energizing source for a variety of spectacular observational phenomena, but the underlying processes are poorly understood. Similarly, black holes are key players in thought experiments probing the apparent incompatibility between general relativity and quantum theory, the reconciliation of which is arguably the biggest open question in fundamental physics. In the black hole context, two normally disparate areas--astrophysics and fundamental physics--suddenly share many mathematical and physical threads, and simultaneous study of the two creates new opportunities and synergies. This award is concerned with the appearance and effects of a black hole on an outside observer (its "signatures"), both in real astrophysical observation and for hypothetical observers featured in thought experiments probing quantum gravity. In particular, the award studies how a black hole bends light to create a "photon ring" visible to future radio telescopes, and how a black hole passively destroys ("decoheres") quantum states and their associated information. The team will train students in STEM areas. Studies of the black hole photon ring will focus on which aspects can be observed with the next generation of telescopes, and how these aspects encode information about the black hole spin. The key challenge is that the effects of black hole spin are subtle, and easily confused with errors in modeling the astrophysical plasma (accretion flow) providing the emission. The general strategy to break such degeneracies is to consider the photon ring not in isolation, but in comparison with the main emission. Since the two originate from the same source, only affected differently by the black hole, their relative properties encode information about the black hole. The award pursues theoretical modeling focusing on the relative astrometry, thickness, and shape, aiming to discover a robust method for measuring black hole spin with near-term electromagnetic observations of supermassive black holes. Studies of decoherence by black holes will focus on obtaining precise decoherence rates and comparing those to analogous rates for ordinary bodies at finite temperature. Currently, precise rates are available only for decoherence mediated by electromagnetic or scalar fields; the award will produce analogous results for gravitationally mediated decoherence. The key challenge is that the "laboratory" hosting the quantum state must now be modeled along with the state itself, introducing technical and conceptual complications. However, it is precisely these challenges that give the gravitational problem its special interest: everything gravitates, so the black hole decoherence effect is universal and unavoidable, and may play a key role in questions of information flow in quantum gravity. 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 Evening sleep problems are prevalent in early childhood and increase the risk for poor behavioral and health outcomes. Sleep is regulated in part by the timing of the circadian clock. Light is the primary zeitgeber (time cue) of the circadian system, and evening light exposure can suppress production of the sleep-promoting hormone melatonin and delay circadian timing, resulting in increased alertness and delayed ability to sleep. This K01 research project will examine the feasibility and preliminary efficacy of two evening light mitigation strategies to advance the timing of sleep and the circadian clock in children. Central to this research is accumulating evidence indicating high sensitivity of the early circadian system to light exposure in the hour before bedtime, even at low intensities. To date, however, research is lacking on light-based circadian health interventions in early childhood to improve sleep timing and behaviors. Children aged 5.0-6.9 years with parent-reported sleep onset difficulties will complete a single five-week protocol. After baseline assessments of circadian timing (dim-light melatonin onset), sleep timing, duration, and quality (actigraphy), and parent-reported sleep behaviors, children will be randomly assigned to one of three two-week intervention strategies: (1) adjustment to home lighting environment (implementation of smart lightbulbs to reduce short-wavelength light and light intensity 1 h before bedtime); (2) reduction in evening light exposure (amber-tinted glasses 1 h before bedtime); or (3) a sham intervention (clear glasses 1 h before bedtime). Post- intervention, a secondary assessment of all outcomes will be performed, as well as qualitative interviews with parents. These data will be used to examine the feasibility and acceptability of the intervention components (Aim 1), their preliminary efficacy in advancing children’s sleep and circadian timing (Aim 2), and whether individual differences in photosensitivity (assessed via pupillometry) moderate the response to the intervention strategies (Exploratory Aim 3). In addition to these research aims, this K01 award will incorporate training in four interdisciplinary areas: clinical and translational science, designing and implementing interventions with young children, advanced methods in photometry and photosensitivity, and biostatistics and professional development. The research and training proposed will provide preliminary data for a competitive R01 application and be an important step in facilitating Dr. Hartstein’s transition into an independent scientist with a research program committed to examining modifiable environmental and behavioral factors affecting children’s sleep and circadian health.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY After a mass-casualty radiological or nuclear accident, the first triage will need to distinguish exposed from non- exposed individuals to organize the countermeasure response. In this objective, there is a need to develop a bioassay that can screen tens or hundreds of thousands of individuals in a timely manner directly on field. Our team identified radiation responsive proteins and transcripts in leukocytes that can discriminate samples irradiated with dose < 2 Gy from ≥ 2 Gy. In this application, we propose to design, develop, and test a “sample- in-answer-out” radiation exposure assay, named Self-Administrated MUltiplex RAdiation Indicator (SAMURAI) kit. The SAMURAI kit is a self-administered, unpowered, and cost-efficient point-of-care paper-based vertical flow immunoassay (VFI) system based on a safe “tube and cap” user interface that allows the isolation and multiplex detection of both proteins and RNA from leukocytes. The handheld platform will consist of a sample preparation module (SPM) coupled to a detection (VFI) module and will be able to process sample from collection to data reporting in less than 30 min. To achieve this goal, we propose the following aims: #1) develop biodosimetry protein and transcript bioassays for paper-based format. This will involve the design and testing of sandwich immunodetection for proteins and the development of an assay chemistry allowing transcript detection using an amplification-free approach based on the detection of DNA:RNA hybrids; #2) design and test a SPM to extract proteins and gene transcripts from leukocytes. The SPM will be designed to load fingerstick-collected whole blood, lyse red blood cells, capture leucocytes by anti-CD45 antibodies and isolate RNA and proteins; #3) fabricate a VFI module to process sample directly from the SPM and generate a quantifiable signal on a multiplex paper membrane to assess irradiation status. A capillary-driven pre-existing VFI module will be adapted to fit to the SPM and transfer sample through the reaction pads and to the VFI multiplex membrane to generate a visible colorimetric signal that could ultimately be captured with commercial smartphones and analyzed by our VeriFAST software App. The ability to detect simultaneously protein and RNA biomarkers will make the SAMURAI kit useful, not only for the preliminary triage during radiobiological accident, but for a large variety of applications, broadening its appeal to industry partners.

NIH Research Projects · FY 2025 · 2025-07

Coccidioidomycosis, also known as Valley Fever, is a serious fungal infection caused by the Coccidioides species. These dimorphic fungi thrive in the arid regions of the Americas, including the southwestern United States, Mexico, and certain parts of Central and South America. Recently, there has been a substantial rise in Coccidioidomycosis cases, extending into areas previously unaffected and creating a significant health risk. Predictions suggest that by 2035, more than half of the US could be at risk. Unlike most fungal infections that typically target those with weakened immune systems, Coccidioides can also infect individuals with healthy immune systems. While many people may not show symptoms or only suffer mild, flu-like ones, serious cases can lead to ongoing lung and other organ issues, occasionally resulting in death. The reasons why the disease affects some people more severely than others remain unclear. There is an urgent need to better understand how our bodies fight off Coccidioides, especially through the initial innate immune defense. The primary route of infection involves inhaling fungal spores, leading to lung infection. Our research has discovered that a set of airway epithelial antimicrobial proteins (AMPs), including SCGB1A1 and BPIFA1, were significantly elevated in the lung without apparent inflammation or a spike in inflammatory/immune related genes. These proteins were not triggered by non-virulent fungi, hinting at a unique response to pathogenic Coccidioides. In mouse models, the absence of SCGB1A1 markedly increased susceptibility to lung fungal infection. In vitro studies have confirmed that BPIFA1, but not SCGB1A1, exhibited anti-Coccidioides activity. Furthermore, SCGB1A1 deficiency impaired airway epithelial BPIFA1 secretion by reducing extracellular vesicle production. Thus, the epithelial SCGB1A1-BPIFA1 axis plays a critical role in the early pulmonary defense against Coccidioides. Our goal is to uncover the mechanisms of early innate responses to Coccidioides infection, to understand the mechanisms of antifungal effects of BPIFA1, and to determine the mechanisms of BPIFA1 secretion regulated by SCGB1A1. This proposal represents the first effort to comprehensively investigate the molecular mechanisms and functional impact of epithelial AMPs during Coccidioides infection. Notably, all experiments involving Coccidioides spp. must be conducted within a BSL3 containment facility. Leveraging this critical resource, along with a multidisciplinary team skilled in lung epithelial biology, mycology, EV biology, and AMP engineering, we are uniquely positioned to push the boundaries of mechanistic studies and lay the foundation for the future development of innovative antifungal therapies aimed at advancing the diagnosis and treatment of Coccidioidomycosis.

NSF Awards · FY 2025 · 2025-07

Soft materials—such as leaves, flowers, sea slugs, and corals—bend, twist, and ripple into complex shapes that are both beautiful and functional. These systems belong to a broader class of materials known as soft matter, which are characterized by their ability to deform easily and organize themselves into larger structures with collective, emergent behavior. This project investigates a particularly intriguing subset of soft materials called hyperbolic non-Euclidean plates—thin sheets with built-in curvature that causes them to spontaneously buckle into wavy or ruffled shapes. These forms are not only common in nature, but also offer new possibilities for the design of smart materials and soft robots. By uncovering the rules that govern the shapes and behaviors of these systems, the project advances our understanding of geometry in natural design and supports the development of next-generation materials inspired by biology. This research contributes to the national interest by promoting the progress of science through the development of new mathematical and computational tools for studying nonlinear systems and emergent behavior. It strengthens the connection between mathematics, physics, and engineering, while also offering applications in biology and materials science. The project supports education and workforce development by providing research training for undergraduates, graduate students, and postdoctoral scholars. Through its interdisciplinary scope and training opportunities, the project fosters innovation and builds capacity for a competitive STEM workforce for the nation. The investigator studies the mechanics of non-Euclidean elastic thin sheets, with a focus on hyperbolic geometries that lead to spontaneously formed complex shapes. Recent work by the investigator has identified universal behaviors in these systems that are mediated by geometric defects—line-like and point-like singularities that emerge as non-smooth solutions to hyperbolic Monge-Ampère-type equations. These singular structures provide a framework for understanding the shape selection and evolution of thin hyperbolic sheets. The project develops a suite of analytical and numerical tools grounded in differential geometry, topology, and functional analysis to describe and predict these singular structures. These methods are applied to problems in biomechanics—including plant morphogenesis and marine invertebrate forms—as well as the design of soft robotic actuators and reconfigurable materials. The research advances the theory of singular solutions to nonlinear PDEs and provides a unified framework to understand geometric frustration in thin structures across biology and engineering. 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 · 2025-07

Heart failure (HF) with preserved ejection fraction (HFpEF) is a prevalent disorder; however, our treatment options are limited. Studies show that endothelial cell (EC) dysfunction precedes the development of HFpEF and is a key player in the pathogenesis of this disorder. Hexokinases (HK) catalyze glucose phosphorylation, and one HK isoform (HK1) binds to the outer mitochondrial membrane via its N-terminal hydrophobic domain, encoded in its exon 1. We have generated a mouse model with deletion of the mitochondrial binding domain (MBD) of HK1 (designated as ΔE1HK1 herein). These mice display HFpEF and reduced cardiac microvascular density as they age, and isolated ECs show lower angiogenesis. Accordingly, ECs from mice with HFpEF display increased HK1 mitochondrial dislocation, supporting that HK1 cellular localization plays an important role in the development of HFpEF. Metabolomic studies on ECs from ΔE1HK1 mice showed that hexosamine biosynthetic pathway (HBP) intermediates are decreased compared to WT mice. In addition, protein samples in ECs from ΔE1HK1 mice showed less N-glycosylation of proteins, while increased post-translational O-GlcNAcylation was observed compared to WT mice. These results suggest that HK1 dislocation causes a shift from protein N- glycosylation to O-GlcNAcylation in ECs, and that this switch contributes to EC dysfunction and the development of HFpEF. In this proposal, we will address the fundamental gap in knowledge of the mechanism of HFpEF and whether increased protein O-GlcNAcylation in ECs contribute to the pathogenesis of this disease. Our hypothesis is that HK1 mitochondrial dislocation leads to increased protein O- GlcNAcylation and that HFpEF is associated with increased HK1 dislocation and higher protein O- GlcNAcylation. We also hypothesize that a reduction in protein O-GlcNAcylation can reverse the pathogenesis of HFpEF. In Aim 1, we will determine whether HK1 mitochondrial dislocation and increased protein O-GlcNAcylation in ECs cause EC dysfunction and angiogenic defects. We will inhibit protein O- GlcNAcylation with O-GlcNAc transferase (OGT) inhibitors or “force” HK1 to the mitochondria in ECs from WT, ΔE1HK1 mice and mouse models of HFpEF and will assess their angiogenic potential. In Aim 2, we hypothesize that O-GlcNAcylation of histones are increased in ECs from HFpEF hearts. To test this hypothesis, we will perform mass spectrometry (MS) on the cellular, cytosolic and nuclear fractions of ECs from HFpEF and ΔE1HK1 mice. We will also perform ChIP-Seq and RNA-seq in ECs from WT, HFpEF and ΔE1HK1 mice to determine the differential gene expression in HFpEF. In Aim 3, we will determine whether inhibition of protein O-GlcNAcylation reduces the progression of HFpEF. We have crossed the ΔE1HK1 mice with mice that overexpress O- GlcNAcase (OGA, an enzyme that opposes OGT and reduces protein O-GlcNAcylation) in ECs and will assess cardiac function in these mice. Additionally, we will assess whether treatment of mice with a novel OGT inhibitor reverses the progression of HFpEF, providing a clinical relevance for our studies.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY Increases in protein synthesis during pathological cardiac hypertrophy places demands on protein-folding machinery to avert the accumulation of toxic misfolded proteins. Associated with the endoplasmic reticulum (ER), where many important proteins are synthesized in cardiac myocytes, is a system that recognizes and degrades misfolded proteins, i.e. ER associated (protein) degradation, or ERAD. We discovered a different, non-canonical role for ERAD as a regulator of the levels of the growth-promoting kinase, serum glucocorticoid kinase 1 (SGK1). SGK1 is a cytosolic kinase involved in growth of other cell types, such as cancer cells. Interestingly, SGK1 can traffic to the ER where it is ubiquitylated by ERAD machinery and subsequently degraded by cytosolic proteasomes; however, this unique regulatory mechanism has not been studied in the heart. Our preliminary evidence shows that non-canonical ERAD could regulate SGK1 levels in the heart and, thereby regulating cardiac growth under pathological conditions. We also found that an SGK1-binding protein, called glucocorticoid-inducible leucine zipper protein (GILZ), can bind to and protect SGK1 from non-canonical ERAD-mediated degradation, which we believe increases SGK1-mediated growth of the heart during pressure overload. Accordingly, our hypothesis is that SGK1 is a major inducer of pressure overload-induced cardiac pathology. During pressure overload, SGK1 levels, and thus, SGK1-mediated cardiac hypertrophy and subsequent pathology, are increased by GILZ-dependent diversion of SGK1 away from the ER, which decreases SGK1 degradation by non-canonical ERAD. Ectopic expression of an SGK1 peptide disrupts the GILZ-SGK1 interaction, increases SGK1 degradation, thus decreasing SGK1-mediated cardiac hypertrophy and subsequent pathology. This hypothesis will be examined in mice subjected to pressure overload-induced cardiac pathology in our specific aims, which are to 1-couple cardiac-specific SGK1 deletion with AAV9 encoding SGK1-WT (active; ER-targeted), SGK1-KD (kinase-dead ER-targeted) or SGK1-∆60 (active; not ER-targeted) to examine the effect of SGK1 and ERAD on overload-induced cardiac pathology, 2-combine AAV9-SGK1-WT or AAV9- SGK1-∆60 with AAV9-mediated GILZ overexpression or knockdown to determine whether GILZ diverts SGK1- WT from the ER and protects it from ERAD in the heart, 3-evaluate the potential therapeutic, antihypertrophic effects of a novel SGK1 peptide that interrupts GILZ-SGK1 binding, and increases non-canonical ERAD- mediated SGK1 degradation. These studies are significant because they will reveal previously unappreciated roles for SGK1, GILZ and ERAD in pathologic cardiac hypertrophy. We will use an innovative molecular strategy to mechanistically dissect roles for GILZ and non-canonical ERAD as regulators of SGK1 signaling and cardiac pathology. Peptide-based disruption of the SGK1-GILZ interaction could be a highly specific method for inhibiting the maladaptive pathological effects of SGK1 in the heart by selective degradation of SGK1.

NIH Research Projects · FY 2025 · 2025-07

ABSTRACT Clostridioides difficile infection (CDI) is a debilitating diarrheal disease that is precipitated upon antibiotic-induced gastrointestinal tract dysbiosis. Currently, there is no vaccine to prevent CDI, and the primary FDA-approved treatment relies on substantial antibiotic use. In the hospital as well as community, the elderly and immune- compromised are at most risk; therefore, CDI is a significant problem worldwide. The causative agent, C. difficile, is an anaerobic, spore-forming bacterium designated as an “Urgent Threat” to US healthcare. To date, there is a paucity of organism-specific (precision) antibacterials. Therefore, we developed a novel, water-soluble, cationic bolaamphiphile (CAB) platform nanocarrier, and complexed it with an antisense oligonucleotide (ASO) targeting the essential C. difficile dnaE gene. In preliminary studies, this dnaE*964 nanocomplex was bactericidal, with a C. difficile Minimum Inhibitory Concentration (MIC) comparable to a standard-of-care CDI antibiotic, vancomycin. Crucially, dnaE*964 was inactive against a panel of human intestinal commensal organisms. Pharmacokinetic (PK) assessments in mice and Golden Syrian hamsters revealed that the CAB nanocarrier was safely tolerated, and that it preferentially accumulated in the rodent GI tract; thus, a dosing regimen was defined. In pilot efficacy studies, dnaE*964 ablated CDI pathology, cleared C. difficile from the rodent cecum and stool, and maintained microbiota restitution. dnaE*964 clinical development is therefore in progress. To expand the utility of our CAB platform and also address the inevitable clinical concern of single-target resistance development, we will now evaluate 3 additional ASO leads targeting C. difficile genes encoding cytoplasmic as well as cell wall-associated proteins; all are essential. Preliminary studies reveal that phosphorothioated ASOs customized for each gene completely ablate expression and also inhibit C. difficile growth in a dose-dependent manner. We thus hypothesize that ASO*CAB nanoparticles targeting essential genes (1) will specifically kill C. difficile in vitro and in vivo, and (2) can functionally synergize with each other and with standard-of-care antibiotics without significantly engendering resistance emergence. In vitro (Aim 1; MIC, resistance) and in vivo (Aim 2; efficacy, microbiota sparing) studies will test these hypotheses. Taken together, we thus prioritize key pre-clinical assessments of CAB-based bacterial anti-infectives. Studies in both Aims will be underpinned by quantitative milestones that will inform the translational pathway via a clear framework for go/no-go decisions.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT My lab investigates how human cells detect and respond to stress, how these mechanisms fail in disease, and how they can be targeted therapeutically. We develop fluorescent reporters to monitor key stress response proteins and employ live-cell imaging and quantitative image analysis to capture their spatial and temporal dynamics. By integrating mathematical modeling and 'omics methods, we uncover how dynamic responses influence cell fate decisions. Our research strategically focuses on stresses and pathways relevant to human disease, ultimately aiming to translate these findings into effective treatments. Recently, we discovered a dose-dependent switch where transcription factors and kinases respond differently to varying levels of H2O2. At low H2O2, 'Group 1' proteins like p53, NRF2, and AKT are activated, while 'Group 2' proteins such as FOXO1, NF-κB, and GCN2 remain inactive. However, at higher concentrations, Group 2 proteins are activated while activation of Group 1 proteins is delayed until Group 2 proteins switch off. Prolonged activation of Group 2 is linked to cell death, underscoring the concept that oxidative stress can be categorized as eustress (mild and beneficial) or distress (severe, causing damage and disease). Our findings reveal the shift between oxidative eustress to distress is not gradual but dramatic, resembling a phase transition. H2O2 activates proteins by oxidizing reactive cysteine residues to sulfenic acid (SOH), which is then further modified to more stable post-translational modifications. Thousands of cysteines on diverse sets of proteins are known to be oxidized by H2O2, highlighting one of the key knowledge gaps in redox signaling: given the overwhelming number of reactive cysteines, how does H2O2 selectively oxidize the proper target? The underlying hypothesis of our research plan is that the dose-dependent activation of the two groups of proteins offers a window into how specificity is achieved in redox signaling. We build on our prior research with four separate projects to address this goal. In the first project, we take a targeted approach to identify the proteins directly oxidized under high H2O2 that activate group 2 proteins, and those that block group 1 activation. In the second project, we take an unbiased proteomics approach to identify key cysteine residues that are oxidized under different levels of H2O2 exposure. By coupling these data with phosphoproteomics, we will dissect how cysteine oxidation affects kinase activity. In the third project we test three different models on how PRDX proteins selectively control protein oxidation. Finally in the fourth project we make use of a human colonic monolayer system we developed to understand how redox signaling impacts gut homeostasis. In sum, our research plan aims to uncover the molecular mechanisms behind H2O2-mediated protein regulation, providing critical insights into how cells differentiate between eustress and distress. By elucidating the dose- dependent switches controlling transcription factors and kinases, we will advance understanding of redox signaling specificity and identify new therapeutic targets for oxidative stress-related diseases.

NSF Awards · FY 2025 · 2025-07

With the support of the Macromolecular, Supramolecular and Nanochemistry Program in the Division of Chemistry, Professor Jeffrey Pyun and Professor Jon Njardarson from the University of Arizona (UA) will develop and advance novel synthetic methods to prepare monomers and polymers using deuterium chemistry. Deuterium is a naturally occurring stable isotope of hydrogen, the incorporation of which into polymers has the potential to create a revolutionary class of plastic optics with vastly improved transparency across the visible (VIS) and infrared (IR) spectrum. Currently, there remains a critical need in US defense and consumer sectors (automotive and construction) for low cost, optical glass materials that are transparent across the VIS-IR spectrum. State-of-the-art systems solely rely on heavy, expensive inorganic materials and would tremendously benefit from the creation of an alternative, low cost, light-weight plastic optical material. Hence, the UA team will explore new deuteration chemistry to prepare novel molecules and polymeric materials with the highly desirable combination of high transparency across the VIS-IR spectrum, lightweight, and robust mechanical properties over a range of temperatures. The broader impacts of the project are significant as the technological impacts of this work are far reaching, benefiting US defense systems reliant on IR optical systems, along with the pharmaceutical and nuclear energy sectors that are already heavily invested in new deuteration chemistry. Furthermore, the project will create new opportunities to engage large cohorts of undergraduate students (20-30 per semester) with research experiences in the chemical and polymer sciences via a multi-tiered training model to maximize on effective workforce training for next-generation scientists and engineers. To address the technical challenges of this project, Pyun and Njardarson will develop new synthetic chemistry and polymerization processes to replace all the hydrogen atoms in selected optical plastic materials with atoms of the stable isotope form of hydrogen, known as deuterium. This will require the creation of new synthetic chemistry using alternative deuterated starting materials to prepare these wholly deuterated molecules and perdeuterated polymers using cost-efficient, scalable methods suitable for industrial translation. Earlier work in this area has only been successful with a very narrow subset of molecules and polymers, all of which use prohibitively expensive materials and methods. Hence, the project will focus on developing this new fundamental chemistry which will have profound effects on the optical transparency of the resulting polymeric materials and afford a new class of VIS-IR broadband plastic optics. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-07

Nonnative weedy plants can promote wildfires. In the Southwestern U.S., for example, weedy grasses can fill gaps between native cacti, significantly increasing fire fuel availability, leading to bigger fires. To reduce impacts of this weed-fire connection scientists have traditionally focused on the planting of native plant species. Focusing on plants alone, however, might be misplaced. Important processes that affect fire behavior might occur below ground, in the soil, and may play a crucial role in post-fire habitat recovery. This project will study the bacteria and viruses (microbes) and the different types of organic matter in soil to better understand the relationship between weedy plants and wildfire. Once the researchers understand these soil processes, they will design inocula that contain soil and plant seeds that promote recovery in damaged areas. Combining the right belowground (soil) and aboveground (seeds) ingredients, the researchers hope to create an environment where soil microoganisms promote growth of native plants, which in turn provide nutrients back to the soil that promote growth of beneficial microbes. The project will publicize its results to land managers via workshops, extension publications, and the EcoRestore digital portal. In addition, high school students participating in a free outdoor science program will collect data, identify plants and maintain experimental plots. With increasing temperature, drought severity and fire frequency, western US forests have the potential to transform from net sinks to net sources of CO2. In addition, invasive grasses can create sustained, novel, grass-fire cycles. To understand the effects of grass-fire cycles belowground, the researchers will investigate: (1) the interactive effects of fire and plant invasion on the microbiome and biogeochemistry of the soil; and (2) changes in soil viruses and their role on necromass entombment and carbon sequestration. Finally, to test effective and economically viable approaches to assist post-fire recovery, the project will design and deploy inocula to disturbed areas based on different formulations of plant seeds and soils with the ultimate goal of priming the ecosystem towards soil carbon sequestration. In addition to the outreach activities described above, the project will include training opportunities for a Ph.D. student and several undergraduates. 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 · 2025-07

Summary The Target of Rapamycin kinase Complex I (TORC1) is a central hub in the cell growth and metabolic control network of eukaryotes. Studies carried out over the last twenty years have identified numerous components in the TORC1 pathway, and uncovered the important role that TORC1 plays in diseases and disorders such as cancer, epilepsy, diabetes, depression, and aging. However, even as our understanding of TORC1 signaling matures, it remains unclear how TORC1 functions at the systems level. Why are there so many TORC1 regulators--some with seemingly identical functions? And how are the signals transmitted through individual TORC1 regulators integrated to ensure that cell growth and metabolism remain balanced across conditions? Over the past 12 years we have addressed these and related questions by building up a detailed, network level, model of TORC1 signaling in the simple model organism Saccharomyces cerevisiae. Our work has led to the identification of several new proteins involved in TORC1 regulation, but perhaps most importantly has (i) shown that TORC1 is driven into different signaling states in different conditions to optimize the activity of hundreds of downstream targets and (ii) uncovered that the cAMP dependent protein kinase (PKA) pathway acts in parallel with TORC1 to tune the threshold and timing of the cell growth response. Most recently, we discovered that TORC1 is pushed into a unique, intermediate signaling state in poor nutrient conditions, where it activates targets involved in amino acid transport and metabolism, and slows growth via a single transcriptional repressor, but other TORC1 outputs match those seen in ideal growth conditions. Building on this framework, we now propose an ambitious and integrated set of experiments to: (1) Determine how TORC1 is driven into the intermediate signaling state in poor nutrient conditions; (2) Determine how TORC1 signaling is altered, as conditions get worse, to slow growth further and tune metabolism; and (3) Identify the missing layers of TORC1 regulation that push cells into quiescence/arrest during complete starvation. To do this, we will map the impact that known and putative TORC1 regulators have on signaling across a wide range of conditions using several reporters of TORC1 activity, live cell microscopy, and phosphoproteomics. We will also study the impact that over 100 newly identified TORC1 pathway interactors have on TORC1 and global signaling across conditions, using high- throughput microscopy, phosphoproteomics, transcriptomics, and detailed follow up experiments. The resulting model should serve as a paradigm for future systems level studies of human TORC1 signaling and will shed light on differences between yeast and human TORC1 signaling network, opening the door to creating new (and sorely needed) antifungal compounds.

NIH Research Projects · FY 2025 · 2025-07

Abstract: More than 73% of head and neck cancer patients continue to suffer from the chronic consequences of xerostomia months to years after the completion of radiotherapy making this one of the most compelling issues in salivary gland biology. Despite technological advancements in cancer therapies, collateral damage to salivary glands remains a significant problem for these patients and severely diminishes their quality of life. The field of radiation- induced salivary gland damage is severely hampered by the lack of a comprehensive model detailing the molecular stages of damage. The overall vision (long-term goal) is to restore salivary gland function in patients following radiotherapy by identifying mechanisms that regulate stages of dysfunction in salivary glands. Our prior work has demonstrated that mouse parotid glands 10 months after fractionated radiation have significant increases in T cell populations (CD4+, CD8+, CD4+CD8+, and FoxP3+ T cells), suggesting immune populations may play an active role in the chronic loss of salivary gland function. We hypothesize that radiation treatment leads to chronic dysregulation of metabolic pathways in T cells resulting in prolonged activation of CD4+CD8+, double positive (DP) T cells that inhibit salivary epithelial regeneration and repair. We propose to develop a kinetic model of the metabolic phenotype of infiltrating immune populations and how immune-epithelial interactions contribute to chronic loss of function. The outcomes from this work include: 1) immunometabolic phenotype and the function of T cells following radiation, 2) the effect of modulating T cell metabolism on repair of damaged glands, 3) cellular identity of immune populations surrounding damaged epithelial cells, 4) impact of immune cell metabolic phenotype on the ability of Metformin to reverse salivary gland dysfunction. Understanding this process would have a positive impact by revealing intervention points that promote restoration of salivary gland function.

NSF Awards · FY 2025 · 2025-07

Realizing Artificial Intelligence (AI) requires modern hardware that is capable of processing complex analog data with an efficiency comparable to the human brain. However, existing semiconductor devices struggle to process large volumes of data due to fundamental limitations like high-power consumption, limited functionality, and low number of memory states. This project seeks to develop a new type of neuromorphic device called moiré synaptic transistors to address these limitations. By putting multiple atomically-thin layers of two-dimensional materials together with specific alignments, these devices are able to achieve lower power consumption, higher memory state density, more tunability and more biomimicking functionalities. These devices can be used to meet the precision and energy demands of modern computing in AI and enable applications like AI-powered robots, autonomous drones, and personalized wearable electronics. The educational outreach goal of this project will aim to increase awareness of some of the most exciting concepts and challenges at the intersection of semiconductor manufacturing and neuromorphic computing applications among all levels of learners (i.e., pre-school, K-12, undergraduate, graduate, and working adults), with a special focus on providing research opportunities to K-12 and undergraduate students. The research program will be tightly integrated with training future technical leaders to have the capabilities to tackle interdisciplinary problems in these fields. This project aims to address critical challenges in advancing AI hardware by developing moiré synaptic transistors (MSTs), a new generation of devices built by stacking and twisting two-dimensional materials. These devices capitalize on excitonic ferroelectricity, a unique phenomenon in correlated 2D moiré heterostructures, to achieve high memory density, low power consumption, high operation speed, high reconfigurability, and novel biomimicking functionality. Advanced fabrication techniques will be explored to design new MSTs with optimized performance and scalability. These will be applied to innovative computing-in-memory-and-sensor applications using neural-network-based MSTs. Integration with CMOS circuits and neuromorphic computing frameworks will allow MSTs to achieve unprecedented functionality and efficiency in analog computing systems. This project will create simulation and circuit design models of MSTs and establish a co-design framework that links excitonic ferroelectric physics, MST devices, and circuit design. These innovations are expected to enrich the fundamental understanding of excitonic ferroelectricity, create MST device innovations, and advance circuit-level applications based on MSTs for AI hardware and wearable electronics. The education plan will synchronize with the research plan by enhancing education in semiconductor device fabrication, characterization, and device-circuit-algorithm co-design techniques to foster the development of the next generation of interdisciplinary STEM leaders. 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 · 2025-06

PROJECT SUMMARY/ABSTRACT Phthalates are used in beauty and personal care products, food packaging, medical devices, and the coating of some medications. Human biomonitoring analyses demonstrate constant human phthalate exposure due to the ability of these chemicals to leach from these products. Many epidemiological studies have reported associations between phthalate burden and human metabolic and reproductive health outcomes. Women of reproductive age are considered a high exposure/high risk population based on biomonitoring data showing higher phthalate burden, greater use of cosmetics and personal care products, and higher exposures in the occupational setting. Phthalate exposure in women has been associated with early menopause, decreased ovarian follicle counts, reduced egg yield, increased early pregnancy loss, and reduced clinical pregnancies and live births. Concurrently, phthalate exposure has also been associated with metabolic dysfunction including obesity, metabolic syndrome, and fatty liver disease. Unfortunately, the mechanisms underlying these associations are not understood and make preventative or therapeutic actions challenging. We developed a phthalate-treated mouse model in which exposure to human relevant levels of phthalates replicates phenotypes associated with phthalate exposures in humans. Using toxicoproteomic and lipidomic approaches we show that antral follicles from these mice have dysregulated abundance of lipid metabolism proteins, high intrafollicular saturated free fatty acids, and high intrafollicular acylcarnitine content. We propose to test the overall hypothesis that phthalate mixture exposure leads to stimulated fatty acid synthesis with concurrent inhibition of fatty acid oxidation. We propose that these effects are mediated via changes in the transcription of fatty acid synthesis and oxidation proteins through dysregulated LXR-SREBP1c and PPAR signaling pathways, and that persistent, long-term exposure to phthalate mixtures will lead to metabolic and reproductive disorders in our mouse model. Our hypothesis will be tested via completion of three specific aims designed to identify the relevant tissues and molecular events leading to phthalate-induced elevated intrafollicular free fatty acids (Aim1) and acylcarnitines (Aim 2), and identify which known reprometabolic phenotypes associated with phthalates in humans are replicated by long-term exposure to epidemiologically-based phthalate mixtures in our mouse model. Our findings will provide unique insight into the interplay between systemic and ovarian effects of phthalates.

NSF Awards · FY 2025 · 2025-06

The overarching goal of this project is to lay out a theoretical foundation for the economics of multi-operator spectrum sharing (SS) over both licensed and unlicensed frequency bands considering market uncertainties. Despite intensive efforts to assign more of the electromagnetic spectrum for mobile broadband, it is now widely believed that the traditional exclusive spectrum assignment approach is too limiting to meet the high demands of next-generation (NextG) wireless networks. SS remains critical at all frequency bands, including sub-6 GHz, millimeter-wave bands, and bands in between (7.125 to 24.25 GHz). To usher a new era of SS of licensed and unlicensed bands between (bilateral) and among (multilateral) wireless operators, new sharing models are needed. At their core, these models should incorporate proper incentivization mechanisms, as profit is ultimately the primary factor that motivates operators to share their spectrum. This project focuses on novel privacy-preserving game theoretic models for SS that are particularly suited for exploitation of the short-term spatiotemporal variations in traffic demands between operators. The research agenda is organized into three thrusts. Thrust A: Non-collaborative SS Between Operators. In this thrust, inter-operator SS is investigated in a non-collaborative setting, where operators view each other competitively and do not wish to reveal private information. Several game-theoretic models, including a repeated double-sided Bayesian spectrum auction game with transferable seller and buyer, an incentivized oligopoly game, and a repeated single-sided spectrum auction game with unknown and private valuation will be analyzed. Thrust B: Collaborative SS between Operators. Collaboration between operators can potentially bring mutual benefits, but it may also harm their interests if not carefully managed. Understanding these complex interactions requires new game theoretic models for both licensed and unlicensed spectrum. The project will explore coalitional game theory to model these interactions. For inter-operator SS on unlicensed bands, the concept of value-of-right will be utilized to characterize the benefit obtained by each operator. Thrust C: Collaborative SS between Heterogeneous Wireless Systems. Cellular operators can lease part of their underutilized licensed bands to other non-cellular systems. To analyze the economic implications of these interactions, the project will study a hierarchical game framework consisting of a multi-leader multi-follower Stackelberg game. The project will have broad technical, societal, industry, and educational impacts. If successful, the project will provide a much-needed understanding of which SS models are economically justifiable and under what conditions. It will drive operators to experiment with SS models deemed appropriate for their systems. The outcomes of the project will be shared with industry through various venues, including industry forums, NSF-funded wireless research centers, and others. The project also involves a comprehensive educational plan to broaden its impact, including research integration into curricula and training of students. A website for the project will be created at wireless.ece.arizona.edu, and will be maintained throughout the course of the project. Measurements, datasets, and produced software will be provided to the public on that website. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-06

Whole numbers are among the most practical and most important mathematical objects. Humans have studied them for millennia. Number theory aims to understand patterns possessed by whole numbers. Fundamental questions revolve around multiplication: how often are numbers in some sequence even (i.e. divisible by two)? Divisible by three? Or five? Nineteenth century researchers introduced symmetry actions to reveal hidden patterns in numbers. And, in the 1970's, Robert Langlands made far-reaching conjectures on symmetry. These conjectures have occupied number theorists ever since. They predict patterns seen by symmetry actions will arise equally from the calculus of complex numbers ("modular forms"). A pattern appearing in two places is an example of a mathematical reciprocity. This project will refine Langlands' reciprocity prediction. The new tool is geometric spaces of symmetry actions, constructed by Emerton and Gee over the past fifteen years. These spaces are believed to convert reciprocity questions into geometrical ones. This project establishes instances of this belief. It will connect divisibility patterns from the world of modular forms to geometrical theorems on Emerton and Gee's spaces. The project has substantial broader impacts. Computational data will be included in the widely-used L-functions and Modular Forms Database. The project also develops computational tools for teaching. Open education resources (OERs) are learning materials placed in the public domain. Their primary benefit is providing learning experiences at low costs. They can be adapted to fit a diversity of learning environments. The project develops OERs for computer-based learning of number theory and abstract algebra. The project supports education and outreach in two more ways. First, Math Circles will be run in public schools. Second, research projects will be developed to support the Program in Mathematics for Young Scientists. Finally, the project plans two research workshops in number theory. Both aim to disseminate new advances in number theory and reciprocity. The more detailed aim is a new study of p-adic slopes of modular forms and Galois representations. The p-adic slope of a modular form is how often its p-th Hecke eigenvalue is divisible by a fixed prime p. Predictions and theorems on slopes have been around since the 1980's. Seven years ago, Bergdall and Pollack proposed a way ("the ghost conjecture") to unify almost all prior ideas. The ghost conjecture's input is a congruence class of modular forms. The output is an elementary recipe for slopes in the class. The main caveat is the ghost conjecture only applies to "regular" classes. But, assuming regularity, Liu, Truong, Xiao, and Zhao (LTXZ) recently established the conjecture. The current project removes the regular assumption in the ghost conjecture. The new tool is Emerton and Gee's (EG) moduli stack of Galois representations. In Galois terms, regularity is a generic property on the EG stack. The project's technical innovation is thus deforming slope questions over the stack. A geometrical reformulation will open the door to generalizing the LTXZ proof. It will also create space for novel studies of Hilbert modular forms or higher rank automorphic forms. 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 · 2025-06

HOST EVOLUTION IN THE WAKE OF CONTEMPORARY OUTBREAKS OF DISEASE Project Summary/Abstract In the wake of the spillover or introduction of a novel parasite or pathogen into a naïve host population, attention focuses on the resulting host morbidity and mortality. However, emerging disease has much broader effects on host populations, including demographic shifts, life history changes, and genetic and epigenetic evolution. These extended effects have shaped human evolution and remain relevant in an era of biodiversity loss and increasing zoonotic disease risk. Nevertheless, studying the evolutionary consequences of disease remains challenging because historical disease events leave diffuse and complex genomic signatures and because attributing changes in the host population to parasites can be difficult without adequate replication and controls. The investigating team works in the Galapagos Islands, an iconic natural laboratory, to study the real-time evolution of hosts to emerging disease. Over the next five years, the team will leverage the natural experiments created by two separate parasite introductions that occurred ~125 years ago and ~25 years ago to study changes in avian host populations in response to these novel challenges. The Galapagos songbird (passerine) community is dominated by two endemic radiations: Darwin’s finches and Galapagos mockingbirds. The species within each of these groups provide the replication to test hypotheses about how host defenses against disease arise and spread, and to determine how repeatable co-evolution is between hosts and novel parasites. Three fundamental questions guide the overall focus on how hosts change in the wake of emerging disease: 1) How do population size and genetic diversity govern adaptation to a novel virus? Variation in host population size and parasite pressure among Galapagos islands will help identify how demography and diversity shape the response to hosts to novel disease. 2) What mechanisms underlie adaptation to a novel virus? The team’s existing work uniquely prepares them to study to what extent regulatory and epigenetic changes drive host adaptation to novel pathogens and how routes to adaptation may vary among host species. 3) How do hosts evolve in response to a novel parasite? Contemporary host genomes will be compared to host genomes from before the parasite introduction to identify regions and genes under selection. With over a decade of experience working in the Galapagos Islands and extensive local connections, the McNew Lab is uniquely prepared to conduct the ambitious experiments in the study of host-parasite coevolution. The results will illuminate the processes that shaped human evolution and anticipate consequences of future emerging diseases on Earth.

NIH Research Projects · FY 2026 · 2025-06

Project Summary: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy, affecting ~1/300-1/500 individuals worldwide. In the clinic, HCM displays a high degree of phenotypic variability which presents major challenges regarding targeted therapeutics and determining the mechanisms which drive disease progression. HCM has been definitively linked to mutations in genes encoding the protein components of the cardiac sarcomere, including the cardiac thin filament (CTF). The CTF is an essential regulator of sarcomeric contraction and couples the availability of cytoplasmic calcium to force development. Previous work has shown that in human late-stage HCM samples, there are increased levels of Ca2+/Calmodulin-dependent kinase IIδ (CaMKIIδ) phosphorylation and oxidation. Both post-translational modifications, along with several others, render the kinase autonomous of its physiological regulation via calcium, increasing kinase activity. As CaMKIIδ targets several proteins which maintain electromechanical and calcium homeostasis, increased activity has high pathophysiological potential and has been noted in several cardiac diseases in addition to HCM. Our lab has demonstrated that this increase in autonomous CaMKIIδ activity is dependent on the specific point mutation in the CTF. Specifically, increased CaMKIIδ is observed in mice expressing the R92W mutation in cardiac troponin T (cTnT), but not in mice expressing the R92L mutation. This mutation-specificity suggests that there are specific primary alterations in biophysical properties of the CTF, which can be altered in differing fashions by mutations, that act as triggers for increased CaMKIIδ activity. To the best of our knowledge, these specific alterations, and the mechanisms by which they increase CaMKIIδ activity, have yet to be investigated. We hypothesize that increased CaMKIIδ activity is a result of early, myofilament-based calcium dysregulation, specifically accelerated calcium dissociation kinetics from the CTF, and that the increased activity drives pathological remodeling and thus can be a therapeutic target in a subset of HCM. In Aim 1 we will perform experiments utilizing mass spectrometry, a novel CaMKIIδ biosensor, and sarcoplasmic reticulum calcium uptake techniques to define CaMKIIδ activity and the state of calcium dysregulation in three separate mouse models of HCM which express mutations in cTnT associated with HCM: R94H, I79N, and R92W. We will use these data to determine whether calcium dysregulation stemming from acceleration of calcium dissociation kinetics is strictly associated with increased CaMKIIδ activity. In Aim 2 we will assess the efficacy of the small molecule CaMKIIδ inhibitor ruxolitinib, currently FDA-approved for various bone marrow and skin diseases as a Janus kinase 1/2 inhibitor to alter pathogenic remodeling in HCM in vivo. We will treat cTnT-R92W mice at early- and late-stage disease to determine if CaMKIIδ inhibition can be a viable treatment option at any point in disease progression or only at specific times. The data from these experiments will identify new links between molecular phenotypes, provide new insight into mechanisms of HCM progression, and describe a novel therapeutic target for cTnT-linked HCM.