University Of Washington

NSF Awards · FY 2025 · 2025-04

This I-Corps project is based on the development of a generative artificial intelligence (AI)-driven platform to enhance diagnostic accuracy in medical imaging. This solution may accelerate the diagnostic and treatment processes. In addition, the platform uses explainability, which supports early detection, diagnosis, triage prioritization, and treatment planning, particularly for surgeries. The technology is designed to enhance medical practices in imaging centers and hospitals. It may be used to sharpen the precision of surgeries on brain tumors, reducing operation times and fostering quicker patient recovery. This technology may lead to lower healthcare costs and a reduced need for repeat surgeries, ultimately boosting the overall quality of patient care and outcomes. In addition, the technology may be used in emergency rooms to differentiate between types of strokes —conditions that require distinctly different treatments. This ability to distinguish types of strokes may improve the speed and accuracy of stroke diagnosis, helping patients receive the right treatment at the right time, enhancing outcomes in critical care situations. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of neuroimaging algorithms for improving brain tumor segmentation and stroke diagnosis. The technology is designed to identify the boundaries of various brain malformations to enhance diagnostic accuracy in medical imaging. The platform employs explainability, which helps physicians understand the algorithm's suggestions, and ultimately enhances decision-making. This technology leverages the power of advanced, trustworthy neural network models designed for high-precision brain tumor segmentation as well as a deep-learning tool for stroke lesion identification and classification. This advancement may improve the accuracy of tumor segmentation over current tools. The technology is based on the development of an end-to-end object detection model. The model uses a vision transformer as its backbone to effectively identify and segment the stroke lesion areas. This tool also employs adaptive learning techniques that continuously refine its performance. Research findings show that the tool recognizes the complex variations in tumor shapes and sizes. This ability may allow the technology to adapt and evolve, providing reliable and enhanced diagnostic capabilities and improving patient outcomes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-04

Seafloor spreading centers are plate tectonic boundaries where submarine volcanoes generate new oceanic crust. They account for about 80% of the Earth’s volcanism. During a volcanic spreading event, the tectonic plates move apart along a section of the plate boundary and magma rises into an approximately 1-m-wide vertical crack where it can feed volcanic eruptions. When the magma in the crack solidifies, it forms a geological feature known as a dike. Many small precursory earthquakes occur before a diking event as stress builds up in the Earth’s crust and the rupturing that occurs during the diking event is accompanied by a large swarm of earthquakes. At any one location on the plate boundary, diking events occur at intervals of a decade or more and because the precursory earthquakes are too small to detect from land, it is difficult to anticipate when they will occur. This project takes advantage of a cabled observatory on Endeavour Segment of the Juan de Fuca Ridge that is in a location where the spreading center volcano supports several large hydrothermal vent fields. A small network of seismometers on the cabled observatory has detected the precursory seismicity of an impending diking event. This project will deploy autonomous seafloor seismometers to enhance the cabled seismic network so that the earthquakes associated with the anticipated diking event are well recorded. The earthquake locations and characteristics will be used to investigate what triggers diking events, determine whether some extension occurs by creep on faults, and improve the understanding of how hydrothermal systems are supported by submarine volcanos. The earthquake catalog will be of value to scientists using the cabled observatory to investigate the impact of diking events on black smoker hydrothermal vent fields and the biological communities they support. This project will train both undergraduate and graduate students in seagoing research and in modern computational techniques to analyze earthquake recordings. Seafloor spreading through diking is a fundamental geological process that regenerates 60% of the Earth's surface on timescales of 100 Myr, but it is hard to capture with autonomous ocean bottom seismometers alone because the decadal timescale of spreading cycles is an order of magnitude greater than the recording duration of an autonomous instruments. The Endeavour segment of the Juan de Fuca Ridge is an intermediate rate spreading center that last ruptured in a sequence of diking events from 1999-2005 and has been monitored for approaching a decade by a small network of 4-5 cabled OBSs on the Ocean Networks Canada NEPTUNE cabled observatory. Based on observations with this network of accelerating rates of microseismicity, another spreading event is expected soon. This project is the US component of a US-Canadian collaboration to take advantage of this rare opportunity for a preemptive seismic response. The cabled seismic network will be augmented for 5 years by the addition of 5 Canadian National Facility for Seismological Investigations autonomous broadband ocean bottom seismometers. This will expand the seismic network to a size that allows the determination of focal mechanisms and depths near the center of the segment and the triangulation of epicenters on the southern part of the segment. In 2025-6, the network will be further expanded to include 20 ocean bottom seismometers. This larger network will fully cover the footprint of off-axis seismicity near the center of the segment that is related to two propagating rifts. The experiment is designed to address the following questions: (1) Are diking events at the Endeavour triggered by extensional stresses, or magmatic pressures from a centralized source? (2) Do temporal changes in seismic velocity show evidence for precursory aseismic strain or ridge extension events that are not linked to dikes? (3) Is carbon dioxide exsolution linked to off-axis seismicity at the Endeavour? (4) Is the permeability beneath the Endeavour hydrothermal vent fields enhanced by the nearby propagating rifts? To analyze the data, an artificial intelligence-aided earthquake catalog building procedure will be implemented to detect, pick and associate volcanic-tectonic earthquakes, hybrid/long period earthquakes, and notably, seasonal fin whale calls which confuse the current conventional earthquake catalog building software. Earthquakes will be located using existing 3-D models of P- and S-wave velocity structure, the double-difference technique will be applied to improve relative earthquake locations and focal mechanisms determined from P-wave first motions and P- to S-wave amplitude ratios. To detect velocity changes linked to strain, time-lapse imaging of structure using 4-D travel time tomography will be explored and ambient noise techniques applied to both single stations and pairs of stations. Families of multiplet earthquakes will also be investigated. The improved real-time earthquake catalog for the cabled network will benefit scientists seeking to respond to seismic events that might perturb the Endeavour hydrothermal systems and the retrospective catalog that add the autonomous data will contribute to the interpretation of the hydrothermal response to diking events. The project will train graduate and undergraduate students in seagoing marine geophysics and seismic analysis. 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 · 2025-03

Project Summary/Abstract The goal of our research is to better define the molecular mechanisms cause and perpetuate systemic lupus erythematosus (SLE). Based on our discovery that transcripts from a large number of genes are spliced differently in neutrophils from SLE patients compared to neutrophils from healthy donors or COVID-19 patients, we propose a novel hypothesis of SLE pathogenesis, namely that dysregulated mRNA splicing in SLE granulocytes can affect their function and generate (neo)autoantigens not seen by the immune system before. We propose to expand and substantiate the analysis of altered mRNA splicing and begin to search for its cause(s). We will define how specific it is to SLE, understand the relation of altered splicing to sex, age, disease activity, type I interferons, and patient heterogeneity. Our work will also embark on the quest to elucidate why mRNA slicing is dysregulated in SLE. Next, we propose to explore the consequences of altered mRNA splicing in SLE. Although we have high confidence in the alignment of RNAseq reads to support all the splicing events we detect, and the transcripts are present at good read counts, it needs to be demonstrated that at least some are translated into altered proteins. We will continue to use targeted LC-MS/MS to find evidence for those with novel amino acid sequences. The proteolytic processing into antigenic peptides presented on MHC seen by T cells will then be explored. We know the MHC haplotypes of all our donors from the RNAseq data, so can match putative neoepitopes with the right MHC. Our work will clarify whether the production of novel, and perhaps individual, neo-autoantigens are a feature of SLE. If so, the production of such antigenic peptides would drive an immune response against the specific cell type that produces them (rather than all cells expressing the gene), adding a new element of tissue or cell linage-targeting to the autoimmune response. This model also introduces a new avenue for the development of therapeutics: modulating mRNA splicing to eliminate the production of neo-autoantigens. This will only be possible once the mechanism(s) underpinning abnormal splicing have been elucidated.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY Although survival from breast cancer (BC) has improved, BC treatment is associated with an increased risk of cardiovascular (CV) complications due in part to the cardiotoxic effects of BC treatment. BC treatments are also linked to reduced exercise capacity and cardiac function, which may contribute to the increased risk of CV events in women receiving BC treatment. Accelerated aging is one possible mechanism that could explain the declines in exercise capacity and cardiac function observed in women treated for BC. BC treatment is known to cause age-related cellular changes through multiple mechanisms including epigenetic alterations, such as DNA CpG site methylation which is a well-known marker of accelerated aging. Accelerated aging has been linked to CV disease risk and declines in cardiac function in the general population. However, no study to date has examined the association between accelerated aging and exercise capacity or cardiac function in BC patients. Identifying the mechanisms by which reduced exercise capacity and cardiac function during BC treatment occur could lead to targeted interventions. For instance, accelerometer-assessed physical activity in a healthy community-based cohort was shown to negate the effects of accelerated aging. This suggests that the rate of epigenetic age acceleration may be modified by physical activity, identifying a potential lifestyle modification to improve exercise capacity and cardiac function in BC patients. The purpose of the proposed study is to examine epigenetic changes during BC treatment and their association with changes in exercise capacity and cardiac function during BC treatment. We will utilize samples from the NCI-funded Understanding and Predicting Fatigue, CV Decline and Events after BC Treatment (UPBEAT) study, a prospective cohort of BC patients receiving cancer treatment. We will quantify DNA CpG site methylation in 100 samples of women with BC and 20 samples of non-cancer controls collected at both enrollment and 3-months after enrollment using the Illumina Infinium MethylationEPIC v2.0 BeadChip. We will characterize epigenetic changes during BC treatment compared to non-cancer controls and examine the association between epigenetic aging with changes in exercise capacity and cardiac function in women receiving BC treatment. The UPBEAT study is an ideal dataset to investigate the proposed research study as it obtained DNA specimens required to examine epigenetic changes prior to and during BC treatment, includes non-cancer controls, and has detailed data on CV risk factors, treatment data, physical activity, medications, and CV comorbidities and longitudinal data on exercise capacity and cardiac function. Findings from this study will aid in identifying mechanistic pathways in which BC treatment impacts exercise capacity and cardiac function. Understanding the role of accelerated aging in relation to exercise capacity and cardiac function in BC will provide information needed to develop targeted interventions with the long-term goal of reducing the risk of CV events in BC survivors. Additionally, this data could be used to identify BC patients at high risk of developing CV dysfunction and reduced exercise capacity, which could be used to improve risk stratification.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY/ABSTRACT Inhibitory neurons likely underlie many neural computations. They are highly conserved in neural circuits throughout the brain and their dysfunction has been implicated in many neurological and psychiatric disorders. But very little is known about how they contribute to neural computations, especially in the primate brain. An important computation that inhibitory neurons likely mediate is gain control. Gain control is the process by which neural sensitivities are adjusted so firing rates stay within their dynamic ranges without altering stimulus selectivity. Gain control exists throughout the brain, but it is especially well-characterized in the visual system, where it can contribute to many processes such as contrast-invariant orientation tuning, attention, and multisensory integration. A type of inhibitory neuron likely specialized for gain control is parvalbumin expressing (PV+)-neurons. Optogenetically activating PV+ neurons in mouse primary visual cortex (area V1) represses the responses of excitatory neurons without altering their orientation selectivity. However, it is unknown if PV+ neurons in primates modulate their targets in the same way because of the lack of genetic tools that enabled the mouse experiments. Fortunately, recent advances in viral genetic tools now allow for selective targeting of PV+ neurons in macaques. In the proposed research, we will use these tools to determine if PV+ neurons in the primate brain mediate gain control. Aims 1 and 2 are to determine if PV+ neurons are specialized for gain control by activating/inactivating them optogenetically and measuring their effects on excitatory neurons. Additionally, many models of gain control make predictions about the tuning of PV+ neurons. Some models predict that PV+ neurons are broadly tuned, while others predict they are tuned similarly to their excitatory counterparts. Aim 3 is to determine which type of model is more accurate. PV+ neurons will be identified by their responses to optical stimulation, then their orientation tuning will be compared to excitatory neurons. For all these experiments, cell-type specific optogenetics and high-density Neuropixel recordings will be paired in primates, which will allow for extremely high-throughput characterization of specific cell-types. This work is a crucial step towards understanding the roles of PV+ neurons in the primate brain and how they contribute to cortical processing. This improved understanding will in turn pave the way for future treatments of diseases associated with PV+ neurons. The proposed research will also provide valuable training in neurophysiology, optogenetics, hardware engineering, and data analysis. Moreover, it will support professional development by providing opportunities for scientific communication, mentorship, and teaching. This research will be conducted at the University of Washington under the supervision of Dr. Gregory Horwitz, who has significant experience with primate physiology and optogenetics. This work will also benefit from the support of other faculty members and the resources of the Washington National Primate Research Center.

NIH Research Projects · FY 2026 · 2025-03

SUMMARY The objective of this R38 is to increase the number of next generation physician-scientists that can apply knowledge of microbiology, immunology, and research techniques for the improvement of reproductive, maternal and child health. We request support for 4 physician-scientists in pediatrics or obstetrics/gynecology residency to complete one year of laboratory-based immunology or infectious disease training. The major strength of our program is the world-class faculty mentors that span expertise across bacterial and viral infectious diseases, immune system development, infectious disease immunology, autoimmunity, allergy, cancer immunology and vaccines, immunodeficiencies, innate and adaptive immunity, vaccinology, antibody response, functional genomics of the immune system and response, and immunotherapeutics. Our program features a training program that combines research with an R38 seminar series to strengthen and build our students’ critical thinking, scientific communication, responsible conduct of research, and skills in navigating academic medicine unique to physician-scientists. Our trainees will benefit from the rich, diverse, and interactive infectious disease and immunology community at University of Washington and our Seattle partner institutions: Benaroya Research Institute, Fred Hutchinson Cancer Center, and Seattle Children's Research Institute. During and after their R38 year, we will provide trainees with opportunities to interact with one another to build a community of early-stage physician-scientists in reproductive, maternal and child health. Our R38 Seminar Series features training not only in scientific communication, but also in leadership strategies, professionalism, negotiation, and work-life balance that are critical for navigating hurdles in academic medicine. A unique highlight of the program is an ongoing commitment to scholars after completion of their award by providing mentoring in grant writing for their first K38 or other career development proposals by a team of dedicated faculty members. Our program features five Specific Aims: 1) to provide innovative scientific training in immunology and infectious diseases focused on reproductive and child health, 2) to create and support effective mentor-mentee relationships, 3) to enhance success in transitioning to career development awards through grant writing mentorship during and after the R38 award, 4) to recruit and support resident physician-scientists from diverse backgrounds, and 5) to evaluate scholars, mentors and the overall program. In summary, we will leverage the rich scientific environment that supports infectious disease and immunology research in Seattle to enhance the career development of physician-scientists in reproductive, maternal and child health.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY Somatosensory neurons shape an animal’s experience of the world, allowing for perception and discrimination of temperature, touch, pressure, pain, and movement. Perception of these stimuli depends on cell type-specific behaviors of somatosensory neurons: innervation of discrete territories peripherally, projection to stereotyped locations centrally, selective expression of ion channels and sensory receptors, and choice of appropriate synaptic partners. Despite the importance of somatosensory neurons to sensation and motor control in all animals, we have a limited understanding of somatosensory neuron morphology, diversity, and function in Aedes aegypti, a major vector of human diseases. In this application we aim to close this important gap in knowledge, leveraging our expertise in insect somatosensory neuron development to anatomically and molecularly define the repertoire of somatosensory neurons that innervate the Aedes body wall. central hypothesis is that different types of somatosensory neurons mediate different sensory Our modalities, and that features of cell types will be manifest in morphology and gene expression patterns. Using a robust pipeline we developed for RNA-Seq expression profiling coupled to high resolution imaging of peripheral innervation patterns we aim to provide a comprehensive map of Aedes somatosensory neuron diversity.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY Trauma-related injuries, such as from motor vehicle accidents, accidental falls or acts of violence, are the 3rd leading cause of death in the United States, and the leading cause of death for those between 1 and 46 years of age. Damage control resuscitation is initiated by first responders to restore tissue perfusion and oxygen delivery while preventing complications associated with aggressive resuscitation efforts. However, as most interventions for addressing bleeding rely on blood product transfusions, limited treatments are available for use outside the hospital setting. The goal of this proposal is to engineer novel, synthetic therapies for stabilizing trauma victims in the critical “golden hour” after injury. Our main objectives are to develop low volume resuscitants that provide fluid resuscitation while preserving the patient’s coagulation system and immune- modulating polymers that attenuate inflammation and neutralize reactive oxygen species. Successful completion of these aims will lead to new and critically-needed innovations for trauma medicine.

NSF Awards · FY 2025 · 2025-03

This I-Corps project is the development of a medical device designed to improve the safety and efficacy of gastrointestinal (GI) surgical procedures. Currently, there is a need to reduce leakage when part of an intestine is surgically removed, and the two remaining ends are sewn or stapled together (anastomosed). Resultant infections may produce complications that may be life-threatening, costly, and detrimental to patient outcomes. The technology is a bioresorbable 3D-printable tube and compressive band combination. The 3D printing allows for a printed, customized surgical solution to accommodate individual anatomical variations. With widespread adoption, this technology has the potential to set a new standard for GI surgical care, improving patient safety and reducing healthcare costs. In addition, this advance may lead to applications that address leakage in other tubular organs and may inspire the development of new bioresorbable medical devices. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of a bioresorbable stent and compressive band combination to improve the safety of gastrointestinal (GI) anastomoses. The goal of the technology is to prevent anastomotic leakage and its resultant infectious complications. The collapsible, low-profile device design allows for introduction and delivery through laparoscopic ports for use in minimally invasive procedures. After implantation, the components are resorbed by the body by which time the risk of leakage has passed, eliminating the need for follow-up procedures to remove the device. The expandable, low-profile design can be used in minimally invasive procedures. Benchtop testing has demonstrated the device’s ability to create anastomoses with minimized leakage risk. This device may address the current limitations of existing methods such as staples and sutures and improve patient GI surgery outcomes. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-03

Living cells can act as programmable and dynamically-responsive therapeutics to treat cancer. Although engineered human T cells have been effective for cancer therapy, they are almost prohibitively expensive. In contrast, bacterial cells can be manufactured at low cost and therefore hold promise as broadly applicable therapeutics. To enable effective live-cell bacterial therapeutics, this project will develop a unique biosensing system to detect specific tumor antigens and respond with potent therapeutic effectors. In parallel, the proposed research will improve safety by engineering bacteria to make them more effective against tumors at lower doses. Living bacteria therapies have been proposed as an alternative approach to treat tumors by sensing their environments and delivering localized anti-tumor payloads. Bacteria can be manufactured at low cost compared to human cell therapies and therefore hold promise as broadly applicable therapeutics. To address two major outstanding challenges for bacterial immunotherapy, this project will develop new bacterial sensing platforms with specificity for disease tissue and engineer bacteria with improved tumor colonization. Ideally, bacteria would target protein antigens displayed on cancer cells, but engineered extracellular protein sensing is currently not possible. This project will develop a unique sensing system in E. coli bacteria to recognize extracellular cancer antigens and respond with a toxic, immunostimulatory payload. Effects on tumor growth will be evaluated in a mouse tumor model. In parallel, bacteria with improved tumor colonization will be engineered by displaying extracellular factors that evade the host complement system. This approach will allow systemic bacterial delivery at low doses to avoid widespread inflammation, which is important because most tumors are not accessible to direct intratumoral injection. Successful completion of the project will produce improved bacterial live-cell therapeutics with synthetic signaling systems that allow autonomous responses in vivo, and with improved tumor colonization for safe, systemic delivery. This collaborative U.S.-Swiss project is supported by the U.S. National Science Foundation (NSF) and the Swiss National Science Foundation (SNSF), where NSF funds the U.S. investigator and SNSF funds the partners in Switzerland. 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 · 2025-03

User trust in digital applications has been significantly eroded by growing concerns over the collection of personally identifiable information. A major challenge in limiting such collection is that it often takes place for legitimate reasons that are deeply intertwined with the proper operation of the applications themselves. In particular, many applications require some form of user authentication, which often, as a side effect, enables tracking of the user’s journey. This project aims to develop new privacy-preserving techniques that address this inherent tension by enabling authentication methods that reveal only what is strictly necessary. The planned work will establish new theoretical foundations, produce practical solutions, and inform ongoing standardization efforts in industry. The project will also enhance the undergraduate research experience in cryptography at the University of Washington and introduce a new approach to teaching cryptography at the undergraduate level. On a technical level, the project will advance the theory of blind signatures and anonymous credentials, two cryptographic primitives that underpin most privacy-preserving authentication solutions. A key focus will be on more efficient and flexible constructions of these primitives, and on proving their security under the weakest possible cryptographic assumptions. Formal security models will support these efforts, and enable rigorous proofs of security. Two main objectives are to design best-possible constructions from elliptic curves and to develop new techniques to ensure security against quantum attackers. The project will also explore protocols for threshold issuance of blind signatures, distributing the issuance process among multiple parties to eliminate single points of failure. In addition, it will examine the concrete security of the digital signatures behind anonymous credential systems, and investigate the design of larger-scale secure protocols using these primitives. 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 · 2025-03

This project provides funding for the Research Vessels Thomas G. Thompson and Rachel Carson to conduct oceanographic research missions supported by the National Science Foundation. The oceanographic research vessels of the Academic Research Fleet (ARF), operated by the academic institutions within the University-National Oceanographic Laboratory System (UNOLS) framework are multi-use facilities used to expand knowledge of the ocean environment. The surface work of these ships is complemented by human-occupied, remotely operated, and autonomous undersea vehicles and sensors that provide vital tools to understand the oceans and their resources. These seagoing research and educational facilities enable scientists and students to study natural phenomena and train future scientists while on board state-of-the-art oceanographic research vessels utilizing high-quality instrumentation. The ship operators will also conduct learning activities for students and the general public including hands-on demonstrations of marine science research guided by faculty, students, and ship crew members. 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 · 2025-03

SUMMARY mRNA technology is in the public spotlight thanks to its role in fighting the COVID-19 pandemic, and it is also rapidly transforming cancer therapeutics development through application areas such as immunotherapy. This wave of mRNA therapeutics is the result of decades of work on many fronts including improved delivery using lipid nanoparticles and inclusion of modified nucleosides for modulating immunogenicity. However, optimization of primary sequences still remains a difficult yet coveted challenge due to its untapped potential in controlling protein expression or encoding complex pharmacokinetics. Currently, mRNA therapy design typically involves adding UTRs from highly expressed native genes such as globin genes to codon-optimized (choosing most frequent synonymous codons) or GC content-enriched coding sequences. However, there is growing evidence that these strategies may be conceptually questionable and empirically suboptimal. At present, there exists no systematically validated model for mRNA therapeutics that can accurately predict and/or generate an optimal sequence to express a given target gene at desired levels. There is a significant need for such an in silico platform to accelerate therapy development timelines. Finally, mRNA sequences are largely chosen to have high expression but future therapies will impose additional design specifications for controllable expression. For example, it might be desirable to target protein expression to specific locations such as the site of a tumor. Improved design algorithms are necessary to satisfy constraints such as cell type or tissue specificity. Here, we propose to combine machine learning with massively parallel reporter assays (MPRAs) to build predictive models that relate mRNA sequence to stability and translation. We will then combine these models with innovative design algorithms to generate synthetic UTR and CDS sequences that result in (1) high protein expression across cell types or (2) highly cell type-specific protein expression. We will take an iterative approach to sequence design wherein we will synthesize designed UTRs, experimentally test them in a panel of cell types and then use the data to retrain the predictors until we meet the design objective. We will validate our approach by engineering improved mRNAs for cancer immunotherapy. In Specific Aim 1, we will develop MPRAs that interrogate 5’UTRs and coding sequences as well as 3’UTRs. In Specific Aim 2, we will develop machine learning approaches that enable us to integrate results from multiple measurements and generalize predictive rules learned from such assays. In Specific Aim 3, we will validate models by engineering regulatory elements that target protein expression to specific cell types of interest or that result in a specific level of protein expression.

NIH Research Projects · FY 2026 · 2025-02

Project Summary Differentiation into dormant encapsulated cell types, known as encystation, is one of the most common modes of eukaryotic differentiation. Importantly, these changes cause the parasites to release from the host intestine, thus this process could be targeted to clear infections and/or block transmission. Despite its importance, very little is understood about the regulation of Giardia encystation. Here we propose to use single-cell RNA sequencing (scRNAseq) to build an atlas of gene expression during the cell cycle (Aim1) and during differentiation into cysts (Aim2). cAMP signaling is necessary and sufficient to initiate the encystation but not induce the formation of fully formed cysts. Hence, additional signals are required for cyst formation, and we aim to address this important question using scRNAseq. Together these studies will deepen our understanding of the encystation program and reveal unappreciated pathways that work to control the balance between persistence of infection versus transmission of this major parasite and model for the regulation of encystation.

NSF Awards · FY 2025 · 2025-02

‘Cryptobenthic’ reef fishes are a group of thousands of tiny (<5cm), bottom-dwelling species that are difficult to see but occur on coral reefs worldwide in staggering abundances and diversity. In fact, half of all fishes on a typical reef are cryptobenthic, but traditional surveys do not usually include these species. Due to the limited geographic extent of scientific surveys, countless cryptobenthic fish species have yet to be discovered and described, and local biodiversity inventories do not exist in most countries. This project explores the biodiversity of cryptobenthic coral reef fishes in the Indo-Pacific by: 1) conducting a series of local and regional inventories through standardized survey and collection protocols, 2) describing new species by considering multiple high-resolution sources of information to delineate closely related species, 3) analyzing the evolutionary diversification of a particularly species-rich lineage (the dwarf goby genus Eviota) and 4) training a new generation of fish taxonomists with strong ties to coral reef nations to ensure reef fish biodiversity research and conservation for years to come. Inventorying the diversity of life on our planet is a critical challenge that intensifies with the rapid change of the biosphere. Cryptobenthic fishes, which include the world’s smallest and shortest-lived vertebrates, are a biodiversity taxonomic frontier. This research employs standardized sampling techniques across four locations in the Indo-Pacific that promises particularly rich biodiversity discovery (the Lakshadweep, Philippines, Solomons, and American Samoa) with a cutting-edge integrative taxonomy framework and immersive training of young scientists to boost description rates of cryptobenthic fishes for years to come. By implementing an innovative genomics approach to species delimitation, the project will also improve our knowledge about evolutionary processes in the sea, while establishing a promising new model system of small, short-lived, hyperdiverse vertebrates. Finally, the project will establish a dedicated online platform and a museum exhibit to engender scientific discovery and spark public interest in the world’s smallest marine vertebrates. 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 · 2025-02

This project aims to serve the national interest by enhancing science learning and collaboration for undergraduate students in biology and biochemistry. The Nation’s ability to stay on the leading edge of scientific development hinges on a STEM workforce with well-developed collaboration skills. Some evidence suggests that successful collaboration depends on social metacognition, or the awareness and regulation of another’s thinking. Social metacognition occurs when one person stimulates metacognition in another. This happens when one person monitors or evaluates their own understanding or another’s understanding out loud for others to hear. This project will use both qualitative and quantitative methods to analyze audio and video data from introductory college biology labs and biochemistry classrooms to determine how social metacognition and students’ perceptions of social metacognition impact collaboration in these contexts. This project will result in fundamental knowledge and understanding of how social metacognition impacts collaboration. Additionally, this project will allow the principal investigator (PI) to develop skills in fundamental STEM education research through mentoring and formal learning opportunities. The goals of this project are to generate fundamental knowledge about social metacognition’s impact on collaboration and to build capacity in the PI to conduct high quality fundamental STEM education research. To meet these goals, this mixed methods project will 1) characterize social metacognition that occurs across science contexts and its impact on collaboration, and 2) determine how students’ perceptions of naturally-occurring social metacognition vary across different science contexts. To accomplish the first objective, statistical discourse analysis, a form of dynamic multilevel hierarchical linear modeling, will be used to test hypotheses about how social metacognition and other explanatory variables impact collaboration in two science class contexts. The use of statistical discourse analysis will enable strong inferences to be made in a field that traditionally centers qualitative methods. To accomplish the second objective, individual students from introductory biology labs and biochemistry courses will be shown selected video clips of naturally-occurring social metacognition from their group work sessions and asked to recall what they were thinking and feeling in the moment. Through this stimulated recall method and the lens of politeness theory, student perceptions of social metacognition will be identified. Student perceptions of social metacognition are currently missing from the field and this information has implications for the development of social metacognition interventions. A professional development plan that includes coursework and mentorship from experts in social metacognition, statistical discourse analysis, and stimulated recall methods will ensure the primary investigator builds the knowledge and skillset needed to carry out the project. This project is supported by NSF’s EDU Core Research Building Capacity in STEM Education Research (ECR: BCSER) program, which is designed to build investigators’ capacity to carry out high-quality STEM education research in the core areas of STEM learning and learning environments, broadening participation in STEM fields, and STEM workforce development. 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 · 2025-02

Project Summary/Abstract Treating, and in particular preventing, diseases requires an understanding of the mechanisms that lead to their initiation. Parasitic worms and allergens all trigger a “type 2” immune response, but how these agonists are first detected remains poorly understood. Group 2 innate lymphoid cells (ILC2s) are activated early in a type 2 immunity and coordinate downstream inflammation, but they do not directly sense worms or allergens. Instead, ILC2s are activated by signals released from their surrounding tissue, such as the cytokine interleukin(IL)-33. IL-33 is critical for airway type 2 immunity and its release has been linked to cell lysis caused by helminths and many allergens. We have discovered that leukotriene C4 (LTC4) and its metabolite LTD4 are also universally required for ILC2 activation and innate type 2 immunity in the lung. Which cells synthesize LTC4 and how this is activated by helminths or allergens remains unknown. Here we test the central hypothesis that by coordinating the release of both IL-33 and LTC4, loss of plasma membrane integrity (LPMI) serves as a unifying mechanism for the induction of type 2 immunity. First, we identify alveolar macrophages as an important source of LTC4 and study how LTC4 synthesis is regulated in these cells. Next, we examine the unique contributions of LTC4 and LTD4 to acute and long-term ILC2 function and downstream type 2 immunity. Lastly, we use novel tools to examine the link between lytic cell death and type 2 immunity in the lung. Our work promises to uncover novel mechanisms regulating induction of type 2 immunity and will therefore suggest novel therapeutic approaches to treat or prevent diseases such as asthma.

NSF Awards · FY 2025 · 2025-02

The field of Quantum Information Science and Engineering (QISE) seeks to leverage the principles of quantum mechanics to unlock new applications in computation, communication, and sensing. The field is rapidly growing and has been identified as a priority for the United States as part of the National Quantum Initiative. Training the next generation of researchers in academia and industry is key to addressing the many fundamental scientific and engineering challenges that lie ahead, and to maintaining the United States leadership in QISE. This REU (Research Experience for Undergraduates) Site will help address a critical component in the training pipeline of the US QISE research workforce by providing undergraduate students an opportunity to engage in a wide spectrum of interdisciplinary QISE research. The program will also aim to broaden participation in QISE demographically, aiming to have at least half of the students in each cohort be from underrepresented groups. Students will participate in projects ranging from theory and applications (quantum algorithms, cryptography, and complexity theory) to experiments (quantum simulation, and quantum hardware technologies and architectures). The program aims to equip students with the skills and experience they need to engage in QISE research at the graduate level and beyond, and to tackle the important challenges ahead (from fundamental questions in quantum information theory and applications, to the realization of quantum devices). Towards this goal, the program will also provide opportunities for professional development by leveraging the University of Washington’s connections to the quantum industry in the greater Seattle area. 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 · 2025-01

PROJECT SUMMARY Alzheimer's Disease (AD) is the primary cause of progressive dementia associated with cognitive decline, neurodegeneration, and neurocircuit dysfunction. Results from recent attempts to address classical amyloid- beta (Aβ) deposition and hyperphosphorylated tau (pTau) deposits have been limited in providing significant clinical benefits. As a result, researchers are now exploring alternative disease mechanisms that contribute to the pathogenesis of AD. One such mechanism is the loss of perineuronal nets (PNNs), specialized extracellular matrix (ECM) structures that regulate the activity of key neurons involved in memory and cognition. PNNs are significantly reduced in the brains of AD patients and thus represent a novel target for therapeutic investigation. PNN matrices consist of chondroitin and dermatan sulfate-glycosaminoglycans (CS/DS-GAGs) that are uniquely modified with sulfate attachments linked to specific biological functions within the brain. Within the mono-sulfated class, the 6S-CS isomer has been shown to directly destabilize PNN matrices and induce neurocircuit re- organization. Moreover, we recently showed increased cortical 6S-CS expression occurs prior to AD clinicopathology, which is then worsened in association with advanced stages of AD and pTau accumulation. These results suggest that favoring the 6S-CS isomer in PNN CS/DS-GAG composition may destabilize PNN formation in AD brain tissue, leading to reorganization of the underlying circuitry and causing deficits in learning, memory, and cognition while potentially worsening the neurodegenerative process. To investigate the functional impact of increased 6S-CS expression in PNNs surrounding GABAergic neurons, we first induced GABAergic neuronal expression of the 6S-CS isomer using an AAV1-mChst3 (6S- sulfotransferase) in vgat-Cre mice. Our Preliminary results show that GABAergic overexpression of the 6S-CS isomer reduced stable PNN labeling but also unexpectedly increased neuroinflammatory markers, including those for astrogliosis (GFAP) and microgliosis (Iba1). These preliminary results indicate a potential novel role for 6S-CS in driving neuroinflammation associated with the AD pathogenesis. Specific Aim 1 highlighted within this proposal focuses on determining the cell-specific effects of 6S-CS overexpression on neuroinflammation and pTau accumulation using different neuronal, glial, and tauopathy Cre-mouse models. Meanwhile, Specific Aim 2 proposes to utilize MALDI imaging mass spectrometry to spatially resolve CS/DS isomer patterns in human AD brain tissue in association with cellular and pathogenic neuropathology in AD and non-AD human brain tissue. Overall, this fellowship proposal seeks to understand the role of 6S-CS overexpression in neuroinflammation and AD neuropathology accumulation using innovative viral and imaging mass spectrometry techniques, the results of which will contribute to a better understanding of how CS/DS-GAGs drive the AD pathogenesis.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract Duchenne muscular dystrophy (DMD) is an X-linked, lethal recessive genetic disorder resulting from mutations in the DMD gene, which encodes the protein dystrophin (Dys). The 2.2 MB gene displays the highest new mutation rate of any human gene, reflecting the high DMD prevalence (1:5,000). This large size coupled with thousands of unique mutations creates significant complexity for gene therapy. Previous studies by us and others led to the design of ‘micro-dystrophins’ (μDys) that can be delivered systemically to striated muscles using AAV vectors. This approach, along with anti-sense oligonucleotide (ASO) ‘exon-skipping’ methods, have emerged as promising therapies that are being tested in multiple clinical trials, with one µDys approach and several ASO drugs having now been approved by the FDA. Gene editing has garnered significant attention, primarily as an alternate and potentially permanent way to correct Dys expression. While promising, the ASO & editing methods remain comparatively inefficient, and many AAV-mediated editing methods result in genomic rearrangements & vector insertion due to Cas9-induced double-stranded DNA breaks. AAV-μDys has proven to be far more efficient & is not associated with insertional mutagenesis; however, this approach is limited to delivery of dystrophins carrying only one-third of the full-length sequence. Clinical trials, while encouraging, have also revealed dose- related toxicities that limit the AAV dose, which is suboptimal for gene replacement & editing. Our ongoing structure/function studies of Dys have led to the design of numerous micro-, mini- and full-length Dys vectors, & have extended into gene editing methods. Together these approaches offer the potential to express significantly larger and more functional dystrophins. Furthermore, myotropic AAV capsid variants now enable delivery of more potent gene therapies at much lower vector doses. In this proposal we harness previous discoveries and preliminary data to address limitations of current gene therapy approaches for DMD by developing improved gene replacement & editing vectors. In Aim 1, novel technologies for expressing mini- & full-length Dys and/or it’s paralogue utrophin (Utrn) using multiple AAVs will be refined with the goal of efficiently producing highly functional therapies. This approach utilizes known & novel split inteins to enable production of Dys/Utrn proteins larger & more functional than can be delivered with a single AAV vector (i.e. AAV-μDys). In Aim 2, enhanced Dys gene editing methods will be developed to maximize duration and expression levels of large endogenously regulated dystrophins, through delivery of augmented & inducible editing vectors. A major focus is on Satellite cells. Aim 3 critically evaluates the therapeutic impact & longevity of both Aim 1 & 2 approaches in response to aging & injury, and examines the possibility for synergistic application. All aims take advantage of the recently described ‘MyoAAV’ capsids that enable systemic muscle gene delivery at doses 10-20-fold lower than the AAV9 or rh74 serotypes currently in clinical trials. Together these approaches could significantly increase the safety and efficacy of gene therapy for DMD, and should have important applications to other neuromuscular disorders.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT Cardiovascular Health Study (CHS) is a population-based cohort study of 5888 older adults recruited in the 1990s and designed to study traditional and novel risk factors for onset and course of heart disease and stroke. Subclinical disease measures include pulmonary function, carotid ultrasound, echocardiography, cranial magnetic resonance imaging and others. CHS originated the Working Group (WG) model that provides mentored-access to CHS, an especially valuable model for early-career investigators. The CHS WGs—Cardiovascular, Diabetes, Geriatrics, Neurology, Renal, Bone and Genetics—have been productive. With more than 2120 publications, CHS has an h-index of 240. As of Dec 2023, CHS also has 78 active ancillary studies, 41 of them currently funded by the NIH, and another 22 in revision or under review. NHLBI contract funding for CHS has, however, not been steadfast. Contract funding for examinations ended in 1999. The surveillance calls did continue. In 2005, the NHLBI also ceased contract funding for events data collection. An investigator-initiated grant (HL080295) supported events data collection until 2015. In 2016, when the NHLBI ceased contract funding for CHS altogether, an investigator-initiated grant (HL130114) continued support for the Biorepository, for ongoing surveillance calls to participants, and for the support of working groups through 2020. A new NHLBI contract supports CHS until Oct 2024. In Nov 2024, about 25 of 60 CHS active ancillary studies will have NIH funding that persists beyond the end of the contract. Also, TOPMed has just awarded CHS almost $10 million worth of multi-omics assays (8619 proteomics, 8619 metabolomics, and 8041 DNA methylation) with 3 timepoints as available for participants with WGS data. At this time, the NHLBI lacks an NCI-like mechanism for infrastructure grants for epidemiology cohorts (PAR-20-294), so the only option for CHS is again (as we did in 2016) to seek peer-reviewed R01 funding even though the genre of infrastructure support differs from that of hypothesis-testing grants. The purpose is to provide a scientific service and maintain a major research resource for the scientific community. None of the study aims involves a hypothesis test, but these service aims enable the myriad hypothesis-based activities of the CHS investigators and ancillary studies. The primary aims of this grant application are: 1) to provide infra-structure support to maintain the CHS Coordinating Center, its various databases, and activities, including support for 78 ancillary studies; 2) to assist investigators in developing grant applications for new ancillary studies; 3) to provide support for the CHS Biorepository; 4) to provide mentored access to CHS data and its specimens; 5) to provide limited support for 7 CHS Working Groups; 6) to make CHS data and ancillary-study opportunities widely available to all investigators; and 7) to keep CHS active for critically important participation in multi-omic and multi-study collaborations such as TOPMed. The findings from CHS will be vital for developing novel CVD preventive strategies to improve the health of older adults.

NSF Awards · FY 2025 · 2025-01

Subduction zones represent a boundary between Earth's tectonic plates where one slides under the other. Subduction zones host the largest earthquakes on Earth, and recent research has revealed more complex deformation events that take place over periods of months or years (referred to here as slow slip and tremor or SST). SST events do not have the sudden destructive power of earthquakes but they can influence the occurrence of large earthquakes. Despite the near ubiquity of SST in modern subduction zones, the mechanisms that drive SST remain poorly understood, in part because direct observations of processes occurring deep in the Earth's crust are not possible. Rocks that have been subducted to SST depths and brought back up to the surface provide a window into processes happening deep in subduction zones. This project will: (1) investigate the types of rocks that potentially hosted SST by analyzing the minerals that make up the rocks, including the ages, chemistry, and deformation and (2) compare the rock record to geophysical imaging of modern subduction zones by modeling the geophysical signature of these rocks based on the observations. Collectively, the results of this work will reveal the distribution of potential SST sources as preserved in the rock record and how they correlate to modern subduction zones. This project involves extensive international collaborations and training of graduate and undergraduate students as well as a postdoctoral scholar. Additionally, as part of this work yearly workshops will be developed in seismic properties, rheology/deformation and geochronology/geochemistry tailored in subduction zone science for the participants of the project. These workshops will result in scientific/methodologic resources and workflows for future research on rock record evidence of SST. These materials will become publicly available as resources for the subduction zone research community. At the base of the seismogenic zone stored elastic energy may be released gradually in slow slip events along with low frequency earthquakes and non-volcanic tremor that contribute significantly to the seismic cycle. This project addresses long-standing questions on whether slow slip events can be hosted in metasedimentary or meta-mafic rocks and the potential spatial distribution of SST sources. Geophysical studies find that SST often coincides with sheared and underthrusted metasedimentary rocks or with the uppermost oceanic crust of the downgoing slab. However, field observations integrated with experimental constraints suggest that metasedimentary rocks are not good candidates for SST sources. Three subduction complexes were selected that span deep SST depths and offer excellent exposures of underplated metasedimentary rocks intercalated with meta-mafic and meta-ultramafic lithologies. The project will investigate evidence of SST in these complexes (e.g., vein networks, geochemical signatures of alteration) using a field-based approach coupled with geochronology/geochemistry, structural geology, microstructural analysis, and rheology. By using the results from the rock record to calculate seismic properties coupled with the geophysical observations of SST in modern subduction zones, this work will test (a) whether SST may be preferentially accommodated by metasedimentary or meta-mafic lithologies, and (b) how structural heterogeneity along the subduction interface affects the spatial distribution of SST. The outcomes of this work will have implications for the geologic conditions and slip behavior at the base of the seismogenic zone and will therefore better inform both SST observations in active subduction zones and geodynamic models of the seismic cycle and associated earthquake hazards. 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 · 2025-01

Project Summary / Abstract Single-cell expression quantitative trait locus (eQTL) studies aim to characterize regulatory effects of genetic variants on gene expression in cell types or cell states. These studies present unprecedented opportunities to elucidate the molecular mechanisms underlying variant-disease associations. However, due to lack of statistical methods, integrative analysis of single-cell eQTL and genome-wide association studies (GWASs) have ignored the cell state heterogeneity within cell types. Previous research showed that autoimmune disease-associated variants can be functional in highly specific states of immune cells. The proposed research aims to develop statistical methods for integration of single-cell eQTL and GWAS data at cell state resolution. Specific aims include 1) transcriptome-wide association studies (TWAS) using single-cell eQTL data, 2) quantifying disease heritability mediated by gene expression, and 3) using the methods to analyze a large single-cell eQTL study of peripheral blood mononuclear cells (PBMCs) and GWASs of autoimmune diseases. The study will provide powerful tools to gain biological insights from the rapidly growing single-cell eQTL studies, prioritize causal genes and specific cell states for autoimmune diseases, and guide the design of future studies. Dr. Guanghao Qi is a biostatistician and statistical geneticist who has extensive expertise in GWAS, and experience in allele-specific expression. This career development award will build on his existing expertise and provide in-depth training in single-cell genomics and immunology. Training will be achieved through hands-on research, intensive coursework, and regular meetings with the mentors: primary mentor Dr. Wei Sun (single-cell genomics), co-mentors Dr. Ali Shojaie (high-dimensional statistics and multi-omics) and Dr. Ram Savan (immunology and RNA biology). The mentoring team has deep expertise in complementary areas and a successful track record of mentoring junior scientists. The University of Washington is an excellent research environment with rich resources and numerous collaboration opportunities. The training and mentoring provided by this award, combined with Dr. Qi’s existing expertise and strong institutional support, will propel Dr. Qi to develop into an independent investigator at the interface of genetics, genomics, immunology, and data science.

NSF Awards · FY 2025 · 2025-01

This project provides funding for the Research Vessel Thomas G. Thompson to conduct oceanographic research missions supported by the National Science Foundation. The oceanographic research vessels of the Academic Research Fleet (ARF), operated by the academic institutions within the University-National Oceanographic Laboratory System (UNOLS) framework are multi-use facilities used to expand knowledge of the ocean environment. The surface work of these ships is complemented by human-occupied, remotely operated, and autonomous undersea vehicles and sensors that provide vital tools to understand the oceans and their resources. These seagoing research and educational facilities enable scientists and students to study natural phenomena and train future scientists while on board state-of-the-art oceanographic research vessels utilizing high-quality instrumentation.The ship operators will also conduct learning activities for students and the general public including hands-on demonstrations of marine science research guided by faculty, students and ship crew members. 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 · 2025-01

This project provides funding for the Research Vessel Rachel Carson to conduct oceanographic research missions supported by the National Science Foundation. The oceanographic research vessels of the Academic Research Fleet (ARF), operated by the academic institutions within the University-National Oceanographic Laboratory System (UNOLS) framework are multi-use facilities used to expand knowledge of the ocean environment. The surface work of these ships is complemented by human-occupied, remotely operated, and autonomous undersea vehicles and sensors that provide vital tools to understand the oceans and their resources. These seagoing research and educational facilities enable scientists and students to study natural phenomena and train future scientists while on board state-of-the-art oceanographic research vessels utilizing high-quality instrumentation. The ship operators will also conduct learning activities for students and the general public including hands-on demonstrations of marine science research guided by faculty, students and ship crew members. 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.