University Of Delaware

NSF Awards · FY 2025 · 2025-08

This award provides funding for scientists at six institutions in the United States to analyze cosmic rays using data gathered by the IceCube Neutrino Observatory. IceCube is a particle detector situated at the U.S. Amundsen-Scott South Pole Station consisting of one cubic kilometer of natural ice at a depth between 1.4 and 2.4 km. It is complemented by IceTop, a surface detector array. Both the ice-based and surface detectors identify ultra-short flashes of light from particle cascades that occur when high-energy cosmic rays enter the Earth atmosphere. IceCube's primary scientific mission is to obverse and characterize neutrinos, however, its unique setup is used to also improve our understanding of the origins of high-energy Galactic cosmic rays and the particle physics involved in atmospheric cascades. This award will enable fundamental research in cosmic-ray physics but will also encompass broader scientific impacts through IceCube’s cosmic-ray measurements. The intriguing environment of the South Pole combined with the exciting science of IceCube creates a captivating experience for young scientists and students. In addition to science publications, IceCube maintains a strong presence on both social media and the internet. Through high school MasterClasses and student involvement in scientific research, this project will play a key role in educating the future STEM workforce. With its three-dimensional layout the IceCube Neutrino Observatory is also an excellent detector for cosmic-ray air showers, which are atmospheric particle cascades initiated by high-energy particles from space. The combined measurement of electromagnetic particles and low-energy muons of air showers at the surface and TeV to PeV muons by the in-ice detector makes IceCube a unique instrument. It therefore makes unique contributions to the particle physics and astrophysics related to the most energetic Galactic cosmic rays. Complementing IceCube’s multi-messenger mission and neutrino astrophysics, IceCube measures various features of the Galactic cosmic-ray flux, such as its energy spectrum, mass composition, and spatial distribution. IceCube has provided the first and world’s most sensitive measurements of little understood cosmic-ray anisotropies in the Southern Hemisphere at TeV to PeV energies. Combining data with other observatories and studying the structure and energy dependence of the anisotropy will provide further insight to the origin of Galactic cosmic rays. Efforts for a more accurate measurement of the cosmic-ray energy spectrum will continue, focusing on reducing systematic uncertainties by improving analysis techniques and by evaluating data of new surface instrumentation deployed prior to this award. This project advances the objectives of "Windows on the Universe: the Era of Multi-Messenger Astrophysics", one of the 10 Big Ideas for Future NSF Investments. 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 Endometriosis is an incurable disease in which endometrial tissue grows outside the uterus, causing affected women to endure pain during periods and/or sexual intercourse and suffer from reduced fertility and diminished quality of life. Current treatments include anti-inflammatory drugs, hormonal therapies, and surgery (performed alone or in combination with ablation to destroy the lining of the uterus), but none of these are adequate so recurrence rates among patients are extremely high. Earlier diagnosis and/or improved resection of lesions enabled by advanced imaging technologies may overcome the challenges associated with endometriosis patient care. To address the critical need for better endometriosis visualization, we will develop inflammation- targeted, light-responsive nanoparticles that can accumulate in endometriosis lesions (which are characterized by high levels of inflammation) and serve as photoacoustic imaging contrast agents to visualize lesions with enhanced sensitivity. This technology could be transformative as there are currently no reliable blood tests or imaging techniques to accurately diagnose endometriosis, and improving image-guided resection could greatly reduce recurrence. To enable the nanoparticles (known as “nanoshells”) to target the inflammatory environment associated with endometriosis, they will be coated with phospholipid membranes derived from macrophages. Previous research has shown that various proteins present in macrophage membranes endow wrapped nanoparticles with both immune evasion capabilities (due to “markers-of-self” like CD47) and inflammation-targeting capabilities (enabled by proteins like PSGL-1, L-selectin, MAC-1, and others). Since endometriosis has high inflammation, we expect that macrophage membrane-wrapped nanoshells (Mac-NS) will accumulate in lesions more effectively than NS coated with the common passivating agent poly(ethylene glycol) (PEG-NS). In turn, photoacoustic imaging mediated by Mac-NS should have higher contrast and superior sensitivity compared to imaging mediated by PEG-NS. We will test these hypotheses in three aims, which will characterize the optical and physicochemical properties of Mac-NS and PEG-NS (Aim 1), compare their ability to target endometriotic versus non-diseased cells and enhance PAI contrast in vitro (Aim 2), and mediate the detection of intraperitoneal lesions in mice without associated toxicity (Aim 3). Demonstrating this technology can improve endometriosis visualization would be a major scientific breakthrough with potential for huge clinical impact.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The current manufacturing methods for recombinant Adenovirus-Associated Virus (rAAV) is transient transfection, which faces numerous challenges, such as low productivity of rAAV from host cells, difficult scalability of the rAAV-producing bioprocess, and high levels of impurities (e.g. empty/partial capsid) materialized during production. Furthermore, nucleic acid production represents the majority of the rAAV manufacturing costs. A stable producer cell line could address all of these concerns; however, it requires the integration of not only the gene of interest (GOI), Rep, and Cap genes for genome replication and encapsidation, and the helper proteins that initiate the rAAV replication. The cytotoxicity induced by the continuous expression of rep and helper genes after integration have hindered efforts to establish a stable cell line for rAAV. This project brings together several innovations necessary to achieve this long-desired goal in the field of viral vector biomanufacturing. Efforts to move from transient transfection manufacturing processes have been hindered by the instability of producer and packaging cells lines caused by the cytotoxic effects of the Rep78 expression and its regulation of the E1a, E2a, and E4 adenovirus early promoters. Precise control over gene expression is necessary to overcome this limitation. Therefore, our project builds our refactored the rAAV expression pathway enabling inducible control of the expression of rAAV genes and helper genes. This level of control also enables dynamic regulation and tuning the expression levels to achieve high quality rAAV with a high filled capsid ratio. The use of oscillating degron tags will enable periodic reduction of Rep78 levels as Rep78 arrests the cell cycle. Proper stoichiometry and expression dynamics will be achieved through the design of post-transcriptional control of gene expression by a series of nested gene circuits that autonomically control the timing of gene expression. The general expression patterns and dynamics will be guided by mechanistic modeling of rAAV biogenesis in stable cell lines, while the precise tuning of the system will be more empirical. These efforts are combined with cell line engineering strategies informed by transcriptomic data of rAAV producing HEK293 cells, which targets ER stress and protein processing genes, innate immune response, and energy metabolism. If successful, this project would establish stable cell line production of rAAV, significantly driving down manufacturing costs, and increasing gene therapy accessibility.

NSF Awards · FY 2025 · 2025-08

The University of Delaware (UDel) requests funds for oceanographic instrumentation that are needed to carry out NSF-supported scientific research on board the R/V Hugh R. Sharp, a research vessel operating as part of the U.S. Academic Research Fleet (ARF). The specific instrumentation requested included new Surface Mapping System (SMS) upgrades to modernize the ships’ SMS sensors, which are critical to display and record meteorological, surface water, and navigation data. The requested sensors require little to no maintenance, reducing support time. These upgrades will help ensure the vessel maintains its high-level capabilities to support NSF-funded research. The principal impact of the present proposal is under Merit Review Criterion 2 of the Proposal Guidelines (NSF 23-525). It provides infrastructure support for scientists to use the vessel and its shared-use instrumentation in support of their NSF-funded oceanographic research projects (which individually undergo separate review by the relevant research program of NSF). The acquisition, maintenance, and operation of shared-use instrumentation allows NSF-funded researchers from any US university or other organization access to well-maintained, high-quality, calibrated instruments for their research. It ensures the collection of high-quality oceanographic data in support of science, reduces the cost of that research, and expands the base of potential researchers. 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

This research examines how living in a border region shapes how residents alter their behavior due to increasing environmental variability such as shifts in temperature and precipitation patterns. Results can inform community-based organizations in border regions on how to best support vulnerable communities when challenged by environmental change and its consequences. Empirical analyses could also provide regional, state, and federal institutions with high-resolution data that could improve policymaking at multiple scales. Faculty leaders will mentor three graduate students, two of whom will be trained at University of Texas Rio Grande Valley (UTRGV), the second largest Hispanic-Serving Institution in the US, with 91% of students identifying as Hispanic and more than half being first-generation. Utilizing ethnographic research including document review, participant observation, semi-structured interviews, and surveys along with community collaboration and geo-spatial analyses over a period of 36 months of fieldwork, this study aims to address this need by investigating the overarching research question: How does living within a border region shape experiences of everyday adaptations to environmental change? This study seeks to answer this question through the following objectives: (1) Investigating how border specific attributes (e.g., surface flooding and its effects in the region, increased surveillance and security, informality) influence how environmental change is unfolding in the research site; (2) Documenting the ways people use everyday adaptations to adapt to environmental change in the region; and (3) Analyzing how adaptation and border policies respond to and reflect social and environmental changes and (Obj1) everyday adaptations (Obj2). This research is a collaborative effort from scholars in anthropology, environmental social science, sociology, and geoscience at the University of Texas Rio Grande Valley and the University of Delaware. Findings will expand theoretical and empirical understanding of the ways that border environments constrain adaptation to environmental change. 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

Human language often allows different ways of saying the same meaning by changing the order of words in a sentence. However, these different word orders are not always understood with equal ease, even when the meaning remains the same. This doctoral dissertation project investigates how people process sentences with flexible word order and examines why some orders are harder to understand than others. It tests two sources of difficulty in understanding flexible word order sentences. One source involves the mental effort needed to connect a phrase that has been moved from its original position (known as filler–gap dependency formation). The other involves a mismatch between what the reader expects to come next and what actually appears (known as prediction mismatch). In addition to training a graduate student, benefits to society include providing innovative training opportunities in research methods including statistical analysis, which supports workforce development for artificial intelligence and other data science industries. To compare how the filler–gap dependency formation and the prediction mismatch affect sentence processing, this doctoral dissertation project uses a combination of online and offline experiments – including self-paced reading and sentence completion tasks – with various types of sentences. The findings deepen our understanding of how people comprehend language, using rigorous experimental methods and high-powered samples, to conduct the research. This project also makes publicly available code used for designing experimental tasks and running data analyses to improve infrastructure for future sentence-processing research. 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 Developmental Language Disorder (DLD) is a lifelong disability characterized by persistent difficulty with language learning and use that impairs daily functioning (Bishop et al., 2017). Families of a child with DLD experience increased stress and have difficulty accessing accurate, specific information about DLD (McGregor, 2020). Participation in support groups improves both knowledge and self-efficacy in families of children with more widely known neurodevelopmental disorders (e.g., dyslexia, Multhauf et al., 2016) by addressing families’ informational, instrumental (e.g., material) and emotional needs (Tétreault, et al., 2014), but to our knowledge no systematic approach to providing peer supports exist for families of people with DLD. A manualized support group curriculum provided by organizations that families most often turn to for developmental advice, such as schools or pediatric practices, is likely to have good reach for addressing the informational and emotional needs of families of children with DLD. Community buy-in and an implementation strategy that addresses barriers faced by providers are critical for long-term success. We address these concerns through EPIS (Exploration, Preparation, Implementation, and Sustainment; Moulin et al., 2019), an implementation process framework that provides tools to (i) innovate to enhance fit of existing evidence-based practices and (ii) build capacity in community organizations to ensure sustainment. To that end, we will engage the DLD community to design a manualized support group curriculum that uniquely meets their informational and emotional needs. Following adaptation of existing curricula for other groups based on focus groups with families with a child with DLD and SLPs, we will conduct a small-scale pilot for feedback on format, topics, and accessibility. We will also engage community practitioners to determine setting-specific barriers and facilitators and develop an implementation strategy in anticipation of future work. We then integrate these two strands in a community- based implementation trial to assess acceptability and early efficacy. Throughout, we employ mixed-methods approaches and rely on advisory boards to guide our practice and return information rapidly to the community. Thus, we aim to 1) Use EPIS to adapt and refine outreach materials and support group curricula to fit the unique needs of families of children with DLD from varied racial, ethnic, and educational backgrounds; 2) identify factors, characterized within the EPIS framework, that influence organizational and leadership capacity to support development of an implementation plan; and 3) assess the degree to which support group participation alters knowledge, self-efficacy, and parenting stress. Successful completion will result in development of a manualized curriculum for use with families of children with DLD and an implementation strategy. Together these will reduce parenting stress, improve self-efficacy and equip parents to advocate for their children thereby improving overall child outcomes. The data derived from this grant will serve as pilot data for an R01 that allows us to test these cascading outcomes through a large-scale Type 3 Implementation Trial.

NSF Awards · FY 2025 · 2025-08

Atoms and molecules are the fundamental building blocks of matter. The attractive forces between them arise from electric interactions between positively charged nuclei and negatively charged electrons. High-powered lasers can stimulate and probe these electric forces, offering a controllable environment for studying molecular dynamics. This project seeks to determine how the full, multi-electron structure of matter contributes to electric interactions. The proposed work includes high-intensity laser experiments and state-of-the-art theoretical modeling. The project will provide intensive, hands-on research training for students and researchers at the undergraduate, graduate, and postdoctoral levels, directly supporting STEM workforce development. The project aligns with national priorities by preparing a highly skilled technical workforce in areas such as advanced manufacturing, machine vision, and remote sensing for national defense. In physics, chemistry, and biology, electric fields—rather than gravity or nuclear forces—govern molecular reactions, condensed matter properties, and plasma behavior. Electric fields involved in interactions between two reacting molecules are significantly more complex than those of a single molecule exposed to a laser field. For this reason, we will use tunable laser fields to investigate multielectron dynamics in matter. Field strengths will range from the intensities that barely ionize neutral molecules to ultra-strong fields reaching intensities up to 10,000 petawatts per square centimeter. Experimental measurements will include ion and electron spectroscopy of singly- and multiply-ionized fragments. The electronic states probed will reach beyond bonding orbitals, delving deep into atomic structure. This research addresses a key gap between simplified one-electron models and the collective, multielectron responses that dominate real-world molecular interactions. By advancing our understanding of these complex systems, the project supports U.S. goals in scientific leadership, technological innovation, and strategic 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.

NSF Awards · FY 2025 · 2025-08

Powered lower limb prostheses have made significant technological progress, yet they continue to face major challenges in navigating real-world environments. Individuals with lower limb amputation often struggle with activities involving transitions between surfaces such as grass, gravel, or slopes, where current prosthetic controllers are limited in providing the necessary stability and agility. This Smart and Connected Health (SCH) project seeks to address that challenge by advancing the control strategies used in robotic ankle-foot prostheses. By understanding how humans adapt their movement when walking on different terrains, the research will inform the development of next-generation prostheses that can proactively and reactively adjust to changing environments. The goal is to enhance the independence, safety, and quality of life of individuals who rely on powered prostheses. In doing so, this work contributes to the national interest by promoting the progress of science and engineering, improving public health and welfare, and inspiring future innovation in assistive technology. The project seeks top support education by engaging students in hands-on research experiences that foster interest in robotics, biomechanics, and assistive technologies. The project will investigate the sensorimotor mechanisms that enable humans to walk dynamically over uneven and unpredictable terrain. These insights will be used to develop and validate a novel, multi-level control architecture for powered prosthetic limbs. The approach integrates proactive strategies based on predictive terrain recognition with reactive feedback-based stabilization. The control framework will be tested in real-world scenarios with individuals with limb loss to assess performance and identify failure modes. The research seeks to improve understanding of how to merge human neuromechanical signals with environmental feedback in a unified, robust control system. Outcomes look to include new methods for real-time adaptation in wearable robotics, advancements in the field of human-in-the-loop control, and broader applications in rehabilitation robotics and mobility assistive devices. Through rigorous experimental evaluation and community engagement, the project seeks to redefine the future of lower limb prosthetic function. 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

With the support of the Chemical Synthesis Program in the Division of Chemistry and the Office of Strategic Initiatives, Professor Mary Watson of the University of Delaware is studying the development of new methods for the synthesis of cyclic molecules containing oxygen and nitrogen atoms. The products of these methods are of societal importance in pharmaceutical, natural product, polymer, and other material applications. Preparing these molecules as single three-dimensional geometrical isomers, or “enantiomers,” is particularly significant in biomedical applications because opposite enantiomers often elicit different bioactivity. In this project, Dr. Watson and her research group are developing a catalytic strategy for the synthesis of oxygen and nitrogen heterocycles that will allow efficient access to molecules that are currently difficult to prepare as single enantiomers. Dr. Watson is also actively engaged in outreach activities to provide opportunities for students of all levels to engage in science. Her research program provides excellent training for undergraduate students through guided research opportunities. In addition, through outreach at the University-associated daycare, Dr. Watson is exciting young children (pre-school through third grade) about science and scientific careers. This project focuses on developing enantioselective copper-catalyzed additions of alkynes to cyclic oxocarbenium and iminium ion intermediates to deliver oxygen and nitrogen heterocycles with both tri- and tetrasubstituted stereocenters adjacent to the heteroatom. Due to the prevalence of disubstituted heterocycles in bioactive molecules, enantioselective difunctionalization approaches are being established to efficiently increase the complexity and value of simple achiral starting materials. In addition, enantioselective alkynylation of a variety of cationic intermediates are being investigated to provide efficient access to a wide range of heterocyclic products, which may be derivatized into valuable acyclic amines with tetrasubstituted stereocenters or elaborated into natural products and natural product analogues. Students involved in this project are receiving training in chemical synthesis and enantioselective catalysis. 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

With the support of the Chemical Synthesis Program in the Division of Chemistry and the Office of Strategic Initiatives, Professor Donald Watson of the University of Delaware is studying the development of new chemical reactions to install boron and silicon atoms in organic molecules. Organic molecules containing boron and silicon are important to a wide variety of fields, including the preparation of new medicines, the synthesis of electronic components, and in agrichemicals used to boost crop yields. The development of new chemical methods to prepare these compounds is important as it allows accelerated access by enabling the use of more readily available starting materials and facilitates the synthesis of new sub-classes organoborane and organosilicon molecules that cannot currently be accessed with known reactions. Prof. Watson is also leading efforts to expand interest in STEM careers by carrying out an early childhood science outreach program at a local preschool, and by collaborating with a Primarily Undergraduate Institution (PUI) to carry out a student exchange program that exposes PhD students to PUI teaching environments and PUI students to the advanced research environment at the University of Delaware. Despite their importance as targets and intermediates in the synthesis of molecules of societal importance, the efficient preparation of many boron and silicon compounds remains limited. Prof. Waston and his research group are developing new uses of boron and silicon electrophiles in transition metal-catalyzed cross-coupling reactions to address this critical gap in chemical synthesis. New reactions involving the coupling of boron and silicon electrophiles to organic nucleophiles allow the rapid introduction of boron and silicon centers into common organic frameworks. Silyl-Heck-like reactions of alkynes, nucleophilic alkylation reactions of silyl halides, and boryl-Heck reactions are being investigated for expanded and improved routes to these important compounds. This research is both practical, as it allows access to highly valuable organoboron and organosilicon compounds, and fundamental, as it is exploring the underlying chemistry of metalloboron and metallosilicon chemistry. Students involved in this program are receiving training in both synthetic and mechanistic aspects of organic and organometallic chemistry. 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

ABSTRACT Many craniofacial structural birth defects result from disrupted formation, migration, patterning, or differentiation of neural crest (NC) cells that populate the pharyngeal arches, including the mandibular arch (first arch). Following patterning, cranial NC cells differentiate into various cell fates including bone, cartilage, and connective tissue. SIX1 is a transcription factor that can act as a transcriptional activator or repressor depending on interaction with co-factors. Loss of Six1 in the mouse results in severe craniofacial defects including a smaller and deformed mandible, Meckel’s cartilage, tympanic ring and middle ear ossicles, and mirror image duplication in the upper jaw accompanied by ectopic cartilage on its posterior end. Variants in SIX1 that decrease its dosage (p.Q22X) or alter its function (p.R110W) are linked to branchio-oto-renal (BOR) syndrome, an autosomal dominant disorder characterized by sensorineural and/or conductive hearing loss, pharyngeal arch anomalies, and renal abnormalities. Although published and preliminary data suggest a requirement for SIX1 function in NC differentiation towards osteogenic and chondrogenic cell fates, there is a gap in our knowledge regarding the role of Six1 on NC cell fate decisions within the mandibular arch and the impact of BOR SIX1 variants on NC cell differentiation towards bone and cartilage. In this R03 application I am testing the hypotheses that Six1 transcriptional activity is required for NC cell fate determination within the mandibular arch (Aim 1); and that variants that decrease Six1 dosage and alter its function disrupt craniofacial bone and cartilage development leading to craniofacial dysmorphologies such as BOR (Aim 2). In Aim 1, I am identifying changes in cell populations within the mouse mandibular arch of mouse embryos from a novel knockin line carrying the p.R110W variant and comparing these changes to wild type and Six1 knockout embryos using scRNA-sequencing and spatial transcriptomics. In Aim 2, I am determining the effects of Six1 variants on osteoblast and chondroblast differentiation by using cultured NC cells and guided differentiation towards cartilage or bone followed by quantitative cytochemistry and qPCR. This application will provide novel knowledge regarding SIX1 function during NC cell fate determination within the mandibular arch. Results from this application will characterize a new mouse line (Six1pR110W) that can become an important model to study SIX1-related birth defects. These mice will constitute a critical tool in future studies whose results will provide information for patient diagnosis and care. This application aligns with a Notice of Special Interest (NOSI): Single-Cell Level Spatiotemporal Mapping of Dental and Craniofacial Embryogenesis (NOT-DE-22-003). The proposed experiments in this R03 application will represent the initial phase of my research program, aimed at uncovering the mechanisms by which SIX1 variants contribute to the BOR phenotype and how these variants interfere with interaction with different co-factors (future R01 grant).

NSF Awards · FY 2025 · 2025-07

The University of Delaware (UDel) requests funds for shipboard scientific support equipment that is needed to carry out NSF-supported scientific research on board the R/V Hugh R. Sharp, a research vessel operating as part of the U.S. Academic Research Fleet (ARF). The specific equipment request is an upgrade to the Sharp’s dynamic positioning system, a computerized navigation control system which allows the ship to maintain a precise position and orientation at sea during oceanographic sampling. This upgrade will help ensure the vessel maintains its high-level capabilities to support NSF-funded research. The principal impact of the present proposal is under Merit Review Criterion 2 of the Proposal Guidelines (NSF 23-525). It provides infrastructure support for scientists to use the vessel and its shared-use instrumentation in support of their NSF-funded oceanographic research projects (which individually undergo separate review by the relevant research program of NSF). The acquisition, maintenance, and operation of shared-use instrumentation allows NSF-funded researchers from any US university or other organization access to well-maintained, high-quality, calibrated instruments for their research. It ensures the collection of high-quality oceanographic data in support of science, reduces the cost of that research, and expands the base of potential researchers. 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

This project develops a system of co-robots collaborating with a human operator to map underwater structures. Underwater structure mapping is an important capability applicable to multiple domains: marine archaeology, infrastructure maintenance, resource utilization, security, and environmental monitoring. The underwater environment is challenging and dangerous for humans in many aspects, while robotic operations face additional challenges compared to the above-water ones. In particular, both sensing and communications are restricted, and planning is required in three dimensions with limited information. The project will generate a 3D model of the underwater structure providing a high-resolution photo-realistic representation. Autonomous Underwater Vehicles (AUVs)will be operating in close cooperation, generating a dense vision-based reconstruction of the observed surface, and coordinated with remote human operators.. The project integrates research and education through training of undergraduate and graduate students, who will have the opportunity to work in an inclusive, interdisciplinary team across South Carolina, New Jersey, and New Hampshire. The system will be integrated and tested for archaeological mapping at field sites. Research will be conducted along three directions. (1) Robust underwater state estimation based on a deep learning approach and a hybrid representation for 3-D reconstruction that will encode probabilistic occupancy for both navigation and initial inspection from users. (2) Collaborative planning, for the proximal observers based on a local optimization framework that originally considers multiple criteria, including information gain, uncertainty reduction, and loop closure, active positioning of distal observers, and user preference to make joint measurements and inform proximal observers on where to go. (3) Information driven communications, with careful design of efficient data representation of the 3-D reconstruction and of a cross-layer optimization for deciding when and how to share. These three components will contribute towards the overarching goal of enabling a team of co-robots to operate autonomously and produce a realistic map of an underwater structure. 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

When glaciers scrape across Antarctica, they pick up rock fragments and incorporate them into their bottom layers while transporting them toward the coast. There, icebergs break off, drifting towards lower latitudes and warmer waters. Along the way the icebergs melt and the rock fragments sink to the seafloor, leaving behind a trail of these rock fragments called ice rafted debris. Ice rafted debris accumulates at the bottom of the ocean and over time preserves a record of activity at their source, the Antarctic ice sheet. In this study investigators will use sediment cores recovered in the Indian Ocean by the Ocean Drilling Program to reconstruct the accumulation of ice rafted debris over time. The drill site is about 500 miles north of the Antarctic continent, and in the path of the ice bergs that it sheds. When looking at the variations in ice rafted debris over time, the team will obtain a record of changes in the glacial activity of the Antarctic ice sheet through time. The study is motivated by the mystery surrounding changes in glacial activity in response to changes in the shape of Earth’s orbit around the sun, the wobble of its axis, and the degree of the tilt of the Earth’s axis, the so-called Milankovitch cycles. For a period of time between about 1.2 and 1.6 million years ago, it is not clear if ice sheet growth and melt responded to changes in incoming solar energy related to changes in the shape of the orbit or to changes in its tilt toward or away from the sun. This study will contribute data to help understand how these external mechanisms cause variations in the size and behavior of Antarctic ice sheets. Investigators will conduct this research alongside a number of undergraduate students and one graduate student. Records of ice rafted debris provide an ideal teaching tool as they are reasonably easy to assemble by students independently (after initial training) and thus provide students with a sense of self-reliance and self-confidence, increasing their motivation to remain in a STEM related field. Thus, ice rafted debris is an ideal proxy to teach students about paleoclimate and paleoceanography. Broader impacts activities include training and mentoring undergraduate students and a graduate student, outreach with a local middle school, and efforts to expand access in STEM. Legacy Ocean Drilling Program Site 745B - drilled during Leg 119 in 1988 south of the polar front in the Indian Ocean sector of the Southern Ocean - provides a rare opportunity to study paleoclimate at the full orbital scale back into the late Miocene (Shipboard Scientific Party, 1989) in a vastly understudied region of the world ocean. Investigators propose to construct records of ice rafted debris (IRD) to infer Antarctic ice margin dynamics during the early Pleistocene (~1.1-1.8 Ma) and during specific late Pleistocene interglacial intervals (Marine Isotope Stages 1,5, 7, 11, and 15). Recently, orbital-scale resolution records of biogenic opal and magnetic susceptibility have been tuned to the Lisiecki and Raymo (2005) oxygen isotope stack unlocking the site’s full potential for paleoceanographic reconstructions. With the early Pliocene record, the team will test the hypothesis that the dominance of 41 kyr ice volume fluctuations observed during this interval of time is an artifact of the oxygen isotope proxy. Precession-related variations in the IRD record would support interhemispheric cancellation of the precession signal in oxygen isotope records. Dominance of obliquity would suggest that fluctuations in marine-terminating ice sheets did occur on this time scale. With the late Pleistocene interglacial intervals, which correspond to different amplitudes of obliquity versus precession in insolation forcing, investigators will examine the response of marine terminating ice margins under these different conditions. 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

This project will investigate the critical issue of saltwater intrusion in Delaware's complex coastal environment. Saltwater intrusion, the movement of seawater into freshwater resources, poses significant threats to the state's drinking water supplies, agriculture, natural ecosystems, and infrastructure. This project aims to advance understanding of the processes driving saltwater intrusion and develop strategies to mitigate its impacts. The research team, consisting of faculty, staff, and students from Delaware State University, Delaware Technical Community College, Goldey-Beacom College, Wilmington University, and University of Delaware, will collaborate with partners across the state to address this pressing challenge. They will collect field data, conduct experiments, and develop computer models to study how various factors affect saltwater intrusion in urban, suburban, rural, and natural areas. The project will also explore innovative solutions, such as developing salinity-resistant crops, facilitating marsh migration, and promoting wetland-based carbon removal. By engaging partners throughout the State and training the next generation of social and natural scientists and engineers, the project aims to enhance regional resilience and promote long-term economic well-being. Ultimately, the project will provide vital information to support sustainable water management, protect Delaware's valuable water resources, and ensure a resilient future for coastal communities in Delaware and beyond. The project will employ a convergent, multidisciplinary approach to elucidate the complex hydrologic, geologic, biogeochemical, economic, and social factors impacting saltwater intrusion in Delaware's coastal environments. The project team will establish a network of monitoring wells to continuously measure groundwater salinity, collect geophysical data to characterize subsurface aquifer structure, and use advanced geochemical tracers to fingerprint the sources and pathways of saltwater intrusion. High-resolution numerical models, coupling surface water and groundwater dynamics, will be developed to simulate the interplay between various environmental factors, groundwater abstraction, and human decision-making on saltwater intrusion. The project will investigate the physical risks (hazards, exposure, and vulnerabilities) and assess how people make decisions related to water withdrawals, land uses, stormwater and infrastructure management, adaptation, and mitigation in urban, suburban, rural, and natural systems. Innovative solutions, such as targeted aquifer recharge, coastal wetland restoration, salinity-resistant crops, marsh migration strategies, and ecosystem service incentives, will be proposed and developed to mitigate the impacts of saltwater intrusion. The project will support and mentor six early-career faculty, two post-doctoral researchers, 36 graduate students, and at least 40 undergraduate students, engaging them in professional development cohorts across institutions to build workforce skills, team science, communication, and problem-solving. Outcomes of this research will provide a robust scientific foundation for the development of adaptive water management strategies to enhance the resilience of Delaware's coastal communities and ecosystems in the face of increasing water demand and complex environmental conditions. This project is supported by the EPSCoR Research Infrastructure Improvement Program: EPSCoR Research Incubators for STEM Excellence (E-RISE). E-RISE supports the development of sustainable research infrastructure and capacity in EPSCoR jurisdictions through collaborative, hypothesis-driven, or problem-driven research and workforce development to improve competitiveness in selected STEM fields. 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

Many closed physical systems are modeled mathematically by self-adjoint differential operators. Analysis of the spectrum is of central importance in understanding the long-term behavior of such systems. In some examples, the spectrum can be interpreted of as the color of light, or the energy range at which a semi-conductor allows electron travel. To obtain differential operators that are self-adjoint, boundary conditions must usually be imposed; think of a vibrating string that is clamped down or otherwise restricted at both ends, or a vibrating drum. In many examples, we know the complete spectrum of an operator with one set of boundary conditions, while the physical behavior of the same system with other boundary conditions is hard or impossible to compute directly. Perturbation theory will be developed to allow access to the spectral information to a wide class of operators under changing boundary conditions, even though this behavior is often quite unstable. The project will provide research opportunities for graduate students and postdoctoral researchers and engage the PI in conference organization; outcomes of the project will be disseminated widely through research articles and conference presentations. More specifically, the two parts of this project’s intellectual merit are trace class perturbations of self-adjoint operators on Hilbert space, and Aleksandrov-Clark theory on the polydisk. The first part concerns the singular spectrum under infinite rank perturbations such as trace class perturbations and beyond. Of particular interest is the development of an Aronszajn-Donoghue-type theory. The proposed methods fall within function theoretic operator theory, but touch to varying degrees harmonic analysis, measure and spectral theory, as well as abstract perturbation theory. In the second part, although Aleksandrov-Clark theory on the polydisk was established ‘only’ in 2020, it has become evident that it harbors a rich theory and is rather distinct from the one-variable setting. To date, investigations for the polydisk are lacking the connection with unitary perturbations, and therefore also to spectral theory and applications. Seeking remedy and providing a systematic study of the field are the main goals. Inspiration is drawn from classical Aleksandrov-Clark theory, reproducing kernel Hilbert spaces and analytic function theory. 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

Project Summary The histone lysine methyltransferase SETDB1 trimethylates lysine 9 on histone 3 (H3K9me3), which leads to the formation of heterochromatin, silences gene expression, and impacts three-dimensional chromatin structure. However, SETDB1 has recently been shown to play important roles in the cytoplasm as well as the nucleus. Altered activity of SETDB1 has been associated with multiple rare diseases including Huntington’s Disease, Duchenne muscular dystrophy, acute myeloid leukemia, and mesothelioma. It is important to identify and characterize the full range of different activities for SETDB1 in order to better understand how this protein impacts the development of these diseases. MET-2 is the C. elegans homolog of human SETDB1. Our imaging of a functional GFP-tagged MET-2 fusion protein showed that MET-2::GFP localizes to the cytoplasm of C. elegans body-wall muscles. We found that knockout of met-2 or sequestration of MET-2 in the nucleus caused hypersensitivity to the acetylcholine receptor agonist levamisole, suggesting a cytoplasmic role in muscles. Based on the periodic localization of cytoplasmic MET-2::GFP and our previous work, which showed that reduced cellular ATP causes levamisole hypersensitivity, we hypothesized that MET-2 could impact the mitochondria. Using RFP-tagged Translocase of Outer Mitochondrial Membrane 20 (TOMM-20) to visualize muscle mitochondria, we discovered that loss of met-2 caused severe defects in mitochondria morphology. This is highly significant, as a connection between SETDB1 and mitochondria has not been previously reported. The proposed research will use unique genome-edited C. elegans strains, advanced imaging techniques, and a new sample processing method for quantitative proteomics to define the impact of MET-2 on mitochondria morphology, function, and protein abundance. We will generate new strains using CRISPR/Cas9 to determine if MET-2 affects mitochondria by 1) methylation dependent or independent activity and 2) nuclear or cytoplasmic function. We will determine the functional consequences of the fragmented mitochondria in the met-2 mutant by measuring ATP levels and oxygen consumption rate. Finally, we will perform a quantitative comparison of the wild-type and met-2 mutant transcriptomes and proteomes, with initial focus on mitochondrial proteins. Since mitochondrial dysfunction is a key factor in SETDB1- associated diseases, this basic science research could have significant impact on our understanding of how altered SETDB1 activity contributes to pathogenesis of multiple rare diseases.

NSF Awards · FY 2025 · 2025-06

WIth support from the Chemical Structure, Dynamics & Mechanisms-B (CSDM-B) Program of the Chemistry Division and the Established Program to Stimulate Competitive Research (EPSCoR), Carsten Milsmann of the Department of Chemistry at West Virginia University is developing new synthetic routes to molecular transition metal photosensitizers based on earth abundant group 4 elements that can be utilized in photochemical applications. The goal of this research is to provide cheap and readily available light-absorbing molecules with characteristics required for solar fuels production, photocatalysis in polar solutions, and the construction of photovoltaic devices (e.g., dye-sensitized solar cells). Fundamental insights gained from the proposed work will broaden the scope of available photosensitizers and allow the targeted design of light-harvesting molecules in a more sustainable way. The proposed studies combine elements of synthetic organic and inorganic chemistry with detailed photophysical investigations, allowing for training and education of graduate and undergraduate students with diverse interests for their future careers as scientists. Early transition metal photosensitizers with long-lived ligand-to-metal charge transfer (LMCT) excited states are an emerging class of inorganic chromophores that have found application in photocatalysis, photon upconversion, and biological sensing. The proposed research includes the use of postsynthetic modification of existing molecular architectures to (i) improve performance critical parameters such as stability and solubility in polar solvents; (ii) incorporate anchoring groups for immobilization on metal oxide surfaces, thereby facilitating light-driven hole injection into p-type semiconductors; (iii) explore the influence of molecular symmetry on the optical properties of group 4 photosensitizers (e.g. intersystem crossing rates, lifetimes, and quantum yields) and provide asymmetric complexes to facilitate directional charge transfer upon visible-light excitation; and (iv) explore the chemical space for group 4 photosensitizer design and provide fundamental understanding of the underlying design principles for early transition metal chromophores. 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

The study of plasma turbulence at the boundary of space environments holds profound implications for our understanding of space weather, planetary magnetospheres, and astrophysical systems. This research focuses on the dynamic interactions between the solar wind and Earth's magnetosphere, particularly within the turbulent magnetosheath. By analyzing this environment, we aim to enhance our knowledge of how plasma conditions evolve across boundaries especially in inaccessible regions in the universe such as the heliosphere interface with the interstellar medium, and supernovae remnants. The project is significant as it addresses key challenges in space physics, including the complex interplay of nonlinear interactions and the multiscale nature of turbulence, which remain difficult to model and simulate. This project will also contribute to developing novel algorithms for the upcoming era of multiscale multispacecraft missions. From a technical perspective, this study employs a combination of theoretical modeling, numerical simulations, and spacecraft observations to investigate plasma turbulence in the vicinity of Earth’s bow shock. The interaction of the solar wind with the bow shock produces a downstream region (the magnetosheath) with unique properties. It is a very turbulent medium of limited size where the dynamical evolution of the recently shocked solar wind can be investigated. The research focuses on three primary objectives: (1) extending our understanding of the inertial range of turbulence, (2) measuring energy dissipation rates, and (3) characterizing equilibrium states that emerge in turbulent flows. We utilize advanced multispacecraft techniques, such as the Lag Polyhedra Derivative Ensemble (LPDE), alongside high-resolution data from the Magnetospheric Multiscale (MMS) mission and hybrid particle-in-cell simulations using the Menura code. The results will provide a more comprehensive picture of turbulence across planetary magnetospheres and interstellar boundaries, contributing to the broader field of space plasma physics and informing future space missions like HelioSwarm, PUNCH, and IMAP. 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

PROJECT SUMMARY Dysfunctions are observed at multiple cellular and subcellular levels in heart diseases. However, current therapeutics are designed to tackle a single subcellular disease mechanism or molecular target. Our long term goal is to develop strategies to correct several pathways simultaneously, which can ultimately improve clinical outcomes. In this regard, Hsp90β is a desirable target, as it can affect many downstream signaling pathways. However, the role of Hsp90β in cardiac function is not clear due to a lack of viable ablation animal models. To this end, we generated a cardiac-specific inducible Hsp90β knockout (Hsp90βCM-/-) mice and to our surprise, their hearts were protected from myocardial infarction induced by ischemia/reperfusion (I/R) injury, which is paradoxical to its known pro-survival role. Furthermore, this protection is specific to Hsp90β as Hsp90αCM-/- hearts were not protected. These findings suggest that specific Hsp90β inhibition may be a good therapeutic strategy for I/R injury. Thus, our main goal in this application is to carefully examine the protective role of cardiac Hsp90β and dissect the Hsp90β specific interactome to identify the underlying mechanisms. Based on our previous publications and existing pilot data, we hypothesize that removal of cardiac Hsp90β confers cardioprotection, partly by preserving mitochondrial membrane integrity. In this R01 application, we will address this hypothesis in three independent but related aims. In Aim 1, we will thoroughly examine if our new Hsp90βCM-/- hearts are protected from ischemic insult at young (3 months) or old (12 months) age. We will examine the potential pro-death role of cardiac Hsp90β in sensitizing the opening of mitochondrial permeability transition pore and necrotic cell death upon I/R injury. In Aim 2, with our previous knowledge on the role of Hsp90β/HCLS1-associated protein X-1 (HAX-1) interaction in mitochondrial membrane protection, we will map out the minimal binding domains and test the feasibility of using this mimetic peptide to confer protection only in the mitochondria. In Aim 3, we will furthermore examine the effect of Hsp90 ablation in chronic cardiac diseases. We also aim to identify the gene dosage effect of Hsp90 on cardiac function by using Hsp90αCM-/-, Hsp90αCM-/- βCM+/- and Hsp90αCM+/-βCM-/- mice as well. We will perform interactome analysis for both Hsp90α and Hsp90β in human patient hearts to identify isoform-specific interactome and their shift during cardiac diseases. Lastly, we have developed a prediction tool for binding interface for Hsp90 substrates. We will combine the use of this prediction tool and mimetic peptide to identify novel Hsp90 isoform specific binding partners in the heart. By the completion of this study, we expect to gain important insight on how to specifically study particular Hsp90α or Hsp90β complex and evaluate the potential therapeutic application in the future.

NSF Awards · FY 2025 · 2025-06

Software plays an increasingly important role in scientific discovery and innovation. Nuclear fusion, quantum science, space exploration, cancer research, and biotechnology are just a few of the many scientific disciplines benefitting from software. However, like all software, programs used in science may contain defects ("bugs") --- errors in the code or mistaken assumptions ---that can render the output erroneous. Consequently, developers of scientific software expend significant effort debugging their code, reducing their productivity. Worse, some defects evade even the most extensive debugging efforts. This project is developing tools to help developers easily find subtle defects in their code and even verify (under reasonable assumptions) that the code is defect-free. The project's novelties are: a new modular approach to the specification of program components based on simple mathematical abstractions that are familiar to scientists; simple-to-use, automated methods to verify a program component adheres to its specification (or report a defect when it does not); and the application of these techniques to two state-of-the-art scientific software packages. The project's impacts are, first, the advancement of software verification technology generally, which can reduce development costs and increase software quality throughout industry, government laboratories, and academia. Second, improving public confidence in the soundness of conclusions based on scientific software. Third, the training of students and scientists in the use of advanced verification techniques, contributing to a cultural change in the way scientific software is constructed. These advances are based on new symbolic execution techniques implemented in the CIVL model checker. Libraries are being developed to support abstract mathematical concepts such as "vector" and "matrix". Symbolic "representation functions" are used to tie these abstractions to the significantly more complex data structures in a scientific program. Such a function consumes a data structure (which may be distributed across multiple processes) in the program and returns the abstract construct represented by that structure. This allows the user to specify correctness properties on the abstract level while the model checker verifies that the program structures implement the abstract operations correctly. Model checking techniques are used to verify concurrent algorithms, such as those expressed using Message Passing Interface (MPI), OpenMP, or Compute Unified Device Architecture (CUDA). These techniques are being applied to select components of PETSc, a widely used numerical linear algebra library and core component of numerous software projects, and to Flash-X, a state-of-the-art multiphysics simulation system used in astrophysics and other scientific disciplines. 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

Project Summary Adolescent depression and anxiety commonly co-occur, and this co-occurrence is associated with poorer health, psychological, and social outcomes than either presentation in isolation. Yet, little is known about the potential neural substrates driving the co-occurrence of depression and anxiety in adolescence. Thus, an essential next step is to examine specific neural mechanisms underlying this co-occurrence to provide critical insights into prevention and treatment targets. Although extant research in this area has identified disturbances in specific brain regions, this approach is inherently limited, as the brain functions as a network. The examination of disturbances in the organization of brain networks related to emerging, co-occurring depression and anxiety may provide a more complete delineation of underlying etiological mechanisms. Moreover, the majority of research in this area has used variable-centered approaches, which fail to reflect the vast heterogeneity in network organization. Alternatively, person-centered approaches leverage the associations between individuals to identify subgroups based on (within-group) convergence and (between-group) differences in network organization. Identifying subgroups of individuals with similar network patterns allows us to examine whether such subgroups display distinct profiles of depression and anxiety, a critical next step in advancing our etiological and treatment models of depression and anxiety. These gaps in the literature could be addressed via the use of complex, cutting-edge network analyses, specifically graph theory and Subgrouping-Group Iterative Multiple Model Estimation. In line with NIMH’s Strategic Plan Objective 1.3.A, the objective of the proposed research is to isolate disturbances in neural networks that are shared by emerging depression and anxiety (Aim 1) and identify distinct subgroups of adolescents, based on patterns of underlying network connectivity, which may display differing symptom profiles (Aim 2). We use a dimensional (vs. diagnostic group) approach to fully capture the range of pathology, which is particularly relevant during adolescence, when pathology may still be emerging, and thus not at the level for a full diagnosis. The proposed research will use archival data collected from a community sample of adolescents (N=200). Functional magnetic resonance imaging (fMRI) data were collected during an explicit emotion regulation task in which participants were instructed to either react naturally or utilize cognitive reappraisal in response to negative and neutral stimuli. The ultimate goal of this research is to refine etiological models of depression and anxiety in adolescence by identifying shared and unique network mechanisms. The proposed F31 will allow the Applicant to gain expertise in two critical areas that are beyond the scope of the standard graduate curriculum: (i) adolescent depression and its shared mechanisms with anxiety and (ii) complex statistical analysis of brain networks. The institutional environment and mentorship team will provide ample opportunities for the Applicant’s development towards an independent research career.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY Post-stroke balance and gait impairments are a barrier to safe community ambulation for those with chronic stroke. Although an important aspect of post-stroke rehabilitation is restoring a person’s ability to safely ambulate in their community, many post-stroke individuals discharged from rehabilitation are still unable to manage the varied demands of community ambulation. Our premise is that walking adaptability and the control of balance during walking are interrelated factors that can be addressed to improve post-stroke rehabilitation. Walking adaptability is assessed by the performance of complex walking tasks, defined as tasks that increase motor and cognitive demands to a greater extent than simple overground walking. Although gait is a task with concomitant demands on balance and mobility, studies of post-stroke walking adaptability have largely ignored the mechanisms by which balance is controlled during complex walking. Control of the lateral acceleration of the COM, an aspect directly influencing walking balance, is a function of three mechanisms that we can quantify through biomechanical analyses: 1) foot-placement, 2) push-off, and 3) counter-rotation of the body segments. Although we know stroke alters lower-limb control and propulsive capabilities during walking, it is unknown how the contributions of these balance control mechanisms are affected by stroke. Furthermore, we do not know how the contributions of each mechanism may change with increased task complexity that constrains or places more demands on these mechanisms. Our study aims to 1) characterize the balance control mechanisms of those with and without chronic stroke during unconstrained walking, 2) characterize the balance control mechanisms of those with and without chronic stroke during complex walking tasks, and 2) determine how walking adaptability is related to balance control mechanisms in those with chronic stroke. To address the first aim, we will use biomechanical analyses to quantify the contributions of foot-placement and push-off in controlling the lateral COM acceleration during unconstrained walking. To address the second aim, we will use biomechanical analyses to quantify the contributions of foot-placement and push-off in controlling the lateral COM acceleration during narrow-path and fast walking tasks. To address the third aim, we will establish the relationship between the performance of complex walking tasks, and the change in contributions of the balance-control mechanisms utilized during those tasks in those with chronic stroke. The results of this study will provide evidence that balance mechanisms are different in those with chronic stroke, and that an inability to alter the contributions of those mechanisms during complex walking tasks may be a barrier to that task performance. This evidence would inform future work aimed at promoting safe community ambulation for those with chronic stroke by targeting balance control as a means for improving complex walking performance.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY The biggest translational hurdle to advancing inhaled therapeutic and vaccine systems is predicting how they will work in the lung. Predictions are challenged by the complex variability of airway structure and motion, the tremendous surface area, and the highly coupled physical phenomena of orally inhaled and nasal drug products (OINDPs). Given the high degree of complexity, there remain no preclinical tools capable of measuring spatial deposition of an entire OINDP dose under simulated breathing conditions. Without knowing where aerosols deposit in each individual, predictions of how well the therapeutic will work once there are severely insufficient. This dearth of realistic in vitro models leads to a complete lack of high throughput screening approaches to new inhalation therapies and creates significant challenges to establishing efficacy, toxicity, and/or bioequivalence (BE) of OINDPs. Given this major bottleneck, pulmonary drug delivery remains a low pipeline priority, despite the overwhelming potential to directly treat a plethora of respiratory diseases. To address this, our lab has created a multiscale dynamic preclinical tool to spatial measure deposition as a function of patient-specific breathing, anatomy, and disease state. Coined the “total inhalable deposition in an actuated lung” (TIDAL) model, this platform leverages advances in additive manufacturing to recreate spatial aerosol collection efficiencies across the five lung lobes. Our overall goal in this project is to realize the potential of the TIDAL tool as an effective measure of inhaled deposition to address outstanding issues in inhalation therapeutics. In Aim 1, we will validate healthy an adult TIDAL prototype with clinical dosimetry benchmarks for aerosols of different average aerodynamic diameters and breathing profiles and identify an optimal upper airway. In Aim 2, we will develop advanced features of the TIDAL model to capture interpatient variability, including aspects of airway disease and altered ventilation. In Aim 3, we will upgrade the TIDAL model to include representative humidity and mucosal mimicry to effectively evaluate DPI products. Progressing in parallel, these aims will yield 1) a novel, integrated preclinical tool to measure spatial deposition and improve predictions of inhalation efficacy (and/or toxicity), 2) broad correlations between regional deposition, BE, and existing in vitro measures, and 3) a platform technology that can support therapeutic development for a wide range of respiratory patients and disease pathologies. The integrated multiscale features of TIDAL within a single physical mode of the entire lung volume will enable the first experimental quantification of how patient geometry, disease, breath maneuver, and aerosol size combine to dictate lung response, leading to a transformative step-change in inhalation therapeutic approaches. The project will catalyze new OINDP model creations and transform opportunities in inhalation medicine.