Oregon State University

NSF Awards · FY 2024 · 2024-08

Neutrino Physics at Oregon State The DUNE experiment that will begin taking data late in this decade consists of three major components, a powerful neutrino beam, near detectors located at Fermilab to monitor the beam and enormous Liquid Argon detectors now being assembled in the Homestake mine in South Dakota. The combination of the near and far detectors will allow precision measurements of CP violation in the neutrino sector starting early in the next decade. This award will develop a prototype open data access systems for DUNE data in preparation for first astrophysical data near the end of this decade. The emphasis of this system will be on atmospheric and solar neutrinos and potential supernova candidates. DUNE is sensitive to electron neutrinos from supernovae through the interaction of electron neutrinos in Liquid Argon. These interactions will be of immediate interest to the broad scientific community and the general public. This award will develop a prototype data access system that will allow public distribution of data from DUNE supernova and solar neutrino candidates. The prototype will have real data from the ProtoDUNE experiment and simulated supernova interactions to test the delivery system and allow non-collaborators to perform simple analysis of real data. The award will also allow further work on data analysis for the ProtoDUNE test runs at the CERN laboratory in Geneva, Switzerland. The prototype access system will allow DUNE collaborators, other scientists, students, and the general public to learn about neutrino physics and astrophysics using real data and test methods for analyzing data. The prototype will lead to a full-scale system that will make these valuable data accessible to the public for reanalysis and for use in education. For example, the raw data arrives as digitized waveforms, finding neutrino signals in those data can introduce students to modern signal-processing and statistical techniques. 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 2024 · 2024-08

Wildfires are happening more often with increasing impact on communities and ecosystems. Wildfires affect water availability and quality. Recently, there have been big fires in forests where wildfires used to be rare, especially in the Pacific Northwest. People who manage forests need to know how these fires are impacting water resources. This research aims to understand how wildfires affect water production in Oregon’s Willamette National Forest by measuring water quantity and quality parameters in an area that has recently been burned to varying degrees. The project will support six students and train those students how to communicate findings to the public. The goal of this project is to understand how changes in vegetation cover (above ground) and soil structure (below ground) affect water production after wildfires in the wet montane forests of the Pacific Northwest. Wildfires can vary in intensity, sometimes burning only the vegetation and leaving the soil intact, or burning both the vegetation and the soil. These two scenarios impact snow accumulation and melt differently, which in turn affects the amount of water delivered to streams and how much water can be stored underground. This project will use data from the H.J. Andrews Experimental Forest in western Oregon. This includes 70 years of hydrometric data including streamflow and precipitation and unique pre-fire water chemistry data from various watersheds with different hydrological conditions. Planned activities include conducting snow surveys and geophysical measurements, and assessing soil infiltration and burn severity across multiple watersheds with varying levels of soil burn severity and vegetation mortality. Additionally, watershed modeling will be performed to compare how water moves through the study watersheds, how the streamflow is generated, and to evaluate sensitivity to the transition zone between snow and rain. 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 · 2024-08

PROJECT SUMMARY Understanding the forces that shape patterns of genetic and phenotypic variation in populations is a central goal of evolutionary biology. Within a biomedical context, this translates to questions like: Why are some individuals more susceptible to disease? Or why do some naturally age “better” and live longer? Answering these questions is a crucial step toward true personalized medicine, and would pave the way for intervention strategies and treatments that could transform how we approach human health. However, efforts to answer these questions are often hampered by difficulties associated with inferring past and present selective pressures, and differentiating between the consequences of selection, genetic drift, and demographic shifts. Here experimental evolution offers a path forward. By studying evolution in real-time in controlled environments, we are able to directly test hypotheses about how evolutionary forces shape trait variation. The adaptive changes we observe also provide key mechanistic insights into the biology underlying observed differences – a fact that is especially valuable in experiments where selection targets health-relevant traits. In sexually reproducing systems that mirror human populations, we find that adaptation is typically fueled by standing genetic variation and involves hundreds of genes. Taken together, these findings suggest there is abundant functional genetic variation segregating for most complex traits and recent selection significantly impacts patterns of phenotypic variation. However, moving beyond the findings that “standing genetic variation facilitates rapid adaptation” and “complex traits are highly polygenic” has been difficult. While we routinely use experimental evolution to identify genes associated with specific phenotypes, we lack the ability to validate and explore their functions in mass. As such, efforts to generate deeper biological insights have seen limited success. The Phillips Lab is seeking to address this by incorporating molecular phenotyping and metabolomics into the experimental evolution framework. Using metabolomic profiling and 3-dimensional electron microscopy, we are working to understand the factors that drive differences in rates of senescence using experimentally evolved fruit fly populations with radically different aging and life-history patterns. We are also working to establish a new experimental system to study variation in susceptibility to type 2 diabetes. By subjecting fruit fly populations to high-sugar diets for generations, we will effectively create populations enriched for sugar-tolerant individuals. And by collecting genomic, transcriptomic, and metabolomic data from them as they evolve, we will decipher how the relationships between these levels of biological organization shape this phenotype. As a whole, the proposed projects all aim to improve our understanding of the factors underlying common trait variation in real populations.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY In September 2024, the 19th Northwest Reproductive Science Symposium (NWRSS) meeting will be hosted by Oregon State University at the OSU-Cascades campus in Bend, OR. This long-standing series began in 1989 as the Washington State University (WSU) and the University of Idaho (UI) annual joint minisymposium, but now rotates biennially between WSU/UI, Oregon State University (OSU), and Oregon Health & Science University (OHSU). The scientific program serves to showcase the high quality of regional research in reproductive sciences, fertility and contraception, developmental biology, and animal and human health. The objective of the NWRSS meeting is to promote the exchange of information to advance our collective understanding of the mammalian reproductive tract both in normal function and in pathophysiological dysfunction. Because most of the attendees are concentrated in the Pacific Northwest region, many lasting collaborations arise from these gatherings. The NWRSS meeting also seeks to support career development within all aspects of reproductive biology, enabling interaction between trainees, new investigators, and established principal investigators. The training mission of the NWRSS extends to meeting organization as well, as an ad hoc trainee committee from all participating schools is solely responsible for organizing the scientific sessions into thematic groups, selection of trainee platform speakers, as well as serving as session chairs during the meeting. The majority of NWRSS talks are delivered by post-doctoral fellows as well as graduate and even undergraduate students. Similar to 2022, in addition to Keynote address from a preeminent leader in the field of reproductive biology, invited speakers addressing health disparities in reproduction and diversity in STEM fields will be featured. NWRSS organizers and participants are committed to providing a safe and inclusive environment to foster the sharing of ideas between developmental biologists, molecular biologists, systems biologists, population health biologists, and clinicians working in reproductive biology.

NSF Awards · FY 2024 · 2024-07

Network security protocols and standards are crucial for the resiliency and trustworthiness of network systems. However, current practices are unable to meet the security and performance requirements of next-generation mobile network systems. For instance, existing systems primarily rely on centralized public-key infrastructure (PKI) and security functionalities, such as symmetric-key cryptography, access control, and key management, that make such systems suffer from various security vulnerabilities and system performance issues. Moreover, despite the recent post-quantum cryptography (PQC) standardization efforts, significant challenges remain unsolved for designing effective, standard-compliant security mechanisms that overcome the hurdles of centralization. The novelties of the project are to create "PKI and symmetric-key alliances" concepts for enabling distributed, standard-compliant PQC and symmetric encryption algorithms, all with enhanced side-channel resiliency. The project's broader significance is on creating innovative solutions that can achieve distributed trust, resiliency against breaches, and seamless device mobility for next-generation network systems to enhance national security. Furthermore, the project broadly offers new educational and publicly adaptable tools. The research team takes a synergistic approach to designing efficient distributed network security frameworks incorporating secure multi-party computation and decentralized architectures to address the limitations of current practices. The first thrust creates distributed NIST-PQC schemes to build compromise-resilient PKIs and scalable PQ-safe PKI alliances with certificateless credentials. The second thrust strengthens core security services by creating distributed NIST symmetric standards for breach-resilient symmetric-key alliances, forward-secure lightweight ciphers, and privacy-preserving access control frameworks. All tasks consider side-channel attacks and their countermeasures in the context of the proposed distributed schemes. The third thrust conducts a comprehensive evaluation and validation of the proposed techniques with experiments on NSF cloud infrastructures and various hardware platforms. The outreach and broadening participation activities include interdisciplinary curriculum development, and summer apprenticeships for K-12 students. The team will explore industrial partnerships for transition to practice, and build open-source platforms for reproducibility and adoption. 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 2024 · 2024-07

With the support of the Chemical Catalysis program in the Division of Chemistry, Professor Kyriakos C. Stylianou and his team at Oregon State University will investigate the fundamental mechanisms of metal-organic framework (MOF)-based photocatalysis. Photocatalysis offers significant advantages over conventional catalysis by using renewable sunlight as an energy source. However, challenges exist, including limited material diversity, catalyst stability, product separation difficulties, sustainable light utilization, and achieving high specificity in complex reactions. Therefore, the development of highly specific and robust heterogenous photocatalysts synthesized from abundant starting materials is of great interest. MOFs are candidates for photocatalysts as their internal porous structures and high surface areas can lead to enhanced catalytic efficiency and selectivity. Although MOFs have showcased their potential as photocatalysts, there is still a pressing need to develop a deeper understanding of their underlying mechanisms and the factors that dictate their efficiency and selectivity. Professor Stylianou’s team will investigate hydrogen-deuterium (H/D) isotope exchange using photoactive MOFs to aid in the identification of structure-activity relationships and to assess how MOF properties influence photocatalytic activity. In terms of broader impacts, this research will develop new catalysts which are appealing particularly to the pharmaceutical industry, where highly selective and sustainable catalysts can lead to breakthroughs in the development of medications. Additionally, Dr. Stylianou is actively engaged in outreach programs to educate and engage the public in science. He strives to spark interest in STEM among young students by exposing them to research and nurturing scientific qualities such as autonomy, skillset development, critical thinking, inclusivity, teamwork, and community involvement. These efforts include presentations and workshops at elementary and high schools focused on increasing awareness of materials’ impact and sponsoring his graduate students to participate in Oregon Museum of Science and Industry Science (OMSI) communication fellowships, where they communicate science to children and the general public. This work supported by the Chemical Catalysis program in the Division of Chemistry is expected to elucidate the fundamental structure-activity relationships that govern MOF photocatalysis and lead to the development of sustainable and highly selective photocatalysts for application in chemical feedstock and pharmaceutical industries. H/D exchange is sensitive to hydrogen atom transfer (HAT) and single electron transfer (SET) reactions. Monitoring the extent and kinetics of H/D exchange through in-situ nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) can provide insights into the occurrence and rates of HAT and SET reactions in MOFs, providing a vital mechanistic perspective. Dr. Stylianou hypothesizes that the extent and kinetics of MOF photocatalyzed H/D exchange delineate the influence of MOF chemical and optoelectronic properties, ultimately dictating their propensity to initiate HAT and/or SET processes. This investigation will establish photoactive MOFs as a unique platform for conducting H/D exchange reactions in a single step on both labile (i.e, formyl C—H) and stable (i.e., C(sp3)—H) bonds, and elucidate design principles for novel MOFs capable of facilitating stereospecific H/D exchange at chiral centers. 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 2024 · 2024-07

As groundwater moves through the subsurface, it often undergoes chemical reactions as it mixes with other chemically distinct waters, which can facilitate the breakdown of pollutants into less harmful substances. These critical processes of mixing and reaction are significantly influenced by unsaturated conditions, where soil and sediment layers contain phases other than water, such as air or gas, within their pores. This project aims to investigate and quantify how flow, transport, and mixing are impacted by unsaturated conditions in subsurface hydrologic systems. Specifically, the project will use new experimental imaging methods in 3D-printed soil structures and novel numerical simulations to visualize and predict how fluids interact and explore how variations in water content and the physical characteristics of the porous matrix influence mixing and reaction outcomes. Collectively, this research will provide a robust scientific foundation for water resource management and advancing water science, ensuring the protection and sustainability of groundwater resources. Moreover, the project will facilitate impactful educational and training opportunities for students across all levels, complemented by public outreach and initiatives to enhance STEM education. This project will develop and use novel experimental techniques and mathematical models aimed at understanding the complexities of reactive transport in partially saturated porous media. The research focuses on investigating and quantifying the interrelated phenomena of anomalous transport, mixing, and chemical reaction in unsaturated porous media, combining pore- and Darcy-scale visual laboratory experiments and direct numerical simulations. The primary objectives include: 1) Investigating the effects of flow dynamics, medium heterogeneity, and the distribution of fluid phases on solute transport and dispersion using experimental observations in three-dimensional porous media. 2) Utilizing experimental data to assess the role of saturation in promoting reaction hotspots and enhancing mixing processes. 3) Employing pore-scale properties, flow and transport statistics, and reaction rates in reactive transport models to mechanistically describe and predict mixing and reaction. The project results will be relevant for the improved prediction and management of contamination of water resources that rely on the transport and mixing of chemicals to target polluted locations. This award is co-funded by the Hydrologic Sciences program and Established Program to Stimulate Competitive Research (EPSCoR). 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 2024 · 2024-07

The rise of greenhouse gases in the Earth’s atmosphere is generally believed to be responsible for global warming and climate change. The dominant greenhouse gas is carbon dioxide (CO2). The world’s oceans are the largest global sink of CO2, capturing over 90 gigatons of this carbon annually from the atmosphere, primarily through growth of photosynthetic plankton and seaweeds in ocean waters. Although much of carbon captured by these organisms goes back to CO2 through a natural cycle, some of the carbon exists in a form that escapes this cycle and remains in the ocean. Seaweeds are large algae that are widely distributed across the globe. Most species of red and brown seaweeds have biological processes that convert their photosynthetic carbon into a form that is not readily degraded, and this recalcitrant carbon gets fed by ocean currents to the deep sea, where it stays there indefinitely. Seaweeds have the potential to accelerate this natural carbon capture process in engineered systems, because they can be sustainably farmed in the ocean to large scale through aquaculture. However, to assess the potential of seaweed-based ocean carbon removal (Ocean CDR), a better understanding of the rate of carbon flow, from CO2 capture to recalcitrant carbon release, is needed. This project will advance fundamental understanding of the connection between CO2 capture and carbon sequestration rates by red and brown marine seaweeds through a combined biological and engineering approach, leading to new models for predicting carbon sequestration potential by seaweeds. The research outcomes will also suggest strategies for development of engineered systems for seaweed-based Ocean CDR. To help stakeholders better understand the research outcomes and move them towards practical application, the project will establish a Red Seaweed Learners Group, which will facilitate outreach, education, and collaborative learning on emerging Ocean CDR processes and their nexus with red seaweed aquaculture. Seaweeds are a potential natural solution for ocean-based carbon removal (Ocean CDR), but the flow of carbon from carbon dioxide (CO2) in the atmosphere to exuded dissolved organic carbon (DOC) available for sequestration by the deep sea is still poorly understood from a rate processes perspective. The overall goal of this proposed research is to provide a fundamental understanding of the rate processes for carbon flow by marine seaweeds under controlled hydrodynamic and environmental conditions in the absence of microbial degradation processes. The project hypothesizes that upstream CO2 uptake, which is driven by hydrodynamic and environmental conditions, is coupled to the downstream exudation of DOC by the seaweed. Therefore, the Research Plan will use clean, clonal seaweed cultures to eliminate microbial degradation processes, so that the upper bound of carbon exudation can be characterized. A recirculating flow system will be used to measure the real-time rates of carbon dioxide capture and dissolved organic carbon release by the model red seaweed Gracilaria and the brown seaweed Sargassum under controlled environmental and hydrodynamic conditions, determine the limiting effects of fluid velocity and environmental stressors such as elevated CO2 gas concentration and hyposaline environments on these rate processes, and develop rate-based models for dynamic prediction of inorganic carbon uptake and dissolved organic carbon release. These studies will advance fundamental understanding of seaweed-based Ocean CDR, and will suggest strategies for harnessing and sustaining these processes within intensified, engineered systems. Research outcomes will also advance the critical role of seaweeds in the development of the Bioeconomy and the Blue Economy, including next-generation aquaculture systems for providing ecosystem services and securing food and valuable products from the sea. Finally, as sustainability, climate change, and marine science aspects of the project are of broad interest to students and the public, the project will engage a diverse range of students in summer research experiences through established programs at Oregon State University, and the project also will establish a Red Seaweed Learners Group. The Learners Group will facilitate outreach, education, and collaborative learning on emerging Ocean CDR processes and their nexus with red seaweed aquaculture though a website, mini workshops, break-out sessions at regional Sea Grant conferences, and presentations to non-governmental organizations. 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 2024 · 2024-07

This IUSE Computer Science Level 2 Engaged Student Learning project aims to serve the national interest by preparing software engineering students to make high-quality contributions to team software projects. The goal of this project is to develop and evaluate a pedagogical approach for undergraduate software engineering courses that include team software development projects. In these courses a significant problem is assessing the contributions that a student makes to their team. This problem will be addressed by deriving the desirable qualities of four key software engineering artifacts that team members contribute to a software project. Based on these qualities, students will learn how to contribute high-quality artifacts by assessing and reflecting on their and their peers’ artifact contributions. This project will strengthen software engineering education by developing rigorous methods for assessing the quality of software project contributions. This project will iteratively refine and empirically evaluate a valid, reliable, practical, and just approach to assessing the software engineering artifacts that individual software engineers contribute to team software development projects. By taking a rigorous empirical approach to deriving the desirable properties of individuals’ contributions, developing a valid and reliable method for assessing individuals’ contributions against those properties, and making assessments practical through a software tool that enables assessments to be easily performed on samples of individuals’ contributions, this project will (a) contribute a novel pedagogy for fostering software engineering competence through peer review and reflection; (b) improve instructors’ ability to assess their students’ learning, and (c) enhance researchers’ ability to study and evaluate pedagogies for team projects in software engineering education. The NSF IUSE:EDU Program supports research and development projects to improve the effectiveness of STEM education for all students. Through the Engaged Student Learning track, the program supports the creation, exploration, and implementation of promising practices and tools. 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 2024 · 2024-06

The West Coast Van Pool currently consists of nine portable laboratory vans – two General Purpose (GP) Vans, three Isotope Vans, two Cold Vans, one Accommodations Van, and one Calibration Van that are all owned by the National Science Foundation or Oregon State University. This Van Pool supports scientific operations and data collection in the West Coast region, aboard National Science Foundation (NSF) supported Research Vessels by supplying required additional specialized portable laboratory space. 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 lab access to working, calibrated instruments for their research, reducing the cost of that research, and expanding the base of potential researchers. The West Coast Van Pool currently consists of nine portable laboratory vans – two General Purpose (GP) Vans, three Isotope Vans, two Cold Vans, one Accommodations Van, and one Calibration Van that are all owned by the National Science Foundation or Oregon State University. Management responsibilities for the West Coast Van Pool include scheduling, van transportation to and from vessels calling in Newport or other ports as required, maintenance, repairs, and outfitting. This Van Pool supports scientific operations and data collection in the West Coast region, aboard National Science Foundation (NSF) supported Research Vessels by supplying required additional specialized portable laboratory space. In the last five years, the West Coast Van Pool has seen a continual increase in use of the portable laboratories in support of NSF-funded projects. 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 · 2024-06

ABSTRACT Estuaries are dynamic environments in which the variability of abiotic and biotic factors support highly diverse microbial communities in sediments, including seagrass rhizospheres. A high likelihood of chemically mediated interactions in these complex, competitive communities makes estuaries an exciting potential source of new biologically active compounds. New pharmaceuticals are needed to combat drug resistance in the treatment of infectious and chronic diseases. Compounds targeting the protein secretory pathway at the endoplasmic reticulum (ER) display potent anticancer, antiviral, and antibacterial activities. Within this Sec61 translocon - mediated pathway, protein chaperone GRP78 is emerging as a potential druggable target with inhibitors showing efficacy against drug resistant cancers and viral and bacterial infection. Environmental sampling of sediments provides access to metabolites from complex microbial communities, for investigating both their role in the environment and potential biomedical relevance. Solid phase adsorbent resin samplers have been used extensively to monitor toxins from harmful algal blooms and have recently begun to be applied to the detection of natural products in marine sediments. The central hypothesis of this project is that microbial communities in estuarine sediments are valuable sources of novel bioactive NPs, with potential for the treatment and management of human disease, that may be accessed by in situ environmental sampling using adsorption resins. Sediments in eelgrass beds and nearby unvegetated areas across an estuarine gradient in Oregon will be sampled both by deploying adsorbent resin samplers and collecting small sediment scoops (Aim 1). The adsorbent resin samplers facilitate direct sampling of sediment metabolites from the environment for chemical and biological characterization. The sediment scoops enable parallel 16S rRNA microbial community analysis and comparison of metabolites obtained by solvent extraction of sediment versus adsorbent resin. High resolution LC-MS/MS and computational tools will be used to identify trends in metabolite production at sampling sites with and without eelgrass and support biological assays (Aim 2) in prioritization of samples for further investigation of new bioactive natural products. In Aim 2, a high-throughput magnetic microbead affinity selection screening assay (MagMASS) will be used to identify ligands of GRP78 from the complex mixtures in sediment extracts. When possible, hits identified in this assay will be verified using a cellular thermal shift assay to test GRP78 binding in cells. Extracts will additionally be screened against a panel of bacterial and fungal pathogens and bioactive components of complex mixtures will be predicted using computational methods (NPAnalyst). In Aim 3, laboratory culturing of stabilized microbial communities from estuarine sediments and monocultures of putative natural product producers will assist in linking natural products to their microbial producers and facilitate resupply of prioritized natural products for comprehensive chemical characterization and advanced biological testing.

NIH Research Projects · FY 2026 · 2024-05

Difficulty finding environmental and public health research, in readily usable form, is a major impediment to public's and study participants' abilities to understand and apply those findings to reduce their exposure to environmental hazards and improve health outcomes. Such available report-back of research results (RBRR) requires easily understood and visualized data presentations, dissemination, and overcoming ethical concerns to effective information distribution. This project aims to develop an ethically-sound RBRR approach that can build environmental health literacy (EHL) by creating the novel Translating Research to Action & Knowledge (TRAK) Portal –a web-based, smartphone-compatible tool for study participants and communities. To advance RBRR, our approach aims to effectively serve both individuals and their communities' needs. Earlier we found that study participants want to see how their data compares to those of other populations/geographic regions, and to see their data contextualized both for themselves and their communities. The TRAK Portal will encompass these foundational themes, in a modifiable tool that allows scalability across studies, and will publish open-source code. The project will leverage findings from 17 prior RBRR studies and >900 study participants, to create an interactive TRAK web tool. It will be developed initially to provide RBRR of silicone wristband-based chemical exposure data but will be extendable to scale across multiple data/study types. The project will promote and enable data sharing within and across studies, and will learn directly from RBRR study participants, to inform a qualitatively improved RBRR process and will advance EHL by discovering and thus leveraging people's motivations toward decision-making to reduce and prevent exposures to environmental contaminants. Input from Community and Expert Advisory Boards and Community Engagement Studios will identify preferences, perceived risks and benefits, and facilitators to efficacious RBRR, learning from various populations and by testing the Portal in two current NIH-funded studies: 1) Fair Start – urban cohort; and 2) St. Helen’s – suburban cohort. The project will identify and integrate ethical approaches for RBRR execution.

NIH Research Projects · FY 2025 · 2024-05

Project Summary Cachexia is a debilitating metabolic disorder that affects 50% of all cancer patients. Numerous clinical trials confirmed that the wasting of skeletal muscle mass is the hallmark of cachexia. During the course of the R37 parent grant, the research team developed the first messenger RNA (mRNA) therapy for metastatic ovarian cancer and cachexia-induced muscle wasting. It is based on lipid nanoparticles (LNPs) that deliver follistatin mRNA predominantly to cancer cells following intraperitoneal administration. The secreted follistatin protein, endogenously synthesized from delivered mRNA, efficiently reduces elevated activin A levels associated with aggressive ovarian cancer and ameliorates cachexia in this condition. By altering the cancer cell phenotype, mRNA treatment prevents malignant ascites, delays cancer progression, induces the formation of solid tumors, and preserves muscle mass in cancer-bearing mice by inhibiting negative regulators of muscle mass. Finally, the mRNA therapy provides synergistic effects in combination with cisplatin, increasing the survival of mice and counteracting muscle atrophy induced by chemotherapy and cancer-associated cachexia. Recent literature demonstrates that activin A increases the metastatic potential and decreases survival in head and neck cancers. Therefore, the research team will assess the efficacy of the developed mRNA therapy to reduce metastasis and preserve muscle mass in a new preclinical model of metastatic head-and-neck carcinoma that readily metastasizes to the lung and exhibits all the hallmark features of human cachexia. Whilst the loss of lean muscle mass is the hallmark of cancer cachexia, treatment for cachectic patients must also comprise therapeutic strategies that target systemic inflammation and stimulate appetite to ensure adequate energy and protein consumption. The research team will also develop the appetite-stimulatory therapy based on the above-discussed LNPs loaded with mRNA coding for both ghrelin and its specific O-acyltransferase (GOAT, required for full ghrelin activation). Previous reports suggest that ghrelin, a gut-secreted hormone, is a potential therapeutic agent for the treatment of appetite and weight loss in patients with cachexia. The proposed study will evaluate the efficacy of ghrelin mRNA-based therapy to improve food intake, body composition, and survival in a murine pancreatic cancer model of cachexia. Finally, anti-inflammatory therapy for the treatment of systemic inflammation in cancer cachexia will be developed using anti-inflammatory drug-loaded nanoparticles that accumulate efficiently at the site of inflammation following systemic administration. The research team has already constructed polymeric nanoparticles equipped with peptides as a targeting moiety for vascular cell adhesion molecule 1 (VCAM1) that is overexpressed in endothelial cells during inflammatory insults, with particularly high expression in hypothalamic centers regulating appetite. The efficacy of these IRAK4 inhibitor- loaded nanoparticles to reduce hypothalamic inflammation and increase food intake will be evaluated in the above-discussed murine pancreatic cancer model.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY It was recently reported that tampons, a menstrual hygiene product used by over half the population of people who menstruate, release up to 17 billion nanoplastic particles per use. However, neither the chemical characteristics of the tampon nanoplastic particles nor the physiological effects of these particles coming in direct contact with gynecological tissues have been identified. Therefore, the overall goal of this application is to define both the chemical characteristics of tampon nanoplastic particles as well as their downstream physiological effects on the gynecological tissue, Typically, the mucosal epithelial barriers of the vagina and cervix serve as protective barriers against infection and disease, yet there is currently very little known about how nanoplastics penetrate these barriers, which could potentially induce inflammation, oxidative stress, and dysregulated hormonal signaling, which cumulatively can lead to cervical and endometrial cancer, vaginosis, endometriosis, and impaired fertility. Furthermore, there is growing appreciation that exposure to biologically relevant environments can cause a corona of biological components to form around nanoparticles, altering the surface morphology and enhancing the internalization of plastic particles. Thus, our overarching hypothesis is that proteins found in menstrual blood adsorb to the surface of the nano-plastic particles shed from tampons, forming a biological corona that enables them to penetrate and disrupt cervical and vaginal mucosal membranes. This hypothesis with be explored by pursuing the following aims: 1. Characterize the surface chemistry of tampon nanoplastics shed in a biologically relevant environment; and 2. Determine the role of the biological coronas on tampon nanoplastics' ability to penetrate cervical and vaginal mucosal barriers and detrimentally affect downstream signaling cascades. The proposed research is significant, because it will provide a comprehensive overview of the biophysical interactions between tampon nanoplastics, the physiological environment they encounter, and the gynecological tissue they come in contact with. Absent such insights, people who menstruate will continue to have insufficient information on the potential detrimental health effects of tampon use.

NSF Awards · FY 2024 · 2024-01

Bacteria are abundant on our planet, colonizing diverse environments and playing essential roles in important ecosystem processes such as nutrient cycling. They have an amazing diversity of pathways for generating the energy they need to live and function, and these pathways underlie their survival and ability to contribute to ecosystem processes. Despite this importance, there is a lack of knowledge of how the function of specific energy generation pathways connects to bacterial fitness and these organisms’ role in the function of our environment. This project focuses on better understanding how alternative oxidase (AOX), a component of energy-generating pathways of marine bacteria that play vital roles in nutrient cycling, functions in their growth and survival. This award will allow the investigator to develop skills they will use to discover how alternative oxidase is expressed and functions in diverse bacteria and begin to connect this to nutrient cycling pathways. In addition, the investigator will couple these research activities with student training, outreach to K-12 students in Hawaii and the mainland, and the development of new diversity, equity, and inclusion efforts at their home institution. Research on AOX function in eukaryotes has been a very active area in recent years. Studies in plants, protists, fungi, and animals have revealed a common thread in AOX activity in helping cells deal effectively with environmental stresses and maintain energy balance. However, outside of the investigator’s work in Vibrio fischeri, the physiological role(s) of AOX in marine bacteria is essentially unexplored. Unanswered questions include how AOX functions in diverse bacteria and whether there are commonalities in physiological pathways in AOX-encoding bacteria or correlations between environmental conditions and the presence of aox-encoding bacteria. This project will address these knowledge gaps using three approaches: 1) microrespirometry along with genetic, biochemical, and molecular approaches to determine the physiological role of V. fischeri AOX under environmentally relevant conditions; 2) genetic, molecular, and biochemical approaches to understand the regulation and physiological contribution(s) of AOX in other diverse model marine bacteria; and 3) bioinformatic approaches to identify the genomic features and environmental conditions that correlate with aox abundance and expression. The results of this research will provide valuable new information about AOX regulation and function in bacteria and lay the foundation for further exploration of the influence of bacterial AOX on microbial physiology, marine ecosystem function, and biogeochemical cycling. These results will also provide insight into commonalities in the regulation and function of AOX in different kingdoms of life. 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 · 2023-08

We plan to add an electron diffraction component to a native protein mass spectrometer to create a new instrument that can derive atomic structures of macromolecules such as proteins. The key innovation is the use of superfluid helium droplets for sample cooling thereby effective field induced orientation and alignment. Mass and conformation selected proteins from a native electrospray ionization mass spectrometer are embedded in superfluid helium droplets, and in a pulsed electric field and elliptically polarized laser field, due to the permanent and induced dipoles of the protein, all three Euler angles of the protein can be precisely defined. The large polarizability volume of macromolecules (not the permanent dipole moment) and the low rotational temperature of the embedded macromolecules are the two elements of the “molecular goniometer”: changing the polarization properties of the laser field changes the orientation of the macromolecule. Electron diffraction patterns from macromolecule-doped droplets, one molecule per droplet, all oriented in the same direction, are accumulated with each successive pulse, until a satisfactory signal-to-noise ratio is achieved. Ultimately from the diffraction patterns of all orientations of the chosen macromolecule, the electrostatic potential is derived using the oversampling method for iterative phase retrieval and structure determination. In the past few years, we have accumulated preliminary data on electron diffraction of small molecules and cationic molecular clusters embedded in superfluid helium droplets, and on doping macromolecular ions into superfluid helium droplets. The next phase of the project is to construct a complete instrument to demonstrate the principle of the concept. We now can solve structures of nanocrystals embedded in superfluid helium droplets, both neutral and charged, without sample alignment. Therefore the background issue of the enclosing helium and the particle density issue of charged species are no longer major concerns. Our demonstrated resolution from pyrene dimer cations is 0.5 Å. Moreover, we have succeeded in doping macromolecular ions into superfluid helium droplets using a standard electrospray ionization source. Our accomplishments so far have laid the foundation for the next phase of progress, and we are now ready to demonstrate the principle of the concept. With the acquisition of a new electron gun, a upgrade to a native protein ion source, and a direct electron detector, we have a detailed plan to align all three pulsed beams, the laser beam, the ion doped droplet beam, and the electron beam, to obtain diffraction patterns of field aligned macromolecules. Our ultimate goal is to resolve atomic structures of mass and conformation selected macromolecules with 1 Å resolution from mixtures of protein solutions, microfluidic reactors, or labeled cells for proteins and protein complexes. The final instrument will reshape the landscape of structural biology, transform structure-based drug screening, and rapidly determine effects of mutations and deletions on structure. It will also offer structural assessment of components in polydisperse mixtures of nanomaterials important for biomedical applications. To mitigate the risks, we have recruited a specialist in mass spectrometry, Dr. David Russell, to be our consultant, and a specialist in data processing, Dr. Peter Schwander, to be a member of our team.

NIH Research Projects · FY 2025 · 2023-08

SUMMARY We live in an era of contaminated drinking water. Potable water reuse, climate change, population growth, and intensive farming are factors that drive this contamination. Concurrently drinking water contaminants have been linked with epidemic diseases such as cancer, obesity, dysregulation of the gastrointestinal systems, impaired mental functions, and other developmental and reproductive diseases. Toxic pollutants in drinking water are particularly hazardous for fetal and infant health. They are more vulnerable to harmful contaminants because their organs and tissues are still developing. Previous studies have targeted gut microbiota as an active player of that association. However, the mechanisms underlying these impairments remain poorly defined due to challenges associated to the identification of microbiome-mediated relationships between external factors (i.e., diet and contaminants) and host metabolism. Due to the massive number of organic micropollutants, monitoring using targeted chemical analyses alone is insufficient to assess drinking water quality, covering only a very small subset of the chemicals. Finally, current health risks of drinking water contaminants are typically assessed one chemical at a time, an approach that misses the health impacts of co-occurring contaminants in drinking water and their potential synergistic effects. My central hypothesis is that current tap and well water quality assessments underestimate our exposure to organic contaminants in drinking water and their impact on fetal and infant health. My long-term goals are to (1) improve drinking water quality assessments, by applying high- throughput identification and prioritization strategies of contaminant mixtures, as well as (2) elucidate causal relationships between drinking water contaminants and negative health outcomes in children, specifically those related to neurological conditions. Current knowledge of the risks associated with drinking water contaminants is limited due to the challenges associated with their detection, identification, and testing. Therefore, my overall objectives for this application are to (1) apply high-resolution mass spectrometry (HRMS) and in vitro and in vivo effect-directed analysis (EDA) to expand the coverage of current water monitoring strategies; (2) select and prioritize chemical candidates based on their occurrence, abundance, and toxicity; (3) evaluate associations among prioritized contaminants and water sources according to zip code and open source information found in the Oregon Drinking Water Services at the Public Health Division Website; (4) identify gut metabolites whose variation explains the association between specific gut microbes and zebrafish endpoints; (5) and provide a comprehensive list of prioritized chemicals and mixtures found in rural and drinking water in Oregon. This study will help members from the EPA and DEQ make better informed decisions related to further chemical regulations in drinking water. This application responds to the first theme of the NIEHS strategic plan 2018-2023, Advancing Environmental Health Sciences (EHS), by studying the effects of contaminant mixtures of emerging concern, predictive toxicology, and microbiome responses.

NIH Research Projects · FY 2026 · 2023-08

PROJECT SUMMARY The overarching goal of our research program is to couple computational tools with three-dimensional models of epithelial barriers to interrogate how the epithelial extracellular matrix (ECM) is influenced by extrinsic factors, how changes to the epithelial ECM affect drug delivery, and how the epithelial ECM can be harnessed to tailor drug bioavailability. Epithelial barriers are what lies between us and the outside world, serving as protective barriers and sites of selective permeability. For each type of epithelial tissue, each layer of stratified epithelium has its own unique ECM, a complex network of fibrous proteins that provides mechanical and chemical cues that drive cell proliferation, survival, differentiation, cell polarity, and migration. Dysregulation of epithelial barriers can be indicative of local or systemic disease and permeability of epithelial barriers directly affects how drug is delivered across the ECM and into the circulation. Recently, it has been appreciated that the ECM cannot be fully studied as the fibrous proteins alone, but instead should be evaluated as the interconnected network of proteins that make up the structural core of the ECM along with proteins that are critical to ECM function and maintenance such as receptors and ECM-bound soluble factors. This interconnected network has been defined as the matrisome, a curated collection of 1027 genes, roughly 4% of the known human proteome. While the roles of individual ECM proteins and ECM downstream signaling networks on epithelial function and permeability have been investigated, three key knowledge gaps persist: 1) How does the epithelial matrisome change with extrinsic factors such as age, menstrual cycle, and inflammation? 2) How do changes to the epithelial matrisome affect drug absorption and transport? 3) How can we modulate the epithelial matrisome for selective bioavailability? To address the first knowledge gap, in Project 1 we will evaluate publicly available datasets and biospecimens using our novel machine learning and image analysis techniques to reveal the interconnected relationships between matrisome changes and extrinsic factors such as age, menstrual cycle phase, and immune landscape. These studies will be complemented by orthogonal in vitro studies using our library of tissue engineered models that capture the layered morphology of epithelium. To address the second knowledge gap, in Project 2 we will couple our in vitro models with statistical modeling and systems biology tools to determine key matrisome proteins that influence drug delivery across epithelial surfaces and their corresponding mechanisms of action. Lastly, to address the third knowledge gap, in Project 3 we will identify novel compounds that modulate bioavailability through matrisome-driven mechanisms, opening new avenues of direction for the design and delivery of novel therapeutics with selective bioavailability. Critically, the methods that we are developing are tissue, organ, and disease agnostic, facilitating an increased understanding of a wide variety of biological processes at a molecular, cellular, and tissue level.

NIH Research Projects · FY 2026 · 2023-06

Summary/Abstract Ectopic pregnancy is the leading cause of maternity-related death during the first trimester of pregnancy. Approximately 98 % of ectopic implantations occur in the fallopian tube and, in the event of tubal rupture, prompt treatment is critical to avoid hemorrhage and maternal death. Ectopic pregnancies account for about one in every 50 pregnancies (120,000 per year) in the United States. Current ultrasonography procedures misdiagnose ectopic pregnancy in up to 40% of cases, while methotrexate treatment for confirmed EP has a failure rate of more than 10%. During the time prior to ultrasonographic visualization, the pregnancy biomarker human chorionic gonadotropin (hCG) is used to evaluate growth but is a poor measure of the implantation site. This project aims to establish an imaging modality for localization of the early placenta utilizing nanoparticles targeting the trophoblast layer of the placenta. Contrast-enhanced imaging modalities (e.g., MRI) can substantially improve ectopic pregnancy detection. However, the use of conventional contrast agents, including gadolinium- based MRI contrast agents, is discouraged as low molecular weight compounds cross the placenta and can incur fetal toxicity in viable pregnancies. To address this challenge, a biocompatible polymeric nanoplatform will be utilized that accumulates specifically in placental tissue, but not the fetus, after intravenous injection. This nanoplatform will be loaded with newly developed magnetic nanoparticles that are highly efficient MRI contrast agents, and placenta accumulation/detection/visualization will be assessed in placenta cells and small animal models. Furthermore, the ability to impair the developing placenta, and thus terminate ectopic pregnancy, will be demonstrated by magnetic hyperthermia mediated by trophoblast-targeted nanoparticles. The premise of this proposal is that specifically designed nanoparticles can detect early placentation, and subsequent magnetic hyperthermia can provide a non-invasive option to treat ectopic pregnancy. To advance the proposed approach for ectopic pregnancy management, our multidisciplinary team of investigators with complementary expertise in nanomedicine, magnetic hyperthermia, and clinical placenta research proposes, in Aim 1, to evaluate the biodistribution profile and placenta uptake of the developed nanoparticles (non-targeted and trophoblast- targeted) in human/macaque placental cells and in mice. In Aim 2, the MRI imaging efficiency and short- and long-term toxicity of the placenta-targeted nanoparticles will be evaluated in pregnant mice. In Aim 3, the safety and therapeutic efficacy of magnetic hyperthermia mediated by our magnetic nanoparticles will be accessed for simulated treatment of human ectopic pregnancy in mice and non-human primates, aiming to demonstrate a novel, effective and non-invasive approach for ectopic pregnancy management.

NIH Research Projects · FY 2026 · 2023-01

PROJECT ABSTRACT RNA therapeutics and their corresponding nanomedicines are poised to rapidly change the landscape of healthcare. To address needs in various diseases, RNA-based technologies must function in vivo with biological interactions at various levels from whole body (systemic biodistribution and immunological) to tissues and organs, to intracellular trafficking and endosomal release. Unfortunately in oncology, efficient systemic delivery of lipid nanoparticles (LNPs) to solid tumors has been plagued by poor tissue accumulation largely due to a gap in the knowledge of fundamental interactions between these materials and biological systems. Here we propose to investigate the structure-activity-relationship (SAR) of nanoparticle carriers through use of a chemically and topologically diverse library of lipopolymers fine- tuning the biointerface of RNA-LNP. Utilizing a combined barcoding and serial in-depth mechanistic assays, we will test our central hypothesis that a defined series of first-principles relationships govern the biophysical interactions of LNPs in vivo. Using cancer models, we will correlate the spatial and temporal accumulation of mRNA at target tissues and cells with biophysicochemical properties of the LNP biointerface. The goal of this project is to establish a framework of physiochemical properties to guide the development of RNA-LNP based cancer nanomedicines. We will achieve this goal by the pursuing the following aims: Aim 1 - Structural and topological fine-tuning of LNPs biointerface. Aim 2 - Elucidate the biological interactions of LNPs with respect to whole-body, tissue-level, and intracellular distributions. Aim 3 - Investigate the biological interaction and efficacy of LNPs in the context of multimodal breast cancer therapy. The immediate outcomes of this research will be applied toward advancing the use of nanotechnology in oncology. Our project will yield a critical and detailed understanding of the role the LNP biointerface and its effects on the fate of LNPs in complex biological systems as well as their efficacy. This invaluable knowledge would greatly aid in future developments in nanomedicine as a whole.

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT Inherited retinal dystrophies (IRDs) are a heterogenous group of orphan diseases, inherited in an autosomal dominant, recessive or X-linked pattern in addition to mitochondrial transmission, all leading to the loss of functional vision and often progressing to blindness. As a group, IRDs are due to mutations in over 280 genes. Currently, there is only one FDA approved gene therapy for this large family of retinal degenerations. Prime editing, a new versatile genome editing tool, allows for all 12 base-to-base changes, insertions up to 44 bases long and deletions of up to 80 bases. Prime editors are capable of correcting 89% of known genetic variants associated with human disease, but are still in their infancy for in-vivo use. Our long-term goal is to optimize prime editing platforms for IRDs. Lipid based nanoparticles (LNPs) are a modular platform that can encapsulate and deliver genome editors. Delivering nucleases as mRNA has been an optimal alternative strategy for transient protein expression rather than persistent expression of DNA cutting machinery associated with viral vectors. LNPs are capable of rapid and efficient delivery of mRNA to the retinal pigment epithelium, however, they have limited capacity to transfect photoreceptors, which is necessary to target the many genes associated with IRDs. We hypothesize that by employing phage display techniques, we will isolate promising targeting peptides which will decorate our LNPs and effectively deliver prime editing cargo to the photoreceptors. Our main goal is to generate peptide-targeted LNPs that lead to cell-specific delivery of prime editing components for the treatment of IRDs. To achieve this goal, we propose the following specific aims: 1) Optimize in-vivo phage display biopanning for the identification of targeting peptide moieties that allow for photoreceptor-specific lipid nanoparticle-based gene delivery, 2) Dissect the mechanism of peptide-targeted LNP entry into photoreceptors, and 3) Evaluate the efficacy, and any associated toxicity, of prime editing in two rodent models of IRD. Thus far, we have identified novel peptides that can steer LNPs toward photoreceptor gene delivery and determined that LNPs can package all prime editing components together and lead to efficient prime editing of reporter genes in-vitro and in-vivo. Successful completion of this project will lead to the development of cell-specific gene editing platforms that will advance treatment for IRDs.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY: There is a need for integrative data analyses that anchor transcriptomic research in contexts predictive of human health, as illustrated by growing awareness of disease-associated synonymous transcript variants and RNA biotechnologies such as mRNA vaccines. To help uncover sequence features that are important for RNA regulation, we present context-dependent models of translational efficiency, a key metric of transcript function. We show that position-dependent codon usage bias (PDCUB) identifies start codons among AUGs more consistently than the Kozak sequence, while high-PDCUB transcripts are enriched for medically important genes tied to human development and neural function. Attention-based transformer networks and interpretation techniques will independently predict translational efficiency in human transcripts, with comparison to ribosome profiling and RNA abundance data in multiple human cell lines, to characterize how PDCUB and other sequence features guide translational efficiency across health- critical contexts. Transfection assays validate the roles of predicted sequence features. Beyond sequence, higher-order structures also drive RNA function and stability, including translational regulation and interactions with microRNAs and RNA-binding proteins (RBPs). A new RNA structural alignment method and associated clustering will uncover structural domains and group them by mutual similarity to find common structural motifs that impact RNA structure-function relationships, improving our understanding of the role of transcript structure in pathogenesis. Evaluation will consist of clustering RNA families in our previously built RNA structure meta-database, bpRNA-1m, with identified structural domains analyzed in the context of ribosome profiling data to characterize the role of these domains in regulating translation. Meanwhile, clustering structures according to RNA-protein crosslinking data will let us identify motifs involved in the binding of RBPs. Finally, a comprehensive transcriptome browser and meta-database will integrate transcriptomic data for known and new transcript-level features, including those described above. Easy to access and use, this resource will enable scientific and medical researchers to find and define RNA sequence features and structural motifs. By cohesively cataloging the complex facets of transcript-level interactions, along with sequence and structural features relevant for transcript regulation, our transcriptome browser will help researchers visualize ribosomal occupancy, examine RNA structures, microRNA and RBP binding, catalog splice variants, and understand the sequence features that drive transcript interactions. Allelic variants mapped to RNA transcript positions will be combined our annotations, along with feature-based machine learning predictions incorporated into the browser, to assist researchers in generating first-pass predictions of transcript variants and interpreting their outcomes in the context of human health.

NIH Research Projects · FY 2025 · 2022-08

Preterm infants in the NICU are fed human milk from their own mothers or donors, and exposed to a variety of handling practices, including fresh mother’s milk, frozen and thawed mother’s milk and Holder pasteurized donor milk. Freeze-thaw cycles and pasteurization can alter the structure of milk proteases and proteins, and these alterations can affect the release of milk peptides. Milk peptides present in the infant intestine have an array of activities including antimicrobial, and enterocyte- and macrophage-immunomodulatory. Differences in milk sources, processing, and storage may yield differential release of bioactive peptides, and therefore differential activities in the gastrointestinal tract of infants. There is a critical need to evaluate effects of milk handling practices on release of peptides within the infant and their bioactivities. Our long-term goal is to determine feeding practices for preterm infants that promote optimal ex utero development and growth. The overall objective of this proposal is to identify how common milk handling practices affect the release of gut health-promoting peptides within the preterm infant intestine. Our central hypothesis is that the identity and amounts of milk peptides released within the intestine of preterm infants fed with these milks will be markedly different and therefore will have different profiles of antimicrobial, and enterocyte- and macrophage-immunomodulatory actions. Our specific aims are to determine the 1) antimicrobial and bifidogenic activities, 2) enterocyte-immunomodulatory activity, and 3) macrophage- immunomodulatory activity of peptides in the intestinal contents of preterm infants fed fresh mother’s milk (MM), frozen and thawed mother’s milk (FTMM), Holder-pasteurized mother’s milk (HPMM) and Holder- pasteurized donor milk (HPDM). Our approach will be to collect intestinal samples from preterm neonates within the neonatal intensive care unit (NICU) after feeding milk exposed to different handling practices, extract the peptide component from these samples, test their antibacterial, bifidogenic and enterocyte- and macrophage-immunomodulatory activity in vitro, and identify the peptides via mass spectrometry and database searching techniques. This research is innovative because it identifies the bioactivities of peptides released during in vivo intestinal digestion and examines the effect of human milk handling practices. At the conclusion of this project, we expect to have determined 1) the extent to which milk peptides released in the preterm infant intestine express gut health-related bioactivity; and 2) how different milk handling practices affect peptide release and bioactivity. The positive impact of this research is that it will help determine optimal milk handling practices for preterm infants, and possibly supplementation strategies for milk that will lead to improved bioactivity within the infant gut.

NIH Research Projects · FY 2026 · 2022-08

PROJECT SUMMARY Evolution via natural selection results in organisms adapted to their environment, but also involves trade-offs. Many complex diseases affecting humans today are historical artifacts of our past evolution. Thus, a better understanding of the process of adaptation may provide new tools to combat complex disease. And yet there are considerable gaps in our knowledge of the dynamics of adaptation at the level of genotype and phenotype, in large part due to the challenges of inferring the effects of past selection on human populations. The long-term goal of this proposal is to elucidate the molecular basis of adaptation using an innovative, sexually-reproducing laboratory system of outcrossing yeast (Saccharomyces cerevisiae). Experimental evolution offers a powerful method to test hypotheses about adaptation as investigators observe populations evolve in real time under controlled conditions. With genome sequencing, genetic variation can be sampled from populations during the process of adaptation; this technique is called “Evolve-and-Resequence”, or E&R. Recent E&R work with this yeast laboratory system has advanced fundamental evolutionary questions, for example by providing strong evidence that preexisting genetic variation drives adaptation, rather than beneficial new mutations. Also, it finds that the stable long-term maintenance of genetic diversity is common, even when selection is strong. Building upon these initial discoveries, additional questions are being tested, such as what evolutionary outcomes result from complex selection environments involving fluctuating or otherwise dynamic selection pressures, and what influence gene expression has on adaptive change, over a range of time scales. This proposal takes advantage of MIRA’s flexible research goals, as it would support multiple yeast E&R projects. Each will further understanding of general adaptative dynamics, and will also deliver specific insights into particular traits. A trait of special interest to this proposal is late-life fertility. Senescence, or the decline in survival and fertility with advancing age, is a good example of a complex disease facing humans as a result of evolutionary trade-offs. Preliminary data in this application show that through selecting only the oldest cells to reproduce over many generations, yeast populations evolve to live longer and remain fertile at later ages than control populations. This provides an exciting potential to dissect the genetic basis underlying longevity and late-life fertility, and new research horizons are expected to become attainable as a result. The proposed research is significant, because it is expected to vertically advance and expand understanding of the natural genetic variation underlying healthy versus disease-related phenotypes, and specifically for phenotypes related to late-life reproductive success. Ultimately, such knowledge has the potential to inform the development of approaches in personalized medicine, and/or gene therapies, that will lead to a variety of improved health outcomes.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY/ABSTRACT Consistent with the NHLBI Strategic Objective to “develop and optimize novel…therapeutic strategies to prevent, treat, and cure heart, lung, blood and sleep diseases,” this proposal aims to develop, refine, and preliminarily test a comprehensive, personalized, media-augmented telehealth intervention designed to improve sleep health among shift workers. Approximately 20% of the US workforce engages in some form of shift work. Shift work is common in essential occupations (e.g. nursing, transportation, food service). Shift work is associated with elevated risk for cardiovascular disease, stroke, multiple cancers, metabolic disorders, depression, driving accidents, medical errors, and all-cause mortality. One modifiable factor that contributes to increased risk for disease, accidents, errors, and death among shift workers is poor sleep health, defined as the multidimensional pattern of sleep and wake which promotes optimal health and wellbeing. Poor sleep health in shift workers manifests during both sleep (e.g., insomnia symptoms, short sleep duration) and wake (e.g., fatigue, sleepiness, executive function, depression). The proposed study seeks to improve sleep health among shift workers by developing, refining, and testing a novel intervention, termed Shift Worker Intervention for Sleep Health (SWISH), which will integrate existing effective interventions into a comprehensive program that addresses the constellation of sleep health problems experienced by many shift workers. The aims of this research are to: 1) iteratively refine and finalize the structure and materials of SWISH; 2) examine feasibility and acceptability of SWISH compared to delayed treatment control in a randomized pilot study; 3) preliminarily test the effect of SWISH on sleep health parameters; and 4) preliminarily test the effect of SWISH on wake time functioning. The proposed research plan will be the first step towards building an intervention that can contribute to the improvement and reduce the significant societal burden of poor sleep health among shift workers. This research has potential far-reaching public health implications, as the sleep health of shift workers has impacts beyond the individual (e.g., patients under a nurse’s care). The candidate’s planned training activities are also vital to the completion of this project. As outlined in the Career Development Plan, a multidisciplinary team of experts will provide the candidate with advanced training and mentoring in key areas including clinical trial design, conduct, and reporting, circadian rhythms biology and circadian interventions for shift work, implementation science, and development of rich, engaging media products to support therapist-led interventions. The training plan includes strong mentorship, seminars and didactics, formal coursework and institutes, hands-on training, manuscript and grant preparation, and attendance at scientific meetings. The proposed research project leverages the candidate’s rigorous prior research and clinical training in sleep health assessment and interventions while providing necessary additional training to set the stage for the candidate to become an independent clinical investigator focused on increasing accessibility for sleep health interventions in underserved populations.