Oregon State University

NIH Research Projects · FY 2026 · 2022-02

ABSTRACT Neisseria gonorrhoeae (Ng), the gram-negative bacterium responsible for the sexually transmitted infection gonorrhea, is categorized as a high-priority pathogen for research and development efforts. In the US, over 50% of Ng isolates are resistant to at least one antimicrobial and the CDC has ranked Ng as one of the top 5 urgent antibiotic resistant threats. Gonorrhea outcomes are especially devastating in sexual, gender, racial, and ethnic minorities and resource-limited countries. Ng’s “superbug” status, its high morbidity, and the serious health and psychological impacts of gonorrhea necessitate vaccine development. To address the urgent need for an effective and safe vaccine against gonorrhea, we propose to use a powerful Virus-like-Particle (VLP) vaccine platform with a highly effective split-protein conjugation system to deliver promising Ng antigens (Ag) as full- length and natively folded proteins. We selected for this proposal six promising lipoproteins based on their: 1) exceptional conservation in >5K sequenced Ng isolates worldwide; 2) surface-exposure; 3) ability to elicit bactericidal antibodies (Abs); 4) expression in geographically and temporally diverse Ng strains, during different in vitro conditions and Ng infection in the gonorrhea mouse model; and 5) important functions in Ng pathogenesis and physiology. We will: 1) Design and produce antigen-VLP formulations; 2) Identify Ag-VLP and adjuvant combinations that generate robust immune responses; and 3) Evaluate efficacy of promising vaccines and elucidate the immune correlates of protection. Our approach presents conceptual and technical innovations in the gonorrhea vaccine field by pioneering VLP-display of conserved, full-length Ng lipoproteins, which will be comparatively assessed for efficacy and potential mechanisms of protection.

NIH Research Projects · FY 2026 · 2022-02

The proposed GCE4All Biomedical Technology Development and Dissemination Center at Oregon State University (OSU) will optimize, develop, and broadly disseminate Genetic Code Expansion (GCE) technology – the engineering of cellular translation to express proteins containing non-canonical amino acids (ncAAs). GCE provides unprecedented ways to probe and manipulate macromolecular structure and function, analyze protein malfunctions in disease, engineer bioanalytical tools, and create new precision biotherapeutics. GCE's feasibility is well-established, but it remains difficult for researchers to access and implement, and thus remains little-used – an ideal target for BTDD support. During its envisioned lifespan of ≤15 years, the Center's mission will be to optimize and extend existing GCE technologies to enable facile use by non-specialists, and to broadly disseminate them via widespread education, effective training, and by providing sustainable access to optimized technologies via established repositories – enabling powerful GCE approaches to become standard, widely-used tools of biomedical researchers. Advantageous for creating the proposed Center is our experience and leadership in the groundbreaking predecessor OSU Unnatural Protein (UP) Facility (2012-21), which at a much smaller level developed and disseminated GCE methods and trained researchers. GCE4All Center leaders are thus well- equipped to accomplish the Center mission via its 2 Technology Development Projects (TDPs), 10 initial Driving Biomedical Projects (DBPs), and Community Engagement (CE). The synergistic TDPs will optimize and extend GCE methods for 1) bioorthogonal ligation applications using GCE-produced proteins, including low- background labeling and tracking in mammalian cells, and 2) producing ncAA-proteins that contain biochemical probes and/or native or analog post-translational modifications (PTMs) – ubiquitous but little-understood regulators of protein functions. To ensure broad relevance, targeted technology advances will overcome barriers faced by geographically-diverse, NIH-funded DBPs that will serve as stringent testbeds for the work. To achieve its “GCE for All”goal, Center optimizations will bridge 4 common technological barriers that deter researchers from adopting GCE. These 4 GCE Bridges include: effective tools for 1) incorporating ncAAs of choice; for efficiently producing impurity-free GCE proteins in 2) E. coli and 3) mammalian cells; and 4) creation of stable mammalian cell lines and reliable protocols for reproducible studies in cells. The CE core will provide diverse training activities including hands-on workshops already proven effective by our UP Facility. Via the Center website, CE will disseminate GCE methods, online training, and host a Wiki GCE-knowledgebase and a GCE4All community networking bulletin board enabling peer-to-peer support in the GCE user community. The CE core will also organize biennial International GCE Conferences and ensure all optimized reagents are publicly available from repositories. The GCE4All Center will achieve these ambitious goals in Years 1-5, toward its ultimate goal of transforming GCE from a boutique method to a standard part of the molecular biologist's toolkit.

NIH Research Projects · FY 2026 · 2021-12

OVERALL CENTER PROJECT SUMMARY The Oregon State University Center for Advancing Science, Practice, Programming and Policy in Research Translation for Children’s Environmental Center (ASP3IRE Center) will accelerate the translation of children’s environmental health research. Drawing upon best practices in translational science, the ASP3IRE Center will provide infrastructure, training opportunities, data science tools, stakeholder engagement, and time-sensitive pilot grants to support the development and dissemination of evidence-informed interventions that protect children from environmental hazards where they live, go to school, and play. The Center will be able to rapidly identify and prioritize local areas that would benefit from children’s environmental health (CEH) interventions by creating novel data science surveillance tools that strategically mine social media feeds and existing environmental health tracking and health care utilization databases that are produced by our partners at Oregon Health Authority and Coordinated Care Organizations. Our Center will also leverage the strengths of the Hallie Ford Center for Healthy Children and Families, the Oregon State University (OSU) Center for Health Innovation, Coordinated Care Organizations, and OSU’s Extension Services to expand the network of researchers and practitioners who are able to create, test, evaluate, and deliver evidence- based interventions where they are needed the most. These unique resources will make Oregon a “living laboratory” for the development and delivery of evidence-based CEH interventions for the broader scientific community and help advance the field of children’s environmental health research translation that promote diversity, equity, and inclusion. Finally, the ASP3IRE Center will create an online portal that will serve as a searchable repository for comprehensive evidence-based CEH intervention implementation plans that can be adapted by researchers and practitioners to local communities across the nation.

NIH Research Projects · FY 2024 · 2021-09

Summary/Abstract (30 lines) Thermal therapy is a clinical intervention to eradicate cancerous tissue by increasing the temperature of the tumors. Nanoparticle-mediated magnetic hyperthermia is a form of thermal therapy where magnetic nanoparticles delivered to cancer sites generate heat after exposure to an external alternating magnetic field (AMF). The goal of this project is to advance nanoparticle-mediated magnetic hyperthermia as a non-invasive treatment for endometriosis. Endometriosis is a disorder where endometrium-like tissue is present at “ectopic” sites outside of the uterus. The ectopic endometrium forms lesions that cause pelvic pain and infertility. Despite advances in therapies for endometriosis-related pelvic pain, there remains no medical cure for the disorder, and surgical removal of the lesions remains a treatment for many women. Unfortunately, the rate of disease recurrence exceeds 50% with many patients requiring three or more surgeries. The premise of this proposal is that magnetic hyperthermia can provide a non-surgical option to remove endometriotic lesions. Magnetic hyperthermia for cancer is currently restricted to the treatment of localized and accessible tumors because the required therapeutic temperatures (≥42 0C) can only be achieved by direct intratumoral injection of conventional magnetic nanoparticles. To address this limitation, this research team invented novel magnetic nanoclusters with high heating capacity. The nanoclusters consist of hexagonal-shaped magnetic nanoparticles encapsulated in polymeric vehicles. Animal studies validated that these nanoclusters are safe, efficiently accumulate in cancer tumors after intravenous (IV) injection, and elevate the intratumoral temperature to 44 0C in the presence of AMF. Preliminary studies revealed that following IV injection these nanoclusters also efficiently accumulated in the macaque endometriotic lesions grafted into severe combined immunodeficient (SCID) mice and exposure of these mice to external AMF after nanoclusters delivery increased the temperature inside of the grafts up to 43 0C. To advance this new therapy this multidisciplinary team of investigators with complementary expertise in nanomedicine, magnetic hyperthermia, and clinical endometriosis research proposes in Specific Aim 1, to optimize targeting efficiency of these nanoclusters to human and macaque endometriosis. Targeting will be optimized by modifying the surface of the nanoclusters with peptides that specifically bind to receptors (e.g., vascular endothelial growth factor (VEGF) receptor 2 (KDR)) overexpressed in primate endometriotic stromal cells. Binding specificity and therapeutic efficacy of these new nanoclusters will be assessed in primary endometrial and endometriosis (human and macaque) stromal cells in vitro. In Specific Aim 2, the effect of targeted versus non-targeted nanoclusters on the eradication of endometriosis lesions will be evaluated in SCID mice engrafted with human and macaque endometriotic grafts. In Specific Aim 3, safety and therapeutic efficacy of magnetic hyperthermia mediated by the optimized nanoclusters will be evaluated in macaques with induced endometriotic lesions.

NIH Research Projects · FY 2025 · 2021-09

Human milk bioactive proteins are degraded during commonly used Holder pasteurization of donor milk. Alternative processing techniques that ensure biosafety while preserving bioactive proteins are needed, particularly for at-risk preterm infants. High pressure processing (HPP) and ultraviolet-C irradiation (UV-C) treatment are known to preserve a few bioactive milk proteins, but no systematic research has identified the minimum processing parameters and their effects on the entire array of milk proteins’ structure and function. There is a critical need to perform this research. Our long-term goal is to optimize feeding practices for preterm infants to improve their health outcomes. The objectives of this research are to identify the minimum HPP and UV-C treatment conditions that achieve equivalent microbiological safety to Holder pasteurization while optimally preserving bioactive protein structure and function. Our central hypothesis is that minimal HPP and UV-C treatment conditions will better preserve donor milk bioactive proteins’ structure and function compared with Holder pasteurization. Our hypothesis is based on our work and that of others indicating that HPP and UV- C treatment preserve some bioactive proteins. The rationale for this work is that it can lead to changes in donor milk processing that can improve bioactive protein retention and possibly infant health outcomes. Aim 1. Determine treatment conditions for HPP and UV-C pasteurization that maximize bioactive protein preservation compared with Holder pasteurization. Minimal conditions for HPP and UV-C biosafety will be determined and retention of bioactive milk proteins will be compared between unpasteurized, Holder pasteurized, HPP-treated and UV-C-treated donor milk via ELISA and proteomics analyses. Our working hypothesis is that minimal-condition HPP and UV-C-treated donor milk will have higher retention of bioactive proteins than Holder pasteurized donor milk. Aim 2. Identify the extent to which preserved bioactive proteins maintain their bioactivities after treatment with HPP and UV-C pasteurization. Bioactivity will be examined in whole milk and fractionated protein extracts of unpasteurized and Holder, HPP and UV-C pasteurized donor milk. Our working hypothesis is that HPP and UV-C treated donor milk proteins will retain a higher degree of their bioactivities compared with Holder pasteurized donor milk as determined by in vitro antibacterial, anti-adhesive, antiviral and immunomodulatory assays, lipase and protease assays. We expect to have determined the extent to which minimally processed HPP and UV-C treatment preserves bioactive proteins’ structure and function compared with Holder pasteurization. The positive impact of this research will be guidance for donor milk processors on how to optimally process donor milk for feeding preterm infants and information for clinicians on how to evaluate available donor milk sources. Changes in milk processing to better preserve bioactive milk proteins could improve preterm infant health outcomes.

NIH Research Projects · FY 2025 · 2021-07

PROJECT SUMMARY NIEHS has established Predictive Toxicology as a strategic goal for advancing environmental health sciences. The overarching goal of this RIVER proposal is to predict animal toxicity of chemicals based on their structure. My team and I will expose millions of zebrafish embryos to a library of 10,000 synthetic chemicals across wide concentration ranges. If a chemical shows signs of bioactivity, we will systematically analyze whole animal gene expression changes before the phenotype appears. We will formulate hypotheses about which biomolecular targets the chemicals attacked initially and which pathways led to the observed endpoint. To test those hypotheses, we will edit the zebrafish genome via CRISPR/Cas9 to knock out or over-express critical genes, to discover the ones causally related to the chemical phenotypes. These studies will be highly relevant to human health. Zebrafish possess fully integrated vertebrate organ systems that perform the same functions as their human counterparts and demonstrate well-conserved physiology. Eighty-four percent of the genes that participate in human disease also exist in zebrafish. Zebrafish studies provide a fast, inexpensive way to screen a large volume of chemicals, generate rich hypotheses for drug development, and prioritize candidates for toxicity studies with mammals and human cell cultures. We will compare our results with those of human cell culture studies to clarify the strengths and weaknesses of each method and to reduce the uncertainty associated with applying zebrafish results to human biology. We will post our experimental results in a public database that explains which of the 10,000 Tox21 chemicals are bioactive, which initial targets they strike, and which pathways lead to which endpoints in embryonic and juvenile zebrafish. This information will enable green chemists to detoxify products by substituting a biologically inactive molecule. It will help toxicologists and risk assessors to prioritize chemicals for expensive experiments with rodents and human cell cultures. It will give pharmaceutical scientists thousands of new data points upon which to develop hypotheses about how to modulate a given gene target or activate a given pathway. We will use machine-learning-based chemoinformatic approaches to analyze our zebrafish data and infer the relationship between the structure of a chemical and its biological activity. Our rich data about chemical activity networks will advance the scientific community’s understanding of linkages between chemical exposure and phenotypes. Our work will enable scientists to predict whether a chemical will be biologically active, what target it will act upon, and what networks it will perturb, solely on the basis of its structure. It will enable scientists to reduce, refine, and replace experiments with animals, including zebrafish, and to predict chemical activity networks with computers.

NIH Research Projects · FY 2025 · 2020-12

Groundwater contamination with volatile organic compounds (VOCs) is a widespread issue throughout the United States. Over 50% of more than 3500 groundwater samples collected from 98 major drinking water supply aquifers from 1985-2001 contained at least one anthropogenic contaminant, with VOCs detected most frequently. Among the top 15 VOCs detected, eight were chlorinated aliphatic hydrocarbons (CAHs): chloroform (CF), perchloroethylene (PCE), trichloroethylene (TCE), 1,1,1-trichloroethane (1,1,1-TCA), cis-1,2-dichloroethylene (cis-DCE), trans-1,2-dichloroethylene (trans-DCE), dichloromethane (DCM), and 1,1-dichloroethane (1,1-DCA). All of these CAHs are listed by the Centers for Disease Control and Prevention as being likely human carcinogens. Of increasing concern are emerging co-contaminants, such as 1,4-dioxane (1,4-D), which is also a likely human carcinogen. Common remediation techniques, such as pump-and-treat, are not sustainable for treating contaminant mixtures that slowly diffuse from low permeability zones in the subsurface. These issues highlight the need for long-term, passive, and economical remediation techniques. Passive and sustainable systems are proposed for the aerobic cometabolism of emerging contaminants, such as 1,4-D, that are mixed with CAHs. These passive systems will be created by co-encapsulating axenic bacterial cultures with a slow release compound (SRC) in hydrogel beads. The SRC will slowly hydrolyze in the beads to produce an alcohol, which will serve as a microbial growth substrate and as an inducer for non-specific contaminant-degrading monooxygenases. Groundwater contaminants will diffuse into the hydrogels where they will be cometabolically transformed to non-toxic products. In preliminary studies, the alkane-oxidizing bacterium Rhodococcus rhodochrous ATCC 21198 was co-encapsulated with an orthosilicate SRC in a gellan gum hydrogel. Continuous degradation of 1,1,1-TCA, cis-DCE, and 1,4-D was maintained for over 300 days. In the proposed work, proteomic analyses of this model bacterium will be performed to identify the active monooxygenases and to characterize the enzymatic and physiological changes that ultimately limit the long-term activity of this bacterium in the encapsulated systems. Genome- enabled approaches will also be used to rationally identify other microorganisms with different monooxygenase compliments that can also be co-encapsulated with SRCs to achieve the degradation of a broad range of emerging contaminants. Material science research will determine how to produce hydrogels beads that maintain mechanical integrity for extended periods, focusing on processes that can be easily scaled-up for producing large quantities of beads needed for in-situ treatment. The beads will then be used in different platforms at the laboratory scale to create passive permeable reactive barriers. The hydrogel beads might also be used for treating contaminated soils and sediments and other emerging contaminants.

NIH Research Projects · FY 2026 · 2020-07

SUMMARY/ABSTRACT: Overall The Strategic Vision of the Pacific Northwest Center for Translational Environmental Health Research (PNW EHSC) at Oregon State University is to facilitate innovative research to improve human health, reduce risks of exposure on human health, and advance co-development of knowledge of interactions between exposures and human biology. State-of-the-art Facility Cores intentionally chosen to empower Center members to investigate exposures and biological responses uniquely position the PNW EHSC as an essential research hub for environmental health science (EHS) researchers and interested parties (community groups, policy makers, and health-care professionals). Cores enable Center members to engage in EHS research with each other and, when opportunities arise, interested parties. The environmental health identity of the PNW EHSC thus uses concepts of exposure biology to explore fundamental EHS research questions to co-develop knowledge that will improve human health and reduce risks of exposure on human health. The Administrative Core provides the leadership and administrative and fiscal management to the Center. The Translational Research Support Core facilitates team building to address environmental health questions with a novel Research Discovery Index tool and provides technical support across a range of needs. The Community Engagement Core advances research translation across Cores and builds environmental health literacy in consultation with Center members and, when needed, interested parties. The Pilot Project Program accelerates innovation in EHS research through a model designed to fund Center members whose research will advance methodology, theory, cross-sectoral collaboration, or the establishment of new partnerships that have high research translation potential. The Chemical Exposure Core is a global leader in analytical approaches to support EHS research and has a variety of exposure assessment tools available for Center members. The Zebrafish Biomedical Research Core is the world’s largest specific-pathogen-free facility capable of developing transgenic and gene-edited zebrafish lines and other customizable assays for targeted phenotyping to support EHS research. The translational research vision of the PNW EHSC integrates Facility and Support Cores and builds from a framework of fundamental EHS research that addresses levels of biological organization from molecular to population, integration of systems biology evidence streams into experimental approaches, and co-development of data to knowledge that results in action where changes in understanding of interactions between expsoures and human are measured and/or assessed. The NIEHS mission to disvcover how the environment affects people in order to promote healthier lives is at the core of the PNW EHSC Strategic Vision. Center members are committed to EHS research that supports the NIEHS mission and is at the leading edge of exposure science, predictive toxicology, co-development of knowledge, and environmental health communications to researchers, community groups, policy makers, and health-care professionals.

NIH Research Projects · FY 2026 · 2019-12

Founded 125 years ago, the Oregon State University (OSU) College of Pharmacy is one of the oldest in the United States and has been a leader in natural products research since our predoctoral training program in Pharmaceutical Sciences began in 1952. Founded in 1973 by two-time Nobel Laureate Linus Pauling and housed in the state-of-the-art Linus Pauling Science Center on the OSU campus, the Linus Pauling Institute (LPI) remains focused on using micronutrients, phytochemicals, and dietary supplements to prevent disease and maintain human health. Our graduates occupy leadership positions in academia, industry, and government in the United States and throughout the world. Historically, natural products have accounted for over half of all therapeutic agents and are still the inspiration of nearly 40% of new drugs. Training young scientists for careers in natural products and dietary supplements research is a core mission of our College of Pharmacy and is the focus of this T32 training program. Addressing the need to train a new generation of experts in natural products and dietary supplements research, we established the first T32 training program in the history of the OSU College of Pharmacy in 2019 that currently enrolls five predoctoral trainees. In just four years, six trainees have graduated with Ph.D. degrees from this highly successful T32 program. Our leadership team includes co-Program Leaders with experience leading T32 training programs (Dr. van Breemen), experience serving as a director of graduate studies for our department (Dr. Mahmud), and experience mentoring dozens of Ph.D. and postdoctoral trainees (both co-Program Leaders). Our mentoring team has been expanded from 10 to 12 faculty with expertise in a variety of natural product and dietary supplement disciplines including marine, microbial, and botanical natural products and dietary supplements, natural product genomics, machine learning, natural products biosynthesis and chemical synthesis, natural product and dietary supplement nano-formulation and delivery, as well as natural product-based cancer therapy, chemoprevention, and pharmacology. This T32 training program is enhanced by exceptional institutional commitment in the forms of administrative, personnel, and financial support from the OSU College of Pharmacy, the Department of Pharmaceutical Sciences, and the OSU Graduate School. Based on our on-going success of graduating six Ph.D. students in just four years, experienced Program Leaders, expanded mentoring team, strong institutional support, and a successful recruiting approach that has increased the number of T32-eligible applicants each year, we propose to renew this T32 training program.

NIH Research Projects · FY 2026 · 2019-04

Project summary Cystic fibrosis (CF) is an autosomal genetic inherited disease caused by over 1,000 known mutations in the CFTR gene, which encodes an ion transporter. Gene therapy offers a single therapeutic solution to treat all CF patients, regardless of underlying mutation. Previous gene therapy approaches delivering CFTR DNA via viral or liposomal delivery have not proven clinically viable. Airway administration of CFTR mRNA packaged in lipid nanoparticles (LNPs) offers a promising therapeutic approach for CF patients that is non-invasive, repeatable, and safe. A recent Phase 1/2 clinical trial of CFTR mRNA delivery using repeated administration of inhaled CFTR mRNA-LNPs demonstrated clinical safety but did not adequately improve CF endpoints. Advances have been made in LNP material design and formulation for mRNA delivery to the lungs but clinical feasibility for CF treatment requires additional therapeutic improvements. One neglected area of innovation is modification and optimization of the delivered CFTR mRNA cargo. Current therapies use wild-type mRNA or basic codon optimization to increase translation efficiency of the CFTR mRNA. However, recent advances in AI-based design provide a significantly better method to optimize both protein translation levels and mRNA half-life. This optimization would improve the efficacy of CFTR mRNA therapy and potentially reduce dosage and administration frequency compared to current mRNA cargoes. Another technical limitation is the current nebulizer technology for aerosolization of LNPs, which physically disrupts nanoparticles, reducing their effectiveness and necessitating reformulation of LNPs that can diminish their efficacy and provoke immune responses. New nebulizer technology with reduced LNP disruption would enhance mRNA- LNP delivery and remove the need for deleterious reformulations. We propose to address the efficacy gap of inhaled mRNA-LNP therapies by completing the following objectives: 1) employ AI-based mRNA design with rapid in vitro screening to generate a therapeutic CFTR mRNA optimized for protein expression, half-life, and ion channel function; 2) utilize mRNA barcoding for rapid in vivo screening of longevity of these novel CFTR mRNA sequences delivered by nebulizer; and 3) evaluate therapeutic efficacy and safety of repeated inhaled administration of CFTR mRNA-LNPs using a novel microfluidic nebulizer device in a rat model of CF. These studies will advance inhalable mRNA-LNP therapies by applying new nebulizer and computational technologies to address overlooked aspects of airway mRNA-LNP delivery. This work evaluates new strategies in vitro and in vivo to improve clinical viability of inhalable LNP delivery of mRNA that provides a noninvasive and repeatable treatment for CF and other pulmonary diseases.

NIH Research Projects · FY 2024 · 2019-04

The majority of secreted and membrane proteins in eukaryotic cells are either translocated across or integrated into the ER membrane after the ribosome has docked at the start of the secretory pathway. This process can be selectively and reversibly blocked by a small group of macrocyclic natural products (NPs) produced by fungi, cyanobacteria and human pathogenic bacteria. These specialized NP metabolites bind directly to the Sec61 translocon channel to inhibit co-translational translocation of nascent proteins at the ER resulting in a loss of cellular proteostasis both in the ER and cytosol. Exactly how this group of NP compounds induces either selective or broad inhibition of protein biosynthesis with varying degrees of protein substrate selectivity is not clear. Maintenance of proteostasis is a highly regulated process in mammalian cells and the loss of homeostasis in the cellular secretory pathway is implicated in major human diseases such as cancer, neurodegeneration and diabetes. Thus, our discovery of new potent NP Sec61 inhibitors presents an opportunity to both understand the mechanistic basis of protein import into the ER secretory pathway and provide a reservoir of new Sec61 ligands and potential drug leads based on these complex chemical entities from Nature. We plan to utilize a multidisciplinary approach that includes NP discovery, solid-phase peptide synthesis of macrocycles, pharmacology, chemical and structural biology to pursue the following two aims: 1) Expand and define the class of nonpolar NP-derived macrocycles that target cotranslational translocation; 2) Elucidate the mechanistic basis of Sec61 inhibition using analysis of structure activity relationships (SAR) and cryogenic electron microscopy (cryoEM). In Aim 1, existing NP libraries likely to be rich in non-polar medium-sized macrocycles will be screened for new proteostasis modulators using phenotypic and target-based assays for Sec61-dependent inhibition of ER translocation. Early determination of structural motifs using LCMS2-based metabolomics, NMR spectroscopy and cheminformatics will guide the solid phase peptide synthesis of divergent representatives of NP molecular families to provide a platform for discovery of Sec61 ligands for structural biology studies. In Aim 2 we propose to use cryo-EM to study the specific Sec61 binding of two different NP molecular families by analyzing the Sec61 binding interface of suites of closely related synthetic compounds that have different Sec61 substrate specificity. This multidimensional approach will reveal the feasibility of targeting cellular proteostasis for therapeutic needs, while avoiding toxicities due to non-specific inhibition of secretory protein biosynthesis.

NIH Research Projects · FY 2025 · 2019-01

Schistosomiasis is by far the most important helminth parasitic disease of humans. Vaccines are unavailable, the only effective treatment involves repeated dosing with a single drug, and drug resistance is now a major concern. Schistosomes require aquatic snails for transmission. Mass drug administration alone has proven ineffective at eliminating schistosomiasis. It is now widely accepted that an integrated approach that includes targeting the snail stage is essential. Yet current snail control strategies are unsustainable, involving toxic chemicals or introduced predators or competitors. New approaches are needed to break transmission at the snail stage. Understanding the molecular mechanisms by which snails and schistosomes interact is key for finding new strategies to interrupt transmission. Yet knowledge about molluscan immunology is far from adequate, and decades of painstaking research on the molecular basis of snail-schistosome compatibility have yielded just a handful of candidate genes and mechanisms. BS90 is a highly resistant strain of Biomphalaria glabrata (Bg) that, until recently, was considered completely resistant to all known strains of Schistosoma mansoni (Sm). BS90 has been the subject of many functional studies of why it is so resistant to infection by Sm. So finding the genes behind that trait would be a major advance. We recently determined that two genomic regions we previously discovered using another snail population are involved, and that one or more additional loci still need to be mapped. One strain of Sm can infect some BS90 snails, but there is genetic variation within the outbred BS90 population for susceptibility. In preliminary work we found that a gene in, or linked to, a region we named PTC2 is involved in this resistance polymorphism. The susceptible haplotype appears to act dominantly, suggesting that some molecule on the parasite side must bind to something on the host side to evade the host immune response. Thus, finding the snail protein involved could lead to a key ligand used by schistosomes to defeat the Bg immune response. We will use a combination of GWAS and QTL mapping approaches to narrow down (1) the remaining genomic regions in BS90 snails that make them more resistant to Sm than other populations of snails, and (2) the region/s that control susceptibility to the one strain of Sm that can infect BS90. We will annotate and rank candidate genes within each region (based on predicted function and on sequence or expression difference between haplotypes). Then test candidate genes using RNAi and/or CRISPR knock-out lines. Identifying new resistance genes will substantially advance our knowledge of snail-schistosome immunology. We hope to eventually be able to genetically manipulate natural snail populations to make them less able to transmit schistosomes. Identifying key resistance genes and characterizing their function will be an essential first step toward that goal.

NIH Research Projects · FY 2025 · 2018-08

A common reason cited for dental composite replacement is the recurrence of caries around existing restorations due to microbial activity. Treatment typically involves the removal of decayed tooth structure and placement of a new restoration. Since the microbial environment remains the same, the new tooth-restoration complex may also be susceptible to failure. Thus, the problem is not adequately addressed in current dental treatment approaches. More innovative materials are required that can purposefully bias the microbial environment toward improved health. Our preliminary data demonstrate that Mg2+ or Zn2+ released from bioactive glass (BAG)-containing resin composites can support a healthy microbial environment, thus directly addressing the root of the caries problem. Here we propose a new strategy involving Mg2+-and Zn2+-releasing dental composites that can favorably alter the microbiome on and around dental restorations such that the local pH >5.5. AIM 1: Optimize Mg2+- and Zn2+-releasing bioactive glass (BAG)-containing dental composites for long-term support of a healthy oral microbiome. Scanning electrochemical microscopy (SECM) will be used to optimize pH dependent Mg2+ and Zn2+ release kinetics from different Mg- and Zn-BAG formulations. Later, dental plaque derived multi species biofilm growth rate, volume, species composition and pH at the BAG surface will be quantified and optimized such that local pH > 5.5. AIM 2: Test the effectiveness of new Mg-BAG and Zn-BAG composites in an in vitro secondary caries model. Placement of a restoration has the inherent challenge of gap formation between the dental material and the tooth structure. Currently, little information is available on how bacteria behave in microgaps. For example, microbial colonization, diffusion rates, and organic acid metabolites may be very different within gaps as compared to exposed surfaces in the oral cavity, potentially leading to enhanced tooth decay at the interface. Here we will develop an in vitro microgap model using the electrochemical sensors techniques to measure the biological activity and the effect on the microbial population in these microenvironments such that local pH > 5.5. AIM 3: In situ evaluation of Mg-BAG and Zn-BAG composites with intraoral appliances. The cytotoxicity of Mg-BAG and Zn-BAG will be tested using undifferentiated dental pulp cells compared to standard dental composites. The in vitro optimized Mg-BAG and Zn-BAG composites that are shown to have equal or lower cytotoxicity than typical composite will be placed in intraoral appliances to be tested in volunteers. This real-life scenario will evaluate the effectiveness of the composites when all biologically relevant parameters are present that potentially interfere with the performance of Mg-BAG and Zn-BAG composites. This will also provide a direct comparison between the in vitro model and the clinical situation. Our proposal will lay the foundation for further metal ions driven research on biofilm growth and behavior, as well as for the development of a more realistic in vitro secondary caries model that includes chemical microenvironments created by differential biofilm metabolic activities within microscopic gaps.

NIH Research Projects · FY 2025 · 2017-08

ABSTRACT The OVDL wishes to continue our cooperative agreement with the Vet-LIRN to help provide essential rapid communication, coordination, testing, and surge capacity necessary to support the FDA’s response to a contamination event, disease surveillance and method development. The requested funds will help offset costs incurred as the OVDL expands its on-going state-supported animal health diagnostic and surveillance activities to include supporting the mission of the Vet-LIRN. This will be accomplished by the OVDL’s participation in three major efforts: 1. Participation in FDA/Vet-LIRN sample analysis: The OVDL will provide experienced microbiologists, pathologists, and lab technicians, as well as administrative personnel, to assist FDA/Vet-LIRN during food/drug emergencies. This will include surveillance testing as designated by the VPO, outbreak testing, and surge capacity in times of need. 2. Providing analytical data for potential regulatory use: The OVDL will utilize standardized methods, equipment platforms, and reporting methods for specimen testing. OVDL personnel will participate in method training and proficiency testing as directed by the VPO. The OVDL’s quality program will be complemented by standardized quality management systems required by participation in the FDA/Vet-LIRN program. 3. Participate in small scale method development, method validation, and matrix extension as determined by the VPO: Experienced OVDL personnel appropriate to the discipline will participate in method development and validation, and matrix extension, to support the growth of the Vet-LIRN response network. The Oregon Veterinary Diagnostic Laboratory (OVDL) wishes to continue our collaboration with the Food and Drug Administration Veterinary Laboratory Investigation and Response Network (Vet-LIRN) wherein the OVDL will provide sample analysis, analytical data for regulatory use, and support for small scale method development and validation. These veterinary diagnostic testing activities support the Vet-LIRN’s objectives of facilitating early detection of animal food/drug adulteration or contamination as a component of the FDA’s overall responsibilities in these endeavors. Surveillance and testing for feed contamination in our animal populations promotes public health by protecting our nation’s food supply as well as our companion animals.

NIH Research Projects · FY 2024 · 2015-07

The role of reactive nitrogen species in over eighty human diseases including atherosclerosis, cancer, neurodegeneration, and stroke is well demonstrated by the accumulation of the biomarker 3-nitrotyrosine (nitroTyr). NitroTyr is not randomly distributed across the proteome as might be expected, but rather is found on specific tyrosines on specific proteins. In response to these observations, the PI has greatly advanced this field by developing genetic code expansion (GCE) technologies enabling site-specific incorporation of nitroTyr into recombinant proteins in bacteria and mammalian cells. Collaborative work using these tools has now firmly established that nitroTyr-proteins are causative agents in amyotrophic lateral sclerosis, atherosclerosis, and cancer, supporting our central hypothesis that nitroTyr-modified proteins are key players in human disease and that understanding the basis for their accumulation and removal, as well as their mechanistic roles in pathology will lead to new opportunities for therapeutic intervention. Further support comes from the breakthrough discovery of a denitrase enzyme that is a tumor suppressor: the “D2” pseudo-phosphatase domain of the protein tyrosine phosphatase receptor T (PTPRTD2) is a tyrosine denitrase that when knocked out promotes cancer growth. This upends the paradigm that nitroTyr-proteins are an unregulated by-product of stress and makes possible a new research strategy that should accelerate progress. Instead of identifying specific diseases and associated nitroTyr modified proteins one at a time, under the hypothesis that this denitrase represents a new enzyme family involved in regulating the impact of nitroTyr, characterizing these denitrases and the breadth of their substrates should speed the identification of physiologically relevant nitroTyr modifications and also provide new avenues to define their impact. This will be done through pursuing two aims that encompass: (1) defining the denitrase substrate scope and the structure-function relationships critical for substrate recognition, and (2) converting denitrases and their substrates into traps and inhibitors which will be used to identify denitrase/substrate pairs and aid studies of their physiological/pathological impacts in cells. Preliminary work demonstrating feasibility has already identified two additional denitrase substrates, which have altered function upon site-specific nitration. The proposed work to define what nitroTyr proteins are substrates of denitrases will also help resolve why nitrated proteins accumulate in disease, and for every case in which it is discovered that a denitrase/nitroTyr-substrate pair contribute to pathology development, the mapping of that process will open up a new avenue for therapeutic intervention. As (i) the developer of existing nitroTyr GCE technologies, (ii) an enzymologist and (iii) acting director of the Unnatural Protein Facility, the PI is superbly qualified to lead this work and all needed facilities are available. Furthermore, key collaborators are already engaged who bring the expertise in structural biology and cell biology needed for the breadth of work proposed.

NIH Research Projects · FY 2025 · 2011-09

PROJECT SUMMARY Leptin, originally identified as a regulator of energy metabolism, is required for normal bone growth and turnover, making the adipokine an attractive candidate for coupling optimal bone accrual and turnover balance to energy availability. However, not all skeletal actions of leptin are beneficial; there is compelling evidence that leptin contributes to aging-related skeletal pathologies by promoting a proinflammatory cascade mediating inflammation-driven bone loss. The molecular mechanisms mediating the skeletal actions are poorly defined. We have strong preliminary data indicating that leptin influences bone metabolism, both beneficially and detrimentally, by activating leptin receptor (OB-R) on cells (predominately immune cells) derived from hematopoietic stem cells (HSCs). Based on this, we hypothesize that: (1) leptin signaling by immune cells is necessary for normal bone growth, maturation and turnover, but (2) in the presence of chronic inflammation, leptin signaling by immune cells promotes net bone loss. The proposed research will test these hypotheses in male and female mice by accomplishing two Specific Aims. Specific Aim 1: Determine the contribution of leptin signaling by immune cells to bone accrual and turnover balance. We will reconstitute the immune system of growing and adult male and female mice with HSCs from OB-R+ wild type (WT) or OB-R- db/db mice using adoptive transfer to establish the overall contribution of OB-R on immune cells to leptin regulation of bone accrual in growing mice and turnover balance in adult mice, respectively. We will then determine if the skeletal actions of leptin are primarily mediated via OB-R on cells in the osteoclast lineage by adoptively transferring OB-R+ and OB-R- monocytes into mice with reduced ability to form osteoclasts (Ccr2- mice). Specific Aim 2: Determine the contribution of leptin signaling by immune cells to inflammation-driven bone loss. We will reconstitute the immune system of growing and adult male and female mice with HSCs from OB-R+ or OB-R- mice as in Specific Aim 1 and induce local inflammation by placing polyethylene particles over calvaria to model aseptic periprosthetic bone loss. These studies will establish the overall contribution of OB-R on immune cells to inflammation-driven bone loss. The contribution of OB-R on immune cell subsets to normal bone turnover balance and particle-induced osteolysis in adult mice will then be evaluated following engraftment of subsets of OB-R+ and OB-R- immune cells into mice unable to generate/recruit monocytes (Ccr2-), T-cells (Tcra KO), B-cells (muMT-), or mast cells (KitW-sh). Successful completion of this research will have a major impact on the field by expanding existing concepts regarding the role of leptin in skeletal health and disease. Our approach will provide a powerful tool for unraveling mechanisms mediating the complex actions of leptin on the skeleton and immune systems. The proposed research has the potential to provide new insights for the development of interventions to interrupt leptin-mediated inflammatory cascades without compromising the beneficial skeletal actions of the adipokine.

NIH Research Projects · FY 2026 · 2009-09

SUMMARY – OVERALL CENTER The mission of the Oregon State University (OSU) SRP Center is to identify polycyclic aromatic hydrocarbons (PAHs) in the environment, to characterize their toxicity, and to specify the environmental concentrations below which they pose no threat to human health. The OSU SRC will study the composition of complex PAH mixtures, the changes in composition after remediation and natural attenuation, and the implications of PAH mixtures for human health. The scientific community does not fully understand the toxicity of structurally diverse, substituted PAHs, nor the toxicity of complex environmental PAH mixtures. We do not fully understand the degree to which typical environmental exposures to PAHs threaten human health, particularly in vulnerable populations. We cannot yet predict the biological effects of complex PAH mixtures. We cannot identify the sources of PAHs. Site managers, being unable to distinguish between PAHs from legacy sources (such as petrochemical plants) and PAHs from contemporary sources (such as wildfires), cannot optimize their remediation plans, nor can they evaluate their remediation efforts. Communities can apply passive sampling devices to determine whether they are being exposed to PAHs, but they do not know the sources of those PAHs and therefore cannot devise effective plans to protect themselves. The OSU SRP Center proposes to answer these scientific questions: What doses of PAHs and a-PAHs (what is that?) can cause cancer and evoke other adverse responses in humans? Do typical environmental exposures to PAHs threaten human health? By what biological mechanisms do PAHs exert adverse effects? How does the toxicity of PAHs depend on their chemical structures? Can long-term zebrafish studies evaluate the carcinogenicity of PAHs? Can we identify gene expression pathways specific to each category of PAHs? Do common genetic polymorphisms alter toxicity and subsequent risk to PAH exposure and thereby allow us to identify susceptible individuals? How does the toxicity of PAHs and PAH mixtures depend on variations in susceptibility caused by stressors? How can we identify the components in a complex PAH mixture that are causing additive, synergistic, or antagonistic toxicity? How do novel and abundant a-PAHs contribute to toxicity in mixtures? Can current remediation techniques reduce human health hazards? How can we develop novel, safe, sustainable systems that treat PAH mixtures while minimizing the formation of hazardous PAH breakdown products? How do PAHs move into, through, and away from Superfund sites? How can we identify the sources of PAHs in ways that not only enable communities to minimize their exposure but also enable remediators to optimize their remediation plans and evaluate their remediation efforts?

NIH Research Projects · FY 2025 · 1979-07

PROJECT SUMMARY/ABSTRACT The mission of the Integrated Regional Training Program in Environmental Health Sciences (IRTP) at Oregon State University (OSU) is to provide structured scientific, professional, and career development opportunities to train the next generation of environmental health science (EHS) researchers in toxicology, environmental chemistry, molecular biology, risk analysis, public health, and big data analytics, with an emphasis on transdisciplinary opportunities in exposure biology and co-development of knowledge. Renewal funding is requested to support eight predoctoral and two postdoctoral trainees. The pool of applicants is exceptional and competitive, and applicants are selected by the Co-Directors in consultation with the Internal Advisory Committee. The IRTP is administered by the Pacific Northwest Center for Translational Environmental Health Research (PNW EHSC), a NIEHS-funded P30 Environmental Health Sciences Center at OSU, which provides leadership and staffing support. The academic home of the IRTP is the Department of Environmental and Molecular Toxicology at OSU, which provides curricular and other academic support for most trainees. EMT has a tripartite mission of 1) educating students in toxicological sciences; 2) conducting research on the effects of chemicals and other agents on humans and the environment; and 3) engaging the public through extension and outreach. EMT is ideally positioned to function as the academic home of the IRTP, due to the focus on creating, disseminating, and applying new knowledge to enhance the treatment and prevention of human disease and to ensure protection of environmental public health. The IRTP also cooperates with regional partners at Oregon Health & Science University (OHSU) and the Pacific Northwest National Laboratory (PNNL) to provide mentors with expanded depth and breadth of expertise in aspects of translational research and data science that are not immediately available at OSU. The primary goals of the IRTP are to 1) recruit a diverse cohort of EHS trainees; 2) provide individualized transdisciplinary and experiential learning in EHS through individual development plans (IDP) for each trainee; and 3) provide networking and career development opportunities in EHS research. To this end, OSU is uniquely positioned to provide pre- and postdoctoral trainees exceptional transdisciplinary training in EHS. IDPs continue to be a foundational framework to promote the best combination of required and elective interdisciplinary training and professional development. Trainees acquire core competencies through required elements and have the flexibility to develop skills for career-specific success. Major strengths the IRTP continue to center around highly productive and collaborative training faculty, multidisciplinary educational curriculum, and the unique collaborative training environment provided by OSU, OHSU, and PNNL. The mentor cohort includes over 30 faculty, offering a wide diversity of training topics in EHS. Former trainees continue to make major contributions in the academic, public, and private sectors, demonstrating the effectiveness of the IRTP.

Other NSERC · FY 2024

Geophysics, Glaciology, Physical Geography, Cryosphere, Polar Sciences, Antarctica

Other NSERC · FY 2024

Predator prey interaction, Anti-predation adaptation, Interspecific co-evolution, Aggressive mimicry, Batesian mimicry, Behavioral experiments, Entomology, Herpetology, Ornithology, Phylogenetic