Oregon Health & Science University

NIH Research Projects · FY 2026 · 2024-06

The Oregon Health & Science University School of Dentistry (OHSU SOD) is launching a new initiative to promote oral healthcare careers among high school learners. Most high schoolers have extremely limited knowledge of dental and dental research career paths in healthcare and may not have considered oral health as a viable track. Oregon especially has a need for oral health care providers in rural areas. This proposal will take the first step to meet these needs by immersing and engaging high school scholars locally and from around Oregon and Washington, in pathways to careers in dentistry and dental, oral, and craniofacial research. We are seeking to raise awareness of and provide opportunities for oral health-related research internships and clinical experiences. There is currently no program in Oregon and the surrounding region that provides such experiences, and as the only dental school in the state, OHSU SOD is uniquely qualified to deliver cutting-edge research and clinical care experiences to our high schooler scholars. A team of OHSU SOD faculty will provide an explorer’s program throughout the school year, a paid summer research experience, and touchpoint activities such as preview days and outreach activities around the state to open the windows to learners to the careers in the oral health field. Our WINDOWS program will be a model to other schools across the country of a pathway program for high school learners integrating research with clinical dentistry and integrating oral health research with biomedical research.

NIH Research Projects · FY 2026 · 2024-06

Project Summary Substance P is a sensory nerve tachykinin neuropeptide capable of inducing bronchoconstriction and inflammation. We have recently shown that airway sensory nerve density and neuronal substance P expression are significantly increased in humans with eosinophilic asthma. We have also demonstrated that mice born to allergen-sensitized mothers or transgenic mothers with elevated interleukin-5 (a primary cytokine involved in eosinophil maturation and survival) recapitulate key features of human asthma including increased airway sensory nerve density and substance P expression. When these offspring are exposed to allergen, they develop lethal bronchoconstriction that is rescued by antagonists of substance P's target, neurokinin-1 receptors. The central hypothesis of this proposal is that increased airway substance P innervation causes lethal bronchoconstriction and potentiates eosinophilic inflammation after allergen challenge. In this proposal, we will determine the mechanism by which substance P mediates these effects using both cre-recombinase and pharmacologic methodology to 1) test the role of NK1 receptors on specific airway nerve subtypes (sensory and parasympathetic nerves) and smooth muscle 2) test the role of NK1 receptors and a novel substance P receptor, MrgprA1, on airway dendritic cells and 3) test the role of NK1 receptors on airway eosinophils both in isolation, and synergistically with CCR3 (the target of eotaxin, a potent eosinophil chemoattractant). Endpoints include measurement of airway responsiveness in vivo, eosinophil and dendritic cell activation using flow cytometry, and quantitative assessments of airway nerve density, substance P expression, and eosinophil and dendritic cell interactions with nerves using novel 3D confocal microscopy developed by our group. Results will identify novel pathways and drug targets in severe asthma.

NIH Research Projects · FY 2026 · 2024-06

Project summary Medicaid is an important source of health insurance for people with substance use disorder (SUD), currently covering approximately one in five adults with SUD. States have increasingly contracted with Managed Care Or- ganizations (MCOs) to administer services for their Medicaid population. They have also increasingly included, or carved in, behavioral health services into MCO plans. As a result of these trends, 31 states and Puerto Rico now enroll their Medicaid SUD population through MCOs. States determine, through a competitive procurement process, whether to renew or to end contracts with MCOs operating in their state, and whether to contract with new MCOs. Such MCO transitions may improve access and quality of care for Medicaid enrollees with SUD, but they may also lead to service disruptions that can negatively affect uptake and continuity of care for this vul- nerable population. Despite the importance of the MCO contracting process, little is known whether states are successful in removing low-performing MCOs and selecting high-performing MCOs through the procurement process, and what kind of state and MCO characteristics determine a successful procurement outcome. In this application, we propose a mixed-methods study to examine the effects of MCOs entries and exits as a result of the procurement process, and to explore factors at the state and MCO level that contribute to high- performing MCOs being selected to operate in a state and low-performing MCOs being removed from a state's Medicaid market. We will use the Transformed Medicaid Statistical Information System Analytic Files (TAF), a national Medicaid data file, and collect information about the procurement process, MCO contracts, and per- formance requirements through semi-structured interviews of experts and leaders from states' Medicaid agen- cies and MCOs. Using a difference-in-differences approach, we will investigate the effects of MCO transitions on provider networks (Aim 1) and quality of care as well as health care utilization (Aim 2). Our Aim 3 mixed- methods analysis will bring together quantitative results with qualitative findings of MCO and state character- istics to identify factors that can explain a more or less successful procurement process outcome. This policy- relevant work will provide comprehensive evidence into how state Medicaid agencies can design their MCO pro- curement and monitoring process to improve health care delivery for Medicaid enrollees with SUD.

NIH Research Projects · FY 2025 · 2024-06

Project Abstract Patients with cancer face unacceptable morbidity and mortality from sepsis, a life-threatening dysregulated response to infection. Oncologic sepsis contributes to > 15% of cancer hospitalizations and 10% of cancer deaths in the US, with far greater morbidity and mortality than noncancer sepsis. Timely evidence-based sepsis care bundles improve outcomes, but are frequently initiated too late or not at all in cancer, suggesting that earlier accurate recognition may improve care and outcomes. Current approaches to detecting and treating oncologic sepsis suffer from interrelated limitations including poor accuracy of sepsis prediction tools in patients with cancer as well as general and oncology-specific barriers to their effective implementation. This Career Development Award will support Patrick G Lyons, MD, MS, in addressing this challenge while completing his development into an independent physician-investigator with the training and experience necessary to improve cancer care delivery in the hospital. The overall goal of Sepsis Prediction in Oncology Through Implementation Science and Technology (SPOT-IT) is to use EHR data to develop an oncology- specific sepsis prediction model using machine learning and to use human centered design methods to design and evaluate the usability of a stakeholder-informed implementation strategy for this model. These themes fit with the NCI’s goal of “rapid development, testing, and refinement of innovative approaches to implement... evidence-based cancer control interventions” and the DCCPS’s priority areas in healthcare delivery research and implementation science and are reflected in the Aims: 1) develop an oncology-specific sepsis prediction model using machine learning on EHR data; 2) design and refine implementation strategies to improve oncologic sepsis management; and 3) conduct a pilot trial to determine the early implementation and process outcomes of SPOT-IT. These Aims link to Dr. Lyons’s career development objectives: 1) develop core cancer care delivery knowledge, (2) enrich his knowledge in sepsis epidemiology and outcomes, (3) advance his skills in machine learning and informatics, (4) gain advanced skills in implementation science and human centered design, and (5) enhance his scientific leadership skills. Dr. Lyons will achieve these goals via a 5-year career development plan incorporating didactics, fieldwork and experiential research, and intensive mentoring by Terri Hough, MD (an international leader in sepsis epidemiology and pragmatic implementation research), Brandon Hayes-Lattin, MD (an oncologist specializing in stem-cell transplantation and clinical trials), and Matthew Churpek, MD, PhD (a critical care physician and informaticist with expertise in machine learning using EHR data). Dr. Lyons’s experienced multidisciplinary team of mentors and advisors, combined with the exceptional research environment at Oregon Health & Science University, will provide the support and training necessary to achieve his long-term goal of becoming a leading cancer care delivery scientist.

NIH Research Projects · FY 2026 · 2024-06

Project Summary: A lack of coordination between Medicare and Medicaid services creates a fragmented care system for dually eligible beneficiaries and can increase their risk for poor health outcomes. Dually eligible individuals with Alzheimer's disease and related dementias (ADRD) are exceptionally vulnerable under this fragmented care system. They often need extensive acute care (paid by Medicare) and long-term care (paid by Medicaid) but experience functional and cognitive declines, which compound the challenges of navigating the complex, bifurcated systems of Medicare and Medicaid. Integrating Medicaid-paid long-term care into Medicare services (termed “long-term care integration” hereafter) can improve care coordination for dually eligible individuals with ADRD. Under long-term care integration, people receive Medicaid-paid long-term care and Medicare services from the same insurance company. In this case, the single company bears financial risk for both Medicare services and Medicaid long- term care and is therefore incentivized to coordinate Medicare services and Medicaid long-term care. A common mechanism for long-term care integration is the dual-eligible special needs plan (D-SNP). Long-term care integration occurs through D-SNPs in two ways. First, some D-SNPs bear financial risk for both Medicare services and Medicaid long-term care (which we refer to as “single-capitated D-SNPs”). Second, people can receive Medicare services from a D-SNP and long-term care from a separate managed care plan, both of which are operated by the same parent insurance company (which we refer to as “aligned D-SNP”). D-SNPs is a significant force in long-term care integration, with substantial increases in enrollments in single-capitated or aligned D-SNPs over the past decade. Recognizing their importance, Congress permanently authorized and refined the utilization of the D-SNP for long-term care integration in 2018. However, this rapid adoption of the D-SNP for long-term care integration lacks rigorous empirical evidence. Our long-term goal is to provide a rigorous empirical evaluation of single-capitated and aligned D- SNPs, ultimately supporting evidence-based policies that can improve outcomes for dually eligible individuals with ADRD. Leveraging 2018-2024 Medicare claims linked with Medicaid claims, this proposal will adopt a staggered difference-in-differences approach to obtain the causal effects of single-capitated and aligned D- SNPs on key outcomes. We will accomplish three aims. First, we assess the effect of single-capitated D-SNPs. Second, we assess the effect of aligned D-SNPs and compare the effect of aligned vs single-capitated D- SNPs. Third, we assess the effect of aligned D-SNPs by plan characteristics. As an increasing number of dually eligible individuals continue to enroll in single-capitated or aligned D- SNPs, our study will provide urgently needed information about the effects of single-capitated and aligned D- SNPs for dually eligible individuals with ADRD.

NIH Research Projects · FY 2026 · 2024-05

Project Summary Dental caries is a global infectious disease impacting the lives of 80% of the human population. Severe early childhood caries (SECC) is of particular concern and characterized by extensive tooth decay that can dramatically affect the dental health of children under six years of age. This constitutes a significant economic burden, can have dramatic impact on the child’s well being and may contribute to overall health later in life. Streptococcus mutans is the bacterium most commonly associated with initiation of SECC and early childhood caries (ECC). Biosynthetic gene clusters (BGCs) in bacteria often encode genes for small molecules and other antimicrobial peptides. This research plan proposes to investigate a novel BGC (butyrolactone-ladderane hybrid, BL-BGC) of S. mutans from a high caries risk population to identify its impact on S. mutans virulence and survival traits. Preliminary data suggests the BL-BGC is significantly up regulated in dental caries and occurs in the most prevalent strain type of S. mutans within a high-caries risk study population. The hypothesis is that clinical S. mutans strains with the BL-BGC will have increased virulence properties and cariogenicity. Aim 1 will characterize phenotypes of clinical S. mutans strains containing the BL- BGC and their association with dental caries key virulence and survival traits using gene mutagenesis and in-vivo biofilm analysis. Aim 2 will determine the impact of BL-BGC on expression of virulence genes and metabolites in S. mutans biofilms using RNA-sequencing and metabolomics analysis. Aim 3 will determine the how BL-BGC impacts S. mutans colonization and virulence using animal models of dental caries. The proposed study will elucidate the role of BL-BGC in S. mutans virulence and fitness during the K99 phase. Metabolites produced by S. mutans with BL-BGC impacting key virulence traits will be purified and characterized in the R00 phase, providing new insights into S. mutans’ role in the pathogenesis of dental caries. Characterization of this and other BGCs may lead to new therapeutic targets designed to reduce, reverse, or even prevent SECC. The K99 phase of this award will provide the time and support for additional research training, building effective collaborations, enhancing professional development and submission of publications leading to a successful transition to an independent academic research appointment in the R00 phase. This study is unique in the use of BGCs from clinical S. mutans isolates from a high-risk caries population allowing for clinical translation of results and the use of metabolomics for identification of BL-BGC related compounds/metabolites. This study will enable an independent career path by establishing a multidisciplinary program utilizing molecular biology approaches to validate epidemiological associations, bridging these fields and advancing the knowledge of S. mutans virulence in caries.

NIH Research Projects · FY 2025 · 2024-05

Project Summary This U01 proposal is submitted in response to the NIMH IMPACT RFA (RFA-MH-23-105). It will extend research efforts to both define novel, deployable behavioral phenotypes (highlighting cognitive and emotional transdiagnostic measures) and develop and test diagnostic and prognostic prediction models, using advanced analytics, within the clinic setting. It does so for children aged 7-17, presenting with common forms of psychopathology, characterized by dysregulation of attention, behavior, and/or emotion. Aim 1 uses established longitudinal research cohorts to further refine computational phenotypes for cognition (executive functions, alertness/arousal) and low-cost trait ratings relevant to emotional regulation and valence, and in combination with key environmental variables, tests their cross-sectional and longitudinal predictive utility using machine learning models. Aim 2 uses large electronic medical record (EMR) data to refine sophisticated neural network models to enhance mental health diagnostics and outcome prediction in children. Aims 3 and 4 entail new data collection of several thousand patients in four pediatric and psychiatry clinic sites around the country, and then combines and extends findings from Aims 1 and 2 to test their diagnostic and prognostic effectiveness in these diverse patient populations. The study is significant in its potential to open the way for clinical care to benefit from years of scientific progress in phenotype refinement that are low cost and deployable. It is further significant in its potential to harvest from existing EMR data far more clinically useful prediction algorithms than are currently available. The inclusion of sequential Bayesian logic for aiding clinicians in deciding which cases require additional assessment and which do not will be transformative in opening a path for significant savings in cost and clinician time by improving efficiency of care. The ability to better predict critical outcomes, such as worsening of mental health symptoms, suicidality, or increased resource utilization is urgent and will be addressed in our work. This project is innovative in combining large machine learning models from EMR data with similar models using novel research phenotypes and will be the first prospective test of these models in patients recruited from active clinics in multiple locations to evaluate generalizability. Further significance and innovation are added by careful attention to the role of environmental adversity and extensive plans to minimize or overcome the asynchronous benefit of such efforts to historically under-served and under-represented populations. The project directly, significantly, and with innovation addresses the goals and purpose of the IMPACT RFA by aiming to demonstrate how novel behavioral phenotypes can enhance clinical care even as maximum value is extracted from EMR data already in hand.

NIH Research Projects · FY 2026 · 2024-05

Project Summary This U01 proposal is submitted in response to the NIMH IMPACT RFA (RFA-MH-23-105). It will extend research efforts to both define novel, deployable behavioral phenotypes (highlighting cognitive and emotional transdiagnostic measures) and develop and test diagnostic and prognostic prediction models, using advanced analytics, within the clinic setting. It does so for children aged 7-17, presenting with common forms of psychopathology, characterized by dysregulation of attention, behavior, and/or emotion. Aim 1 uses established longitudinal research cohorts to further refine computational phenotypes for cognition (executive functions, alertness/arousal) and low-cost trait ratings relevant to emotional regulation and valence, and in combination with key environmental variables, tests their cross-sectional and longitudinal predictive utility using machine learning models. Aim 2 uses large electronic medical record (EMR) data to refine sophisticated neural network models to enhance mental health diagnostics and outcome prediction in children. Aims 3 and 4 entail new data collection of several thousand patients in four pediatric and psychiatry clinic sites around the country, and then combines and extends findings from Aims 1 and 2 to test their diagnostic and prognostic effectiveness in these diverse patient populations. The study is significant in its potential to open the way for clinical care to benefit from years of scientific progress in phenotype refinement that are low cost and deployable. It is further significant in its potential to harvest from existing EMR data far more clinically useful prediction algorithms than are currently available. The inclusion of sequential Bayesian logic for aiding clinicians in deciding which cases require additional assessment and which do not will be transformative in opening a path for significant savings in cost and clinician time by improving efficiency of care. The ability to better predict critical outcomes, such as worsening of mental health symptoms, suicidality, or increased resource utilization is urgent and will be addressed in our work. This project is innovative in combining large machine learning models from EMR data with similar models using novel research phenotypes and will be the first prospective test of these models in patients recruited from active clinics in multiple locations to evaluate generalizability. Further significance and innovation are added by careful attention to the role of environmental adversity and extensive plans to minimize or overcome the asynchronous benefit of such efforts to historically under-served and under-represented populations. The project directly, significantly, and with innovation addresses the goals and purpose of the IMPACT RFA by aiming to demonstrate how novel behavioral phenotypes can enhance clinical care even as maximum value is extracted from EMR data already in hand.

NIH Research Projects · FY 2026 · 2024-05

ABSTRACT Leveraging neuroinflammation to improve treatment outcomes for patients with glioblastoma is challenging because the hypoxic tumor immune microenvironment (TIME), mostly comprised of immuno-suppressive tumor-associated macrophages (TAMs), remains incompletely quantified and therapeutically modulated. The long-term goal is to accelerate the development of clinically meaningful imaging technologies as a way to advance therapeutic approaches for patients with deadly brain malignancies. The overall objective in this application is to use novel iron nanoparticle enhanced 18F-fluoromisonidazole PET/MRI derived Segregation and Extravascular Localization of Ferumoxytol Imaging (SELFI) hypoxic fraction to quantitatively determine how hypoxia and TAM based neuroinflammation relate to treatment sensitivity. The central hypothesis is that therapeutic modulation of TAMs, as monitored by SELFI Hypoxic Fraction, ameliorates hypoxic TIME immunosuppression leading to improved treatment outcomes. The rationale for the proposed research is that quantitative elucidation of how the hypoxic TIME relates to treatment outcomes is likely to provide a strong scientific framework whereby new TAM based therapeutic strategies can be developed. The central hypothesis will be tested by pursuing two specific aims: 1) Define a biologically specific imaging measure of the immuno- suppressive hypoxic TIME; and 2) Determine the effect of TAM modulators on the TIME of glioblastoma. Under the first aim, SELFI hypoxic fraction will be optimized and biologically validated in a cohort of 27 patients with IDH wild type glioblastoma needing surgical intervention for the diagnosis of treatment outcome. Additionally, the diagnostic and prognostic performance will be determined through longitudinal assessment of the hypoxic TIME in a prospective phase II clinical trial of 50 adult patients with newly diagnosed IDH wild type glioblastoma scheduled for standard therapy. For the second aim, syngeneic and patient derived xenograft intracerebral glioblastoma rodent models will be used to determine the cytotoxicity and neuroinflammatory capability of concurrent TAM modulation and activation. Additionally, the TIME alterations responsible for treatment efficacy will be defined. The research proposed in this application is innovative, in the applicant's opinion, because the SELFI hypoxic fraction is likely to provide a new method for quantifying treatment outcomes. This capability is likely to directly monitor biological features of efficacious therapeutic TAM modulation. The proposed research is significant because it is expected to improve upon standard gadolinium- enhanced MRI and provide strong evidence-based proof of principle for further development and clinical trials of therapeutically induced TAM based neuroinflammation. We foresee future clinical trials using the SELFI Hypoxic Fraction to specifically monitor the neuroinflammatory effects of novel immunotherapeutic techniques.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY/ABSTRACT Complete or partial loss of chromosome 7 (-7/del(7q)) predisposition syndromes, preleukemia, and leukemia. is the most common cytogenetic abnormality in It is associated with short overall survival and chemotherapy resistance. Given their high prevalence and unfavorable prognosis, there is an urgent need to identify more effective and innovative therapies. Nonetheless, the pathogenesis and therapeutic vulnerabilities of -7/del(7q) remain undetermined. We hypothesize that the hemizygous deletion of one or more haploinsufficient essential genes on chromosome 7q is responsible for ineffective hematopoiesis, akin to the partial loss of ribosomal proteins in 5q deletion myelodysplastic syndrome (MDS) and inherited BM failure syndromes. Such a hemizygous deletion may create specific vulnerabilities that could be therapeutically targeted by further inhibiting the encoded protein, a related protein, or an associated pathway. Nuclear pore complexes (NPCs) play a crucial role in regulating several vital cellular processes by controlling the nuclear-cytoplasmic trafficking of RNA, ribosomes, transcription regulators, and drug targets. We conducted comprehensive statistical analyses and individual CRISPR knockout experiments, which revealed NUP205, an NPC member, to be a haploinsufficient essential gene on chromosome 7q. Knockout or knockdown of NUP205 results in a growth disadvantage or cell apoptosis in a dose-dependent manner. NUP205 hemizygous deletion single-cell clones exhibit resistance to cytarabine and increased sensitivity to elesclomol, consistent with the drug profile of -7/del(7q) primary leukemia samples in the Beat AML cohort. Therefore, we hypothesize that the deletion of the haploinsufficient essential gene NUP205 contributes to the BM insufficiency phenotype observed in -7/del(7q) patients and can be therapeutically targeted using elesclomol-based treatments to specifically eliminate malignant cells harboring -7/del(7q). We propose here: (1) to investigate the functional impacts of NUP205 on hematopoiesis; (2) to elucidate the mechanisms of NUP205 deletion-mediated impacts on cellular activity and chemosensitivity; (3) to investigate elesclomol combination therapies targeting leukemia cells harboring -7/del(7q). Collectively, our studies will elucidate the cellular and molecular mechanisms of NUP205 deletions in driving the BM insufficiency phenotype, creating specific vulnerabilities, and shaping the drug responses for subsets of myeloid malignancies. Ultimately, this effort will provide a basis for further translational work and the development of promising inhibitors for clinical testing. Additionally, our study will serve as a prototype for identifying novel therapeutic vulnerabilities for other chromosome deletions in hematological malignancies.

NIH Research Projects · FY 2025 · 2024-05

Project Summary/Abstract Heart disease is the leading cause of death for Alaska Native men and the second leading cause of death (after cancer) among women and Alaska Native people overall. The overarching goal of the proposed multilevel, multicomponent intervention, Diet and Active Lifestyle - Yuuyaraq (DAiLY), is to reduce consumption of highly processed store-bought foods while promoting intake of subsistence foods, healthy store-bought foods, and a more active lifestyle to reduce heart disease risk. The Yup'ik word Yuuyaraq means `the Yup'ik way of life' and encompasses a worldview in which living in harmony with the environment, as well as sharing of subsistence foods and traditional knowledge is central. The proposed DAiLY intervention is grounded in the Yup'ik worldview and Indigenous Food Sovereignty, and supported by a foundation of trust resulting from 22 years of continuous Community Based Participatory Research on heart disease risk and protective factors with Yup'ik communities. DAiLY is a direct response to the intervention research requests of community partners and input from Yup'ik Community Research Associates and a Yup'ik Community Planning Group during the formative research and community engagement process shaping this proposal. The proposed intervention, based on the Warnecke model of health disparities and social cognitive theory, includes three components: 1) home-based workshops, framed in the Yupik worldview, led by Community Research Associates to facilitate interactive discussions with community members about healthy market foods, as well as the health benefits of locally harvested traditional foods and increased physical activity; 2) local food store interventions to increase access to, and help build demand for, healthy food options; and 3) traditional community activities, including Yuraq (Yup'ik traditional dance), Native sports events, and berry festivals, that provide opportunities to increase physical activity. The three components will be supported and reinforced via community media, including Facebook, text messaging and visual materials. A continuous metabolic syndrome score will be used as the primary outcome to assess changes in heart disease risk, and objective stable isotope biomarkers of diet and a validated food frequency questionnaire will be used to measure intake of traditional and market foods. We will test the DAiLY intervention in four Yupik communities, randomized to immediate and delayed intervention. Aim 1, will determine the effectiveness of the DAiLY intervention on heart disease risk by measuring change in a continuous metabolic syndrome risk score (primary outcome). Aim 2, will assess implementation of the DAiLY intervention using a mixed methods process evaluation to determine fidelity, dose, and reach, as well as barriers and facilitators to implementation of program activities and participant satisfaction and engagement. Aim 3, will determine the impact of the DAiLY intervention on community-level outcomes, including access to, and sales of, healthy foods in local stores, as well as opportunities for physical activity at community venues.

NIH Research Projects · FY 2025 · 2024-05

Project Summary Malaria caused over 619 thousand deaths and resulted in the infection of more than 247 million individuals in 2021. Emergence of resistance to single and combination frontline-therapeutics have been reported in endemic areas and threatens the efforts to eradicate the disease. We believe that continued development of 4- aminoquinolines holds immense un-tapped therapeutic and clinical potential to overcome emerging multi-drug resistant (MDR) strains of Plasmodium falciparum (Pf), the deadliest species of malaria parasite. To this end, I developed an initial compound screen, inspired from previous work in our lab, which produced two separate compounds, MH01-128 and MH01-173, both exhibiting low nanomolar antiplasmodial activity in an in vitro proliferation assay against MDR Pf. In addition, the two compounds demonstrated parasite clearance in a murine malaria model; however, both compounds suffer from metabolic instability, measured in pooled murine liver microsomes. To increase metabolic stability of MH01-173, I performed an iterative structure activity relationship study that produced the compound MH02-060. This next-generation compound exhibited enhanced metabolic stability and produced a non-recrudescence dose without change to intrinsic anti-plasmodial activity. The work I propose hereafter aims to further develop MH02-060 as an antimalarial. In Aim 1 I will use an iterative medicinal chemistry approach to select for compounds that maintain antiplasmodial activity versus MDR Pf, favorable pharmacokinetic properties, and superior in vivo efficacy. In Aim 2, potential targets of MH02-060, will be investigated using chemical biology techniques in tandem with heme binding assays. The scientific impact of the successful completion of this project will result in a superior analog of MH02-060 that has the potential to be accepted into the Medicines for Malaria Venture's antimalarial clinical development pipeline. The completion of this proposal will result in my training in a diverse set of technical methodologies and knowledge of antimalarial drug development. Along with the training that I will receive from Dr. Riscoe and members of his lab, I will have additional training in: cell culture, in vitro antiplasmodial assays, and murine in vivo experiments by Dr. Jane Kelly and Dr. Yuexin Li; bioanalytical sample preparation and analysis from Dr. Andrea DeBarber; interpretation of proteomic data from Dr. Ashok Reddy; and optimization and use of the drug- like probes from Dr. Michael Cohen, all from OHSU. My position in Dr. Michael Riscoe's laboratory will provide me with institutional support from an exemplary department and access to a large group of diverse PI's and trainees to aid in my scientific growth and training. Development in these areas and amongst this institution will provide me with key skills and scientific development to pursue a successful career as an independent academic investigator.

NIH Research Projects · FY 2025 · 2024-04

Metformin is prescribed to 50 million Americans annually, and is currently in widespread perinatal (pre-pregnancy, during pregnancy, and post-natal) clinical use. Over the past decade, clinical indications and pragmatic use of metformin have steadily expanded beyond the treatment of overt diabetes outside of pregnancy, and now include prediabetes and obesity, polycystic ovary syndrome, type 2 diabetes, and gestational diabetes. With its expanded use, questions of unintended long-term harm have arisen. The rationale underlying these concerns for metformin exposure during development as a consequence of expanded maternal use arises from its basic pharmacodynamics and mechanisms of action, which we and others hypothesize converge to disrupt important metabolic pathways during fetal life, which are necessary to establish normal birth weight and appropriate early post-natal growth trajectory. When combined with a maternal Western-style diet (WSD), fetal metformin exposure leads to accelerated early development of a pre-diabetic, pre-obese phenotype with evidence of obesity and insulin resistance in early adolescence (puberty onset). We are inspired by our preliminary data to pursue development of a non-human primate model of maternal metformin use. Powered as a three-armed mechanistic-based clinical study, we will determine the impact of metformin or placebo exposure from pre-pregnancy through lactation on the development of obesity and insulin resistance. This study is adequately powered to test the hypothesis that maternal metformin use in isolation or in conjunction with a maternal high fat diet renders low birthweight and aberrant catch-up growth, driving obesity and insulin resistance in the offspring by onset of puberty (approximately 3-4 years of age). In Aim 1, we will determine if early life metformin exposure in control and/or WSD-fed dams leads to low birthweight and aberrant catch-up growth, resulting in obesity and insulin resistance in pubertal juvenile offspring. In Aim 2, we will determine what the impact of metformin exposure in WSD-fed dams is on maternal, fetal (G145) and juvenile (to puberty onset) metabolic physiology. This will include core measures of maternal and fetal organ metabolism (liver, muscle, gut and pancreas). In Aim 3, we will determine whether weaning offspring onto a control diet can ameliorate or mitigate the effects of maternal metformin exposure in WSD-fed dams. Finally, in Aim 4 we will determine how early metformin exposure wields its molecular impact on control and WSD-induced alterations of core measures of maternal and fetal metabolism in the liver, gut, muscle, and pancreas. Considering the recently emerged epidemiologic evidence and known mechanisms of actions of metformin, there is a rational concern that rather than preventing developmental programming, metformin use during pregnancy may have unintended consequences of accelerating obesity and the metabolic syndrome epidemic in the next generation. The animal, specimen, and uniformly generated multi’omic data generated in the current proposal will collectively inform ongoing clinical trials and future clinical implementation.

NIH Research Projects · FY 2025 · 2024-04

Project Summary/Abstract Oligodendrocyte lineage cells (OLCs) are the myelin-producing cells in the central nervous system, which possess ion channels and are sensitive to neuronal activity. P/Q-type channels are voltage-gated calcium channels that are present in neurons and OLCs, and though their function in neurons has been studied, the role of these channels in OLCs is unknown. Mutations in CACNA1A, the human gene that encodes the main pore- forming subunit of P/Q-type channels, have been shown to cause neurological disorders including episodic ataxia, epilepsy, and intellectual disability in human patients. Studying the role of P/Q-type channels in OLCs will aid in understanding CACNA1A-related disorder pathophysiology and may uncover new targets for treatment. In this study, I will use zebrafish as a model to produce mutations in CACNA1A equivalent genes in OLCs during development, then use in vivo imaging with fluorescent transgenes to determine if myelin formation and calcium signaling is disrupted in OLCs with disrupted P/Q-type channels. My preliminary findings show P/Q-type channel mutations in OLCs cause reduced developmental myelination. To test how P/Q-type channels are involved in CACNA1A-related disorder pathology, I will generate a global mutant zebrafish to model CACNA1A-related disorders by using CRISPR/Cas9-mediated mutagenesis to produce mutations replicating those found in CACNA1A-related disorders. I will use fluorescent imaging to assess developmental myelination in this mutant, and I will use whole-brain calcium imaging and a motor assay to evaluate neural function relevant to ataxia seen in human disease. I will also generate a transgenic mutant zebrafish line with mutant P/Q-type channels in all cells and wild-type P/Q-type channels expressed specifically in OLCs to determine how OLC P/Q-type channels are involved in CACNA1A-related disorder pathology. To further understand the role of P/Q-type channels in OLC development, I will perform whole-cell voltage-clamp recordings in OLCs in the developing zebrafish spinal cord. By measuring currents in developing OLCs in wild-type and mutant zebrafish with and without ion channel agonists and antagonists, I will be able to directly measure changes in OLC electrophysiological properties due to P/Q-type channel mutations. These experiments will establish the new method of whole-cell patch-clamp recording from zebrafish spinal cord OLCs and lay the groundwork for many future studies. Together, this study will provide fundamental insights of ion channel function in OLCs as well as OLC involvement in CACNA1A- related disorders and provide future directions for understanding the role of OLCs in neurological disease.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY: Neurodevelopmental impairment remains the most vexing issue facing the clinical management of premature infants. Intrauterine infection and inflammation are significant causes of preterm birth potentially resulting in lifelong neurodevelopmental impairment, such as cerebral palsy, sensory and cognitive deficits and behavioral difficulties. Ureaplasma is a bacterial species that is a common cause of preterm labor and non-human primates (NHP) are the most clinically relevant animal model in which to study human preterm labor and fetal brain injury. Our unique chronically catheterized rhesus monkey model allows constant physiological monitoring and longitudinal sampling of amniotic, maternal and fetal compartments and evaluation of treatments longitudinally across gestation. In our previous NHP studies, antibiotic treatment (Azithromycin) of intrauterine infection with Ureaplasma has been shown to delay preterm labor and improve fetal lung and hemodynamic outcomes. Novel immunomodulatory drugs proposed for the treatment of preterm labor would need to be combined with antimicrobials such as Azithromycin in the setting of intrauterine infection. However, mechanisms of perinatal brain injury and the action of antibiotics on the fetal brain in relation to intrauterine infection remain poorly understood. Therefore, the objective of this proposal is to determine how Azithromycin treatment may modulate fetal neuroinflammation caused by intrauterine Ureaplasma infection, to improve fetal neurodevelopmental outcomes. Data from our previous NHP studies of intrauterine Ureaplasma infection added to this resubmission includes evidence of: i) placental membrane inflammation and inflammasome activation; ii) maternal Azithromycin treatment normalization of fetal blood flow; and iii) preliminary data that fetal brain microglial activation is fully reversed by azithromycin treatment. We also provide NHP data for detection of fetal neural extracellular vesicle markers of perinatal brain injury. In Aim 1 we will assess physiological aspects of preterm labor and immune responses to intrauterine infection and antibiotic treatment. Aim 2 will determine fetal brain molecular, histological and spatial transcriptomic changes with Ureaplasma infection and Azithromycin treatment. In addition, we will characterize the expression of microglia/astrocyte activation phenotypes and myelin development associated with neuroinflammation. Aim 3 will investigate how fetal brain extracellular vesicles extracted from maternal blood may be used as a novel, non-invasive diagnostic tool for perinatal brain injury and for the monitoring of Azithromycin efficacy and safety. Development of novel diagnostic technologies is essential for the in vivo monitoring of fetal status in response to treatment. Using a combination of novel techniques and our clinically relevant NHP model, this proposal utilizes our team's extensive experience in studying pregnancy physiology, fetal neurodevelopment and immunology. Successful completion of this study will provide essential missing translational data on the mechanisms of fetal neuroinflammation and perinatal brain injury and its treatment.

NIH Research Projects · FY 2026 · 2024-04

Project Summary: Our research program investigates the functional mechanisms that operate in voltage gated K+ (Kv) channels. Kv channels are essential for the generation and conduction of electrical signals by neurons, muscles and endocrine cells. Underlying the physiological roles of Kv channels is their ability to regulate the flux of K+ across cellular membranes. The flux of K+ through a Kv channel is controlled by the processes of voltage activation, which turns on the flux, and inactivation, which turns off the flux of K+ through the channel. There have been extensive investigations on Kv channels but major questions remain on the activation and inactivation mechanisms. In our research program, we use a multidisciplinary approach that combines structural and functional studies with protein modifications using unnatural amino acid (UAA) mutagenesis. UAA mutagenesis is a very powerful method for protein modification compared to traditional mutagenesis because it allows a large variety of side chain modifications and permits the modification of the protein backbone. In the grant period, we will investigate C-type inactivation in the Shaker, Kv1.2 and the cardiac Kv channel HERG. C-type inactivation refers to a conformational change at the selectivity filter, the ion binding region of the channel, that turns off the flux of ions through the channel. We will also investigate the role of the protein main chain interactions in voltage gating. Our studies on voltage gating will be carried out in the hyperpolarization activated and cyclic nucleotide gated ion (HCN) channel. The research proposed is significant because it will provide key mechanistic insights into the working of Kv channels. The research will also provide strategies for investigating the role of the protein backbone and ion binding sites, strategies that will be generally applicable to other ion channels.

NIH Research Projects · FY 2026 · 2024-04

ABSTRACT Growing evidence indicates that the biological response to chronic social stress and distress can promote the progression of ovarian precursor lesions and invasive cancer development via prolonged activation of the sympathetic nervous system and sustained norepinephrine release. While chronic social stress/distress is known to cause chronic inflammation, key questions remain about how stress-related signaling pathways alter the tumor immune response, particularly infiltration by immunosuppressive cell types triggered in response to chronic inflammation, and potential means of mitigating the impact of chronic social stress/distress on immune function. Specifically, we propose to evaluate the hypothesis that chronic social stress/distress enhances the early and late progression of ovarian tumors by promoting recruitment and activity of immunosuppressive M2-type tumor- associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) and that certain medications, including aspirin and other NSAIDs, beta-blockers, and statins, can disrupt immune dysregulation triggered by stress/distress. Aim 1 will use data from four long-term prospective cohorts in diverse populations and a population-based case-control study that have collected self-reported measures of chronic social stress and distress (e.g., widowhood, social isolation, depression, anxiety) and ovarian tumor tissue for tissue microarrays. Aim 1 will measure intratumoral immune markers to assess TAM, including polarization from the M1 to the M2 immunosuppressive phenotype, and MDSC infiltration, using multiplex immunofluorescence. We hypothesize that chronic social stress and distress are positively related to ovarian tumor immune suppression (e.g., increased ratio of M2:M1 TAMs, MDSCs) and that the association of these exposures with ovarian cancer diagnosis and associated tumor immune suppression (exploratory) is attenuated among users of aspirin, non- aspirin NSAIDs, beta-blockers, or statins. Using an orthogonal and interactive approach, Aim 2 will use experimental ovarian cancer mouse models to examine the effects of chronic unpredictable and predictable stress occurring before and after inoculation on MDSCs, monocyte, and TAM populations as well as cytokine networks by polychromatic flow cytometry and multiplex assays. We also will examine if aspirin and one other medication informed by the analyses in humans and existing literature counteracts the effects of chronic stress on TAM, MDSCs, and monocyte infiltration, polarization, and tumor progression. We hypothesize that pre- inoculation chronic stress exacerbates post-inoculation chronic stress-induced ovarian cancer progression in mouse models by up-regulating TAM infiltration, M2 polarization, and MDSC infiltration. In addition, we hypothesize that aspirin will abrogate these effects. This innovative application will inform future work to identify women at increased risk for tumoral immune profiles associated with poor prognosis and to develop novel immunopreventive strategies, pharmacotherapies, and psychosocial interventions to prevent and treat invasive ovarian cancer in women who experience chronic social stress and distress.

NIH Research Projects · FY 2026 · 2024-04

Project Summary More than three in every ten Medicaid enrollees has a diagnosed mental health condition, and many in this group face significant barriers accessing the care they need. In most states, Medicaid enrollees with mental health conditions are covered by managed care organizations, which contract with sets of health care providers and facilities to deliver medical care to its members. The size, composition, and stability of these “provider networks” can affect care continuity and treatment outcomes, particularly in mental health, where provider networks tend to be much smaller than those for physical health. The Centers for Medicare and Medicaid Services requires each Medicaid managed care provider network to provide sufficient and timely access to mental health services. However, little evidence exists to help states understand which mental health network attributes affect patient outcomes and how to design, monitor, and regulate provider networks. Against these knowledge gaps, the overall objective of this proposal is to estimate the effects of mental health networks on health care utilization and outcomes for adult Medicaid enrollees with mental health conditions (including those with serious and mild/moderate mental illness). We propose to use the 2016-2023 Transformed Medicaid Statistical Information System (T-MSIS) Analytic Files (TAF), which provides comprehensive enrollee-level claims data related to service utilization and prescription use for all states and the District of Columbia. We hypothesize that network size, provider churn (exit), and provider panel size (a measure of the degree of plan participation) influence enrollees' mental health care access and outcomes. Specifically, our aims are to 1) identify mental health network attributes associated with plan switching among Medicaid enrollees with mental health conditions; 2) determine the effects of changes in network size and network quality on utilization and patient outcomes; 3) estimate the effects of involuntary network disruption on patient outcomes; and 4) assess how telemedicine affects the attributes and measurement of mental health networks. We apply a number of innovations, including the construction of empirical provider networks from administrative claims data, a focus on psychiatrists and psychiatric mental health nurse practitioners, and a robust study design to evaluate the impact of mental health provider network attributes on patient-level outcomes. In collaboration with an advisory committee of Medicaid and mental health policy stakeholders, results will provide actionable evidence to improve access to high-quality mental health services within a constrained mental health delivery system. 1

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY Dystroglycan is a transmembrane protein that relies on its extensive glycosylation to interact with a number of extracellular proteins. Dystroglycan hypoglycosylation causes a form of congenital muscular dystrophy (dystroglycanopathy) that is frequently accompanied by a wide range of neurological symptoms. On the severe end of the spectrum, patients exhibit hydrocephalus, type II lissencephaly, retinal/cerebellar hypoplasia, and white matter abnormalities. Patients with milder forms of dystroglycanopathy frequently have seizures and cognitive defects even in the absence of obvious brain abnormalities. Mouse models of dystroglycanopathy have provided invaluable mechanistic insight into Dystroglycan’s many functions in the nervous system, as they faithfully recapitulate many of the neurodevelopmental defects seen in human patients. Recently, we and others have shown that Dystroglycan functions cell-autonomously at subsets of inhibitory synapses in the brain, providing a possible explanation into the etiology of neurological dysfunction in dystroglycanopathy. In this proposal, we examine how Dystroglycan regulates inhibitory synapse development and function. The proposed experiments will: 1) Use genetic approaches to dissect the cellular and molecular mechanisms by which Dystroglycan regulates the establishment and maintenance of inhibitory synapses; 2) Determine whether synaptic defects can be rescued, and whether a specific therapeutic window exists; 3) Define the molecular and functional basis of a newly identified interaction between Dystroglycan and the Cntnap proteins at inhibitory synapses in the brain. These experiments will provide insight into Dystroglycan function in the nervous system and lay the foundation for therapeutic interventions to correct neurological defects in dystroglycanopathy.

NIH Research Projects · FY 2025 · 2024-04

Maternal cardiovascular and hemodynamic adaptations during pregnancy are critical for accommodation, growth and development of the placenta and fetus. Insufficient changes in cardiovascular function can lead to pregnancy complications including hypertension and represent a major risk for maternal and fetal health. The causes and mechanisms leading to maladaptations are not entirely understood. We aim to develop a dynamical model of cardiovascular function throughout pregnancy that will serve as a tool to aid understanding of cardiovascular adaptations and maladaptations in pregnancy and guide development of personalized therapeutic interventions. Dynamical modeling uses differential equations to describe the behavior of a system, and in contrast to statistical modeling allows computation of the outcomes of experiments that are significantly different from the ones used to build the model. The model's initial conditions and parameters are determined by patient's phenotype and genetic makeup, and by varying them one can simulate a wide variety of patients. A virtual patient's development can be analyzed through numerical solution of the model equations. The impact of risk factors, individual treatments, and combined effect of treatments aimed at various therapeutic targets are simulated through proper modifications of the equations and parameters. Therefore, dynamical modeling is a perfect tool for development of personalized treatments. It has been successfully applied to research of cancer, diabetes, arthritis, stroke, metabolic, hematologic, and autoimmune diseases. However, to date there is no dynamical model of cardiovascular adaptations throughout pregnancy. We aim to fill this gap by developing such a model based on synergy and integration of fluid dynamics, biomechanics, mathematical modeling, and simulation. We will first develop a compartmental non-pulsatile model of circulatory patterns in major organs and vessels, including the uterus, and their changes throughout pregnancy. This approach provides flexibility, mathematical convenience, and accommodates required features. Then we will test and refine the model by simulating physiological changes known to be associated with pregnancy hypertension and known therapeutic interventions that alleviate the hypertension. Finally, we will perform sensitivity analysis to make the model parsimonious and to gain insights into the order of significance of various pathophysiological mechanisms and the relative potential of various therapeutic interventions. In the future, the model may be used for in silico testing of novel therapeutic targets, management strategies, risk assessment, modeling of O2 and nutrient supply to the fetus, and combined effect of a patient's characteristics leading to development of hypertension, even when each individual characteristic is in the normal range. Innovation lies in integration of existing knowledge and previously developed models of individual organs and their role in hemodynamic regulation, incorporation of the uterus and its changing hemodynamics over the course of pregnancy, utilization of data previously omitted from modeling efforts (e.g., placenta MRI, Doppler US measurements of blood flow), and the extended time scale of the model spanning most of pregnancy. The impact of fetal sex will be modelled explicitly.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY/ABSTRACT Nontuberculous mycobacteria (NTM) are opportunistic environmental pathogens that are present in soil and water. NTMpulmonary infections, most commonly due to Mycobacterium avium complex (MAC), may result in chronic, debilitating pulmonary disease (MAC-PD). Treatment, when necessary, consists of 3-4 antibiotics for 14+ months. MAC-PD disproportionately impacts the elderly and women, and those with underlying lung diseases. The prevalence of MAC-PD is increasing, a trend that will likely continue due to aging populations and increased comorbidities. Our lack of disease biomarkers poses significant diagnostic and therapeutic challenges. In contrast with its well-studied cousin tuberculosis (TB), with NTM it is difficult to discern colonization vs. disease caused by these organisms and determine when treatment is necessary or successful. For many patients it is difficult to obtain sufficient respiratory sputum samples to culture for diagnosis or to monitor for microbiologic response during therapy. There is a critical need for non-invasive biomarkers to monitor disease activity and treatment response, in order to limit sputum induction or bronchoscopy procedures and exposure to computed tomography scan radiation. Furthermore, treatment is frequently initiated to improve the patient's symptoms but there is scant data on the correlation of measures of patient-reported outcomes with biomarkers of MAC-PD. The Hu lab has developed an ultra-sensitive CRISPR diagnostic assay using a portable CRISPR-based test to rapidly detect TB cell-free DNA (cfDNA) directly from blood samples. The test allows early TB diagnosis and precisely quantifies TB cfDNA for rapid assessment of disease severity or anti-mycobacterial treatment efficacy. We have preliminary data to suggest this approach can be applied to MAC-PD; accordingly, we seek to evaluate a cfDNA CRISPR-based diagnostic assay (CRISPR-NTM) to diagnose MAC-PD and measure treatment response. We will conduct Aims 1 and 2, analytical and clinical validation of the CRISPR-NTM in patients with MAC-PD during Years 1-2. Aim 2 will use established NTM Biobanks associated with our NTM Clinical Trial Network (OHSU Coordinating Center) to identify a retrospective cohort of patients with MAC-PD and uninfected controls with and without chronic underlying lung disease. During Years 1-4, for Aim 3, we will further utilize our NTM Clinical Trial Network to prospectively collect longitudinal blood samples from patients starting treatment for MAC-PD (NTM-TREAT) from our 1) ongoing pragmatic clinical trial (MAC2v3) and 2) non-MAC2v3 clinic patients representing a broader “real-world” patient population. We will also enroll a pilot cohort at treatment completion (NTM-TRACK), who are subsequently monitored for microbiologic relapse/re-infection. During Years 3-5 we will complete Aim 3 to evaluate the potential for CRISPR-NTM to monitor microbiologic treatment response and relapse/re-infection. Ultimately, the identification of a biomarker for pulmonary MAC-PD and other clinically relevant NTM species will optimize diagnosis and monitoring, and facilitate therapeutic decision-making.

NIH Research Projects · FY 2026 · 2024-03

Abstract: For the more than 40,000 children undergoing treatment for cancer each year, there is an urgent need to establish scalable complementary health interventions to treat symptoms not controlled by conventional supportive care. Complementary health interventions have been associated with decreased distress, anxiety, pain, and improved quality of life (QOL) in children with cancer. Creative arts therapy and art-making are mind-body interventions that have been related to improved QOL in adults and children with cancer, but foundational evidence lacks rigor and reproducibility. To address this gap, we will use art focus groups with children with cancer to develop a standardized creative arts intervention based on what we learned from our pilot studies. We will then establish feasibility of conducting a randomized controlled trial in 60 children ages 8-13 years in the first year of cancer treatment. This study will occur in two phases. Phase 1 will define and refine the intervention using art groups with participants who represent the future study population. Phase 2 will assess feasibility and acceptability of a 12-week two-arm trial. The intervention arms will consist of four 30-minute sessions of either creative arts or video watching during scheduled cancer treatment every 2-3 weeks over 12-weeks. Patient-reported QOL and symptom outcomes showed significant change in our preliminary work, but we will advance the measures for scalability with the standardized questionnaires: Pediatric PROMIS, Pediatric Patient Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Faces scale. Timepoints for data capture will occur at baseline, pre-/post- each session, and after the total 12-week intervention. Our multidisciplinary study team contributes congruent areas of expertise in clinical research among children with cancer, creative arts intervention development, pediatric symptom assessment, behavioral clinical trial implementation, and feasibility data analysis. This research has the potential to promote the integration of creative arts into conventional cancer care for children and transform the future of symptom management. The outcomes will strengthen the design and overcome methodological challenges in the clinical study of an innovative mind-body intervention for addressing QOL and symptom burden to improve the whole person health of children with cancer.

NIH Research Projects · FY 2024 · 2024-03

PROJECT SUMMARY from Parent Award (unchanged) Substantial theoretical work suggests that mental health disorders have their roots in early childhood development, and that symptoms of psychopathology are in part the result of breakdowns in self-regulatory skills that emerge early in life. Yet early predictors of emergent psychopathology, and/or trans-diagnostic phenotypes such as self-regulation, are poorly understood. Utilizing prospective data from a large sample (N=270) of mothers and their children, the current study aims to address this gap by: a) testing the hypothesis that infant negative affect (NA) undermines children's emerging executive functioning (EF), and that NA- associated deficits in EF are one mechanism through which early emotion-regulatory difficulties convey risk for psychopathology at 3 years of age (Aim 1); b) examining whether prenatal stress moderates associations among NA, EF, and psychopathology at age 3 (Aim 2); c) testing whether maternal immune activation during pregnancy and/or child immune activation in infancy mediate the association between maternal prenatal stress and child symptomatology (Aim 3). The results of this research will inform early identification and intervention. The execution of this research plan, in conjunction with the training activities described, will provide the applicant with the skills for an independent, innovative research program aimed at understanding the earliest origins of psychopathology. The training plan assists in enriching her strong background in development with more independence and more training in assessment and observation of psychopathology in childhood. Additionally, it includes strong training in psychoneuroimmunology, including the role of the immune system in psychopathology (in both the mother and child) as well as the mechanisms through which maternal immune activation during pregnancy may influence child risk for psychopathology. Thetraining objectives include:a) learning theory and methods related to the etiology, nosology, and pathogenesis of childhood psychopathology, b) becoming acquainted with clinical assessment issues and diagnostic assignment as it pertains to research application throughout childhood, c) translating her developmental expertise to clinical populations including conceptualizing developmental findings in relation to psychopathology theory and practice, d) gaining hands-on experience conducting research with clinical measures and clinically at risk populations, e) learning theory and methods related to studying the immune system and inflammation- psychopathology associations, f) better understanding the mechanisms through which maternal immune activation during pregnancy may influence the developing brain and, by extension, child risk for psychopathology, g) gaining hands-on experience collecting and analyzing relevant biological samples and learning about contemporary molecular and immunological methods for analyzing inflammatory signaling networks, and h) further training in the responsible conduct of research, including ethical considerations specific to clinical populations, and in i) research writing and dissemination as it pertains to the field of psychopathology, mental health, and psychoneuroimmunology.

NIH Research Projects · FY 2025 · 2024-03

PROJECT SUMMARY Optical coherence tomography (OCT) is uniquely able to achieve high depth resolution of several microns while imaging a large 3-dimensional (3D) volume. It is already widely used by ophthalmologists to diagnose diseases of the cornea and guide treatments. We aim to extend the range of applications further by pushing the envelope on the ultrahigh-resolution front. The specific aims are to: (1) Develop and validate ultrahigh-resolution OCT microscopy (OCM) using short-wavelength light sources. The recent availability of visible coherent light sources enables the development of OCT microscopy with a higher transverse resolution, potentially better than the current standard for corneal microscopy (in vivo corneal confocal microscopy or IVCM). We will develop an ultrahigh-speed line-scan spectral-domain OCT with dynamic focusing. The goal is to achieve one-micron resolution non-contact volumetric corneal imaging within a few seconds, enabling greater ease of use, faster scan times, and the ability to visualize more clinically relevant microscopic structures within the cornea compared to IVCM. (2) Explore the diagnostic potential of ultrahigh-resolution OCM for infectious keratitis and keratoconus. These are two of the most common causes of corneal blindness globally. IVCM can visualize large corneal pathogens (fungus and amoeba), but not bacteria which are the most common cause of infectious keratitis. IVCM is also not capable of visualizing collagen bundles within the cornea, the site of the primary structural changes caused by keratoconus. Our preliminary findings indicate OCM can visualize fungus and bacteria in addition to larger corneal pathogens as well as collagen bundles in rabbit corneas. Identification of these structures could significantly improve the diagnosis of infectious keratitis and keratoconus. The theoretically superior usability of OCM compared to IVCM may also enable wider adoption of corneal microscopy. We will complete pilot ex vivo and in vivo clinical studies comparing OCM against IVCM for the diagnosis of infectious keratitis and keratoconus. Earlier determination of the correct diagnosis would allow for faster initiation of targeted therapy and improved visual outcomes in these common, potentially blinding conditions.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY Hypertension (HTN) is a leading modifiable risk factor for global cardiovascular disease and stroke morbidity and mortality. Nigeria, Africa's most populous country, has a high HTN burden. Evidence-based interventions (EBIs) for detection and initiation of treatment for HTN are not widely implemented in Nigeria. These EBIs include widely available (1) BP screening (reaching all adults >18 years of age) to identify HTN early and (2) connections to ongoing primary care for HTN management. In partnership with community and clinical stakeholders, we are currently adapting community-based strategies shown to be effective in increasing HIV screening and connections to care. The proposed adapted strategies – called community vital signs (CVS) strategies – will utilize community-based screenings, digital technologies, and supportive approaches to connect people to healthcare facilities, leveraging our practice-based research network of community clinics within the Model Innovation Research Centers created by the Nigeria Implementation Science Alliance. We will use the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) and EPIS (Exploratory, Preparation, Implementation, Sustainment) implementation science frameworks to guide our work. Aim 1 / R61 Phase (Year 1): Engage stakeholders to refine and finalize the co-creation of CVS strategies aiming to increase rates of BP screening and connections to care in Nigeria. By the end of the R61 Phase, we will have final CVS strategies and will recruit, train, and conduct implementation readiness assessments at 12 community-based sites connected with 12 healthcare facilities in 12 Nigerian cities (2 in each of Nigeria's 6 regions). R33 Phase (Years 2-5) Aim 2: Implement and assess CVS strategies aiming to increase rates of BP screening at all 12 study sites (n=24,000 participants). We will initiate quarterly, community-based BP screenings and evaluate using RE-AIM. Aim 3: Implement and compare 2 different CVS strategies to make connections to primary care for those found to have high BP readings that meet HTN criteria at all study sites. We will conduct a nested, hybrid implementation-effectiveness type III trial using a parallel 2-arm cluster randomized design. Arm A (6 sites, n~3,000 participants): support connection to primary care by utilizing mHealth digital technologies with bidirectional sharing of BP data between community screening site and primary care clinic, coupled with a voucher for a medication starter kit (core strategies); Arm B (6 sites, n~3,000 participants): Core strategies plus community health navigators making handoffs to clinic and sending text messages (core+ strategies). This project promotes equitable access to HTN diagnosis and connections to care, especially in cities where HTN prevalence is highest. It has the potential to significantly increase rates of early HTN detection and prevent the morbidity and mortality associated with the downstream effect of undiagnosed and uncontrolled HTN. It will provide evidence for scale-up of interventions to support self- management of non-communicable chronic diseases in Nigeria and other low- and middle-income countries.