University Of Washington

NIH Research Projects · FY 2026 · 2024-09

ABSTRACT/SUMMARY The overall goal of this 5-year R13 grant is to address the substantial underrepresentation of knowledge production and dissemination by individuals from underrepresented populations in addictions research. [For the purposes of this application, underrepresented populations include: (a) individuals from underrepresented and/or structurally minoritized racial and ethnic groups, individuals with disabilities, individuals from disadvantaged backgrounds, and women; (b) individuals from low- and middle-income countries; and (c) individuals from non-English-speaking countries.] This project will specifically increase the involvement of individuals from underrepresented populations in the annual meetings of the International Society of Addiction Journal Editors (ISAJE), an international society which was formed in 2001 to foster collaboration between addiction journal editors globally. It serves editors, associate editors, reviewers and authors of addiction journals and offers trainings and resources in addition to an annual meeting. Our long-term goal is to foster increased participation of underrepresented populations in addiction journal publishing as editors. The current project builds a foundation for this via proposing to support: (a) in-person attendance of editors from underrepresented populations at each ISAJE meeting through a travel award; and (b) attendance of a Keynote Speaker to deliver an address on a topic that is crucial for equity, diversity and inclusion in addiction publishing at each ISAJE meeting. We will cover meeting attendance costs of five competitively- selected editors from underrepresented populations including a Keynote Speaker selected from existing addictions journal editors from underrepresented populations. Meetings over five years are planned to take place both internationally and domestically in: Lisbon, Portugal, in 2024 (just prior to the Lisbon Addictions conference); Seattle, USA (2025); Johannesburg, South Africa (2026); Montreal, Canada (2027); and Istanbul, Turkey (2028). Our meeting will foster increased dissemination of science by and about underrepresented populations, thereby addressing some of the bias in research published in addiction journals.

NIH Research Projects · FY 2025 · 2024-09

Alzheimer Disease (AD) pathogenesis is multifactorial involving multiple cell types which offers several points of intervention. Microglia, the innate immune cell of the brain, are implicated in AD risk and pathogenesis. However, microglia are phenotypically diverse, and which microglial activities are most relevant to AD are not yet known. Until recently, studies to find microglia signatures in human brain tissue were limited by microglia numbers precluding a full appreciation of how microglial states may change or contribute to the disease course. With the explosion of human brain single cell omics studies the field is now empowered to more clearly define regulation of microglia in aging and disease. However, resolving microglial states from human brain omic data is particularly complicated as they are less transcriptomically distinct from each other than different brain cell types are from each other. Better approaches are needed to uncover the suspected subtle microglial changes happening early in disease progression. To address this problem and nominate additional AD relevant microglial states we integrate our novel Explainable AI technique with our deep learning method, ContrastiveVI designed to overcome heterogeneity in samples and pull-out subtle cell states. We hypothesize that our novel AI approach will enable better distinction of AD specific pathways from general aging. Two examples of microglial AD altered pathways we and others have identified are neuronal surveillance and microglial motility. However, it is not clear to what degree these nuanced AD microglia states reflect responses to neuronal damage or pathologic proteins or both. As proof of concept to study computationally identified pathways, we will model the concomitant stressors of AD stimuli and neuronal injury due to aging. We will expose microglia-neuron hiPSC cultures to Aβ, tau and UV irradiated neuronal conditioned media and perform functional and single cell RNA single nuclei-ATAC sequencing. We will validate computationally predicted AD microglial genetic drivers and pathways with network analysis of our in vitro perturbation models. We further hypothesize that the presence of AD pathologic proteins alters computationally predicted AD specific microglia pathways in the setting of neuronal injury which we will test using functional assays. These complementary studies innovate approaches to single cell brain datasets to find the subtleties of microglial AD states while leveraging iPSC perturbation in vitro studies in a controlled setting to systematically test specific pathways and determine the impacts of specific perturbation on gene regulation.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Aging is one of the greatest risk factors for the development of cardiovascular disease and heart failure. Mitochondrial dysfunction in the aging heart is thought to be an important contributing factor to the decline in cardiovascular function with age, including hypertrophy and left ventricular wall thickness, diastolic dysfunction, and reduced contractility and calcium dynamics that contribute to the increased risk for clinically important cardiovascular disease. Despite the growing interest in the mitochondrial biology of aging and the clear clinical and

NSF Awards · FY 2024 · 2024-09

This EArly-concept Grant for Exploratory Research (EAGER) project aims to advance our understanding of customizing safe control strategies for Autonomous Mobility Systems (AMS) interacting with humans, thereby fostering scientific progress and national prosperity. Safety, crucial for AMS operating alongside people in environments like autonomous cars, wheelchairs, and delivery carts, varies among individuals, influencing their perception of safety risks. Misalignment between onboard safety protocols and human safety sensitivities can erode trust in AMS capabilities. This award supports fundamental research to enhance trust in AMS by using human egocentric eyeglasses, with the frame of reference defined from the users perspective, as external AMS sensors. This approach dynamically creates personalized safety models, adjusting AMS movements to align with estimated sensitivities. By better addressing user safety preferences, AMS technologies can gain broader public acceptance and trust. The societal impact extends across various sectors, ensuring efficient, safe transport in human-shared environments—from logistics to healthcare, enhancing mobility independence. This research also promotes inclusivity by involving underrepresented groups and fosters collaboration between egocentric vision and robotics communities. AMS requires a choice of safety model and associated parameters to ensure the plans and controls executed will avoid collision with obstacles, such as other humans. However, each individual interacting with the AMS has different safety preferences. This EArly-concept Grant for Exploratory Research (EAGER) project will consider (i) a computer vision model to identify safety risks in the environment based on an individual’s eye-gaze information, (ii) an online inference approach using egocentric visual feedback to estimate the individual’s safety preference, and (iii) a technique to synthesize empathetically astute AMS motions that adapt to those preferences, such as proactively yielding to accommodate a more cautious individual. The research team will demonstrate the efficacy of the approach on an autonomous wheelchair platform and evaluate the connection between empathetic astute motions and trust in AMS capabilities. This EAGER award has been co-funded by the Dynamics, Controls, and System Diagnostics and the Mind, Machine, and Motor Nexus Programs. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-09

Strengthening American Infrastructure (SAI) is an NSF Program seeking to stimulate human-centered fundamental and potentially transformative research that strengthens America’s infrastructure. Effective infrastructure provides a strong foundation for socioeconomic vitality and broad quality of life improvement. Strong, reliable, and effective infrastructure spurs private-sector innovation, grows the economy, creates jobs, makes public-sector service provision more efficient, strengthens communities, promotes equal opportunity, protects the natural environment, enhances national security, and fuels American leadership. To achieve these goals requires expertise from across the science and engineering disciplines. SAI focuses on how knowledge of human reasoning and decision-making, governance, and social and cultural processes enables the building and maintenance of effective infrastructure that improves lives and society and builds on advances in technology and engineering. Well-functioning food systems are essential for food security, human health, economic growth, and national security, yet the infrastructure that powers food systems is often overlooked, outdated, inflexible, and incongruent. Rather than being seen as a cohesive whole, the component pieces of food systems infrastructure are often considered to be part of other infrastructure domains. For example, school kitchens, food bank storage facilities, cold chain transportation, communication networks that enable recovery of surplus foods, or agricultural and foodservice workforce are often considered separately as part of education, emergency, transportation, energy, broadband, telecommunications, human, or other types of infrastructure. Failure to recognize and treat these elements as a cohesive whole would leave U.S. food systems vulnerable to inevitable future disruptions. The early months of the COVID-19 pandemic revealed deep vulnerabilities in food systems infrastructure, such as bottlenecks in processing and moving food, that resulted in volatility in food availability and prices and rising household food insecurity. In addition, a rapidly changing climate will further stress our food systems infrastructure. This is a critically important time for developing a shared vision of food systems infrastructure. Without a common understanding of food systems infrastructure, it is difficult to identify the biggest problems and the most promising solutions. This SAI project uses social science research methods that tap into the expertise of a diverse array of professionals with food systems and infrastructure knowledge, including those working in food supply chains, food access organizations, and government agencies. The first phase of the project defines and characterizes food systems infrastructure. The second phase analyzes the landscape of existing policies and investments in this infrastructure. The project's final phase explores the policy priorities of key stakeholders. Ultimately, the goal of this SAI research is to lay the groundwork for next generation food systems infrastructure and accompanying decision support systems that can advance food security and resilient food systems in the United States. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

Summary Aging is the main contributor to many human neurodegenerative diseases, such as Alzheimer’s disease (AD), that are common, progressive, and have limited therapeutic options. Our lack of understanding the biology of human brain aging remains a major challenge in the study of age-associated disorders including AD and other neurodegenerative disorders. While multiple laboratory models such as flies, worms and mice, have uncovered major pathways in the biology of aging, translating these findings to humans is still incomplete, in part due to important cross-species differences. Over the past decade, human induced pluripotent stem cell (hiPSC) models have emerged as an experimental platform to model many human diseases and have contributed great insights into AD and neurodegeneration broadly. However, one major caveat to hiPSC models is the fetal nature of the cells. Several methods have emerged to try and integrate ‘aging’ factors into hiPSCs or to directly transdifferentiate ‘aged’ cells. However, these protocols often rely on atypical aging programs or lack the flexibility of the hiPSC system. One advance over the last 5-7 years is the advent of multi-omic data sets from human post-mortem brain. The vast amount of data generated by omics technology has great potential to fill the gap in our understanding of brain aging and age-dependent, cell-type specific genetic programs. A major current challenge, however, is how to leverage these large, unbiased datasets to identify specific genes that regulate aging pathways. Manipulating candidate genes in a human neural cell experimental system would enable understanding and in vitro modeling of cellular brain aging in a tractable experimental system. Such experiments may reveal targets that can be modified to improve aging phenotypes in human brain cells. In order to address these challenges, we have assembled a team of experts in explainable artificial intelligence (XAI) technology (S-I. Lee), human brain ‘omic studies (S. Jayadev), and hiPSC disease modeling for AD (J. Young). We hypothesize that by applying XAI methods to human brain data sets, we can identify a tractable set of molecular drivers of brain aging. We further hypothesize that we can manipulate these drivers in hiPSC models using CRISPR technology to generate aging phenotypes in hiPSC-derived cells. In this two- pronged proposal, we will first perform proof-of-concept experiments to modulate expression of XAI-identified genes in hiPSC-derived neurons and glia (microglia and astrocytes) and perform phenotypic assays to assess cellular hallmarks of aging (R21 phase). Next, we will increase the complexity of our model by integrating additional omics layers, further developing and refining the XAI techniques and modulating candidate aging drivers in hiPSC-AD models in a multi-cellular context (R33 phase). These experiments will improve experimental platforms to study human brain aging and further identify pathways that may be developed therapeutically for neurodegenerative disorders and human longevity.

NSF Awards · FY 2024 · 2024-09

Everything in biology is connected. Our job as life scientists is to reveal important biological properties in the most impactful, efficient, and economical way. To do so we look for model organisms that are particularly tractable for studying complex biological processes and then apply what we learn to better understand other organisms. For more than a century, sea urchins have provided a valuable research model that has contributed significantly to our understanding of many fundamental biological processes such as fertilization, embryonic development, and cell division. Sea urchins have proven to be a valuable model due to their close genetic relationship to vertebrate animals and many features that make experimentation easier. The goal of this proposal is to create the next generation of tools to enhance the utility of sea urchins as research models that will enable new areas of research and to make these tools widely available to the scientific community. Areas of biological research to be enhanced by the tools created from this proposal include a better understanding of how eggs and sperm interact at fertilization, understanding the rules of embryo development, how nerve cells are made, how sex is determined, how animals protect themselves from environmental insults and from infection, and how tissues and organs can regenerate when they are damaged. The outcomes of this proposal will reach far beyond the scientists, to the public, students and teachers and make the sea urchin a highly attractive and impactful research and education tool of the twenty-first century. Sea urchin researchers have long sought to leverage the experimental tractability of the embryo and adult with genetic approaches but, to date, manipulations have been limited largely to dependence on morpholinos or pharmacology. The overarching goal of this EDGE proposal is to build tools that overcome major obstacles to testing gene functionality in echinoderms, opening up a new era of discovery for diverse and integrated studies across all life history stages of this valuable sister group to chordates. This goal will be realized as follows: (1) Simple and efficient protocols for culturing cells from embryos to investigate gene function in vitro; (2) Rapid, scalable DNA transfection of embryos, adult tissues, and cell cultures for conditional, and reversible gene control; (3) Techniques to promote standardization of sea urchin husbandry with open hardware and cryopreservation for sea urchin germplasm and cell lines; (4) Virtual, interactive educational materials to reach secondary school and undergraduate students and investigators learning from and even considering entering this research community. These integrated new technologies with controlled and heritable genetic manipulations and the ability to test gene function and regulation in in vitro cell-based systems will enable new avenues of investigation that fully exploit the important properties of echinoderms as a research organism. The tools developed in this proposal will remove the bottlenecks and provide scalable and sustainable resources for the community of echinoderm researchers. The proposal was funded by the Enabling Discovery through GEnomics (EDGE) program and the Developmental Systems Cluster in the Division of Integrative Organismal Systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Progressive decline in seizure control and cognitive function, coupled with anxiety and depression are often consequences of epilepsy that negatively impact a patient’s overall quality of life. None of the currently available antiseizure medicines (ASMs) prevent or reverse pharmacoresistance or modify the risk for cognitive and behavioral comorbidities associated with drug resistant epilepsy (DRE). Previous findings in our laboratory suggest that oxidative stress contributes to epileptogenesis following a brain insult like TBI, stroke, or status epilepticus (SE), and that treatment with dimethyl fumarate (DMF), the selective blood-brain barrier penetrant activator of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), upregulates the intrinsic antioxidant defenses of cells and reduces the severity of chronic epilepsy in animals following SE. We aim to test the HYPOTHESIS that DMF is disease modifying when administered at the time of neurological insult and at a time well after epilepsy diagnosis (e.g., post-symptomatic disease modification). Specifically, in the R61 Phase of this application, we will: 1) Determine the dose-dependent PK/PD relationship of DMF in naïve male and female Sprague-Dawley (SD) rats (R61 Aim 1A); 2) Demonstrate that sub-chronic (7-day) drug-in-food delivery of an optimized dose of DMF using our innovative automated medication-in-food delivery system will result in predictable and stable blood and brain levels and Nrf2 target engagement roughly equivalent to levels observed in Aim 1A (R61 Aim 1B); 3) Determine whether adjunctive oral DMF treatment with the ASMs, levetiracetam (LEV) or lamotrigine (LTG) will affect steady state blood levels when administered sub-chronically using our innovative drug-in-food delivery system (R61 Aim 1C). In Aim 1 of the R33 Phase of this application, we will define the potential of short-term systemic administration of DMF to prevent or mitigate the anxiety, cognitive decline, long-term seizure burden and ASM pharmacoresistance associated with kainic acid-induced SE in male and female SD rats. In R33 Aim 2, we will determine whether late intervention with orally administered DMF in rats with established DRE will improve pharmacosensitivity to the ASMs, LEV and LTG. At the completion of these studies, we will have defined the early and late treatment disease modifying potential of the novel first-in-class Nrf2 activator, DMF, using a clinically relevant approach in an etiologically relevant model of acquired DRE. The development of a safe and novel first-in-class disease-modifying treatment for patients at- risk for epilepsy would reduce the burden of disease and lead to significant improvements in their quality of life, cognitive function and reduce the incidence of pharmacoresistant epilepsy.

NIH Research Projects · FY 2024 · 2024-09

ABSTRACT Progressive decline in seizure control and cognitive function, coupled with anxiety and depression are often consequences of epilepsy that negatively impact a patient’s overall quality of life. None of the currently available antiseizure medicines (ASMs) prevent or reverse pharmacoresistance or modify the risk for cognitive and behavioral comorbidities associated with drug resistant epilepsy (DRE). Previous findings in our laboratory suggest that oxidative stress contributes to epileptogenesis following a brain insult like TBI, stroke, or status epilepticus (SE), and that treatment with dimethyl fumarate (DMF), the selective blood-brain barrier penetrant activator of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), upregulates the intrinsic antioxidant defenses of cells and reduces the severity of chronic epilepsy in animals following SE. We aim to test the HYPOTHESIS that DMF is disease modifying when administered at the time of neurological insult and at a time well after epilepsy diagnosis (e.g., post-symptomatic disease modification). Specifically, in the R61 Phase of this application, we will: 1) Determine the dose-dependent PK/PD relationship of DMF in naïve male and female Sprague-Dawley (SD) rats (R61 Aim 1A); 2) Demonstrate that sub-chronic (7-day) drug-in-food delivery of an optimized dose of DMF using our innovative automated medication-in-food delivery system will result in predictable and stable blood and brain levels and Nrf2 target engagement roughly equivalent to levels observed in Aim 1A (R61 Aim 1B); 3) Determine whether adjunctive oral DMF treatment with the ASMs, levetiracetam (LEV) or lamotrigine (LTG) will affect steady state blood levels when administered sub-chronically using our innovative drug-in-food delivery system (R61 Aim 1C). In Aim 1 of the R33 Phase of this application, we will define the potential of short-term systemic administration of DMF to prevent or mitigate the anxiety, cognitive decline, long-term seizure burden and ASM pharmacoresistance associated with kainic acid-induced SE in male and female SD rats. In R33 Aim 2, we will determine whether late intervention with orally administered DMF in rats with established DRE will improve pharmacosensitivity to the ASMs, LEV and LTG. At the completion of these studies, we will have defined the early and late treatment disease modifying potential of the novel first-in-class Nrf2 activator, DMF, using a clinically relevant approach in an etiologically relevant model of acquired DRE. The development of a safe and novel first-in-class disease-modifying treatment for patients at- risk for epilepsy would reduce the burden of disease and lead to significant improvements in their quality of life, cognitive function and reduce the incidence of pharmacoresistant epilepsy.

NIH Research Projects · FY 2025 · 2024-09

Abstract The goal of this study is to test the effectiveness and describe implementation of a home based exercise intervention for persons with an implantable cardioverter defibrillator (ICD). This study is based on the NIH stage model of behavioral interventions (stage III effectiveness) that aligns with the strategic mission of the NHLBI, to optimize clinical and implementation research to improve health and reduce disease (Obj #6). The study intervention is based on the protocol and monitoring components that were developed in prior RCTs and a pilot study conducted by our team. From these studies, we created a home based exercise program called Exercise-ICD (E-ICD) for testing in a broader range of ICD patients, that assists individuals to start and monitor exercise safely after an ICD. An randomized two group (E-ICD vs. usual care) pragmatic effectiveness mixed- methods study is proposed, to determine the effectiveness of the E-ICD intervention and describe implementation by cardiac rehabilitation (CR) clinical staff. Two hundred ten (N=210) patients in 3 local study sites (70/site) in the greater Seattle, WA area will participate. E-ICD is guided by the Reach-Effectiveness- Adoption-Implementation-Maintenance (RE-AIM) model. The E-ICD intervention consists of 12 weeks of home walking exercise using exercise prescriptions and protocols validated in our previous work. The primary effectiveness outcome is patient physical activity (steps/day) after the E-ICD intervention at 3 months. We will determine the number of patients who reach the public health walking goal of moderate level exercise of 150 minutes/week at the end of the study. Measures will be taken at baseline, after the intervention at 3 months, and at 6 and 12 months to determine maintenance. The specific aims are to: 1) Test the hypothesis that participants randomized to E-ICD vs. usual care (UC) will demonstrate increased physical activity (minutes walked/week) [primary outcome], health related quality of life, gait speed, mobility, exercise self-efficacy; and reduced ICD shock anxiety and depression at 3 months (E-ICD Effectiveness), 2) Assess longer term effects of E-ICD on participant and health care system Maintenance, captured by 1) participant retention, satisfaction, and adherence at 12 months (total minutes/week), and 2) clinician and institutional intent to sustain use of the E-ICD intervention after the study, and 3) Evaluate the reach, adoption, and implementation of E-ICD by CR clinical staff. Reach will be assessed by the diverse patient participation rate, representativeness, and reasons for non-interest. Adoption is the participation rate and representativeness of the settings and staff who participate, and factors related to adoption. Implementation will be assessed by delivery fidelity of E-ICD and workflow adaptations, implementation costs, and consistency of delivery across settings. Intervention effectiveness will be described by participant social determinants of health (SDoH).

NIH Research Projects · FY 2024 · 2024-09

Project Summary. Ferroptosis is a regulated form of cell death that is dependent on iron and driven by lipid peroxidation. Glutathione peroxidase 4 (GPX4) plays a central role in inhibiting ferroptosis as it reduces lipid peroxides to alcohols, which prevents the initiation of lipid peroxidation via iron-mediated Fenton chemistry. Oxidizable polyunsaturated fatty acids (PUFAs) have been found to sensitize cells to ferroptosis. Endogenous PUFAs in the human body only contain nonconjugated double bonds and undergo lipid peroxidation primarily through the “hydrogen-atom transfer” (HAT) mechanism. On the other hand, we recently discovered that PUFAs with conjugated double bonds display much higher reactivity toward lipid peroxidation than nonconjugated PUFAs, and their oxidation proceeds primarily via a “peroxyl radical addition” (PRA) mechanism. Specifically, conjugated linoleic acid (CLA 18:2) is twice as reactive as nonconjugated linoleic acid (NLA 18:2), while conjugated linolenic acid (CLA 18:3) is over 8 times more reactive than nonconjugated linolenic acid (NLA 18:3). CLA 18:2 and CLA 18:3 are found in the diet that includes meat and dairy products from ruminants and some edible plants. Significantly, it was recently found that CLA 18:3 induces ferroptosis by itself through a mechanism distinct from canonical ferroptosis inducers, such as GPX4 inhibitors. Furthermore, we found that CLA 18:2 is much more potent in enhancing ferroptosis in cancer cell lines than any nonconjugated PUFAs. However, the mechanism of ferroptosis induction or potentiation by CLAs remains to be elucidated. The goal of this project is to elucidate how the different oxidation mechanisms between NLAs and CLAs lead to their different potency in inducing ferroptosis. The unique oxidation mechanism of CLAs is expected to lead to the truncation of the fatty acids and subsequent formation of high levels of aldehydes, which are reactive electrophiles that can form adducts with nucleophiles, such as proteins, in a biological system. We hypothesize that the PRA peroxidation mechanism and the resulting high levels of reactive electrophilic products are underlying the mechanism of ferroptosis induction by conjugated PUFAs. In Aim 1, we will determine the spatial distribution and progression of lipid peroxidation in cells treated with NLAs or CLAs using stimulated Raman scattering (SRS) microscopy and lipidomics. In Aim 2, we will reveal the protein targets of the electrophilic products of conjugated PUFAs using protein pulldown with alkynylated probes and determine the gene targets of these products using RNA sequencing. This project is significant because it will reveal the detailed steps between lipid peroxidation and the eventual cell death, including the location and progression of lipid peroxidation and protein and gene targets of lipid electrophiles, all of which could lead to new ways to modulate ferroptosis for the prevention and treatment of cancer or degenerative diseases. The innovation lies in the concept that the high levels of electrophilic products of CLAs contribute to the induction of ferroptosis through its high reactivity toward nucleophiles, in situ imaging of chemical bond changes by SRS microscopy, and the “click” chemistry-based pulldown proteomics.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Adolescent girls and young women (AGYW; age 15-24) in East and southern Africa are disproportionately affected by poor sexual and reproductive health (SRH) outcomes related to HIV acquisition and unintended pregnancy. Despite increasing recognition of AGYW’s interrelated needs for HIV pre-exposure prophylaxis (PrEP) and family planning (FP) services, facility-based SRH programs struggle to reach at-risk AGYW and up to 50% of AGYW seek contraception outside of health facilities, including at retail pharmacies. Pharmacy-based care models can also increase options for expanding PrEP reach, and efforts are underway to implement pathways for pharmacy-delivered PrEP in Kenya, an African leader in PrEP implementation at scale where AGYW have been identified as a priority group. In collaboration with the Kenya Ministry of Health, our group is conducting a cluster randomized clinical trial (RCT) at 20 pharmacies in Kisumu, Kenya–a region with an HIV prevalence of up to 28% among women–to test the effectiveness of utilizing nurse-navigators at retail pharmacies to enhance AGYW PrEP use. This trial (R01HD108041, NCT05467306) will enroll 1900 AGYW seeking contraception at randomized pharmacies and participants will be offered daily oral PrEP and the dapivirine vaginal ring (DPV-VR) per national guidelines. The WHO and UNAIDS jointly recommend integrated FP and HIV prevention services, yet little is known about the interplay between PrEP and FP use among AGYW seeking care in pharmacies, limiting strategic co-delivery of AGYW-centered SRH services in this context. Given overlapping risk for unintended pregnancy and HIV among AGYW, integrated service delivery in pharmacies could provide positive synergy for acceptability and quality of FP and PrEP services. In this proposal, we apply an explanatory sequential mixed methods design to elucidate the synergies between pharmacy-based FP and PrEP use and service delivery among Kenyan AGYW, and to translate our findings into AGYW-centered implementation strategies for delivering quality integrated FP and PrEP in pharmacies. Aim 1 will use group-based trajectory modeling to identify FP use patterns associated with PrEP use outcomes among a cohort of 1900 AGYW, and to characterize the patterns’ sociodemographic, behavioral, and psychosocial correlates. In Aim 2, we will combine qualitative and human-centered design methods to contextualize synergies in pharmacy-based FP/PrEP use and inform testable implementation strategies for integrated service delivery. Guided by the Theoretical Domains Framework, we will determine the barriers and facilitators to integrated FP and PrEP provision for AGYW in pharmacies. We will triangulate this work with participatory workshop methods, engaging AGYW to identify key design elements for integrated pharmacy-based FP/PrEP implementation strategies. This will be the first study aiming to improve implementation of integrated FP and PrEP access for AGYW using a pharmacy-based model and will prime pharmacies to deliver multi-purpose technologies currently in the pipeline.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Once considered a distant threat, climate change is now dramatically increasing the likelihood of potentially preventable adverse impacts on human health and wellbeing.1 Implementing evidence-based policies, programs, and interventions, collectively called adaptation, is an urgent challenge.2 Prioritizing evidence-based adaptation interventions should be based on community perspective and priorities, practitioner expertise, and scientific information on risks and risk reduction effectiveness.3 Implementation science can support adaptation at scale by identifying factors affecting uptake of evidence-based interventions.4,5 The mission of the University of Washington (UW) Research and Engagement on Adaptation for Climate and Health (REACH) Center is to leverage implementation science in support of implementing evidence-based health adaptation at scale. The University of Washington is an outstanding setting for developing an adaptation-focused climate and health research center. The UW is a leading research institution with large training programs in the health sciences and an outstanding record of community engaged research. The institution has strength in multiple relevant disciplines and in implementation science in several domains, but does not yet have implementation science programming focused on community-engaged climate change adaptation in the health sector. The REACH Center’s focus on implementation science to advance adaptation is a key innovation in the field, and the Center will also advance several other innovations, including a novel climate and health decision support tool (the Climate and Health Risk Tool, or CHaRT), a new climate and health implementation science curriculum, a new interdisciplinary planetary health curriculum at the UW School of Medicine, a suite of pilot climate and health intervention activities in communities in the Pacific Northwest, and community engagement activities in support of the research project and the climate and health interventions.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Youth living with HIV (YLH) have high rates of viral non-suppression and non-retention, particularly during the period when they transition from adolescent to adult autonomous care. In partnership with the Kenya Ministry of Health (MoH), we used a community engagement approach to develop the Adolescent Transition Package (ATP), a healthcare worker (HCW) toolkit that includes structured educational materials and tracking tools to facilitate the transition process. We recently tested the ATP in a cluster randomized clinical trial (cRCT) of >1000 YLH in 20 clinics and found the ATP effective at improving transition readiness. The ATP was acceptable and feasible. The Kenya MoH is committed to supporting transition among YLH and scaling up the ATP. We propose testing strategies to SCALE-UP the ATP in Kenya using a data driven youth led implementation strategy. Aim 1: Using a hybrid III implementation-effectiveness design, compare two implementation strategies for scale- up of ATP: Kenya MoH SoC implementation strategy (cascading training of trainers) to an enhanced scale-up implementation strategy (ATP-YES) (SoC plus youth-led data- driven intervention adaptations). Approach: Thirty-two HIV clinics (8 per county) will be randomized 1:1 to SoC or ATP-YES. In intervention sites, youth leaders will lead routine ATP implementation assessments and targeted adaptations to optimize reach, effectiveness, adoption, and implementation (fidelity) through data audits, cyclical small tests of change and cross-facility learning. Aim 1a: Compare 3-year ATP reach, adoption and effectiveness between intervention and control sites. Reach: proportion of YLH age 15-24 years exposed to the ATP intervention. Adoption: proportion of HCWs using the ATP. Effectiveness: successful transfer to adult care, post-transition retention and viral suppression and transition readiness scores. Aim 1b: Using the Consolidated Framework for Implementation Research (CFIR) framework, identify determinants of ATP adoption, implementation (fidelity to the ATP) and maintenance of the ATP. Aim 1c: Summarize intervention adaptations using the Framework for Reporting Adaptations and Modifications to Evidence-based Implementation Strategies (FRAME-IS). Aim 2: To evaluate the cost-effectiveness and budget impact of the ATP-YES implementation strategy. Approach: We will conduct micro costing, HCW interviews and time and motion observations to estimate the incremental costs of implementing the ATP-YES strategy in routine HIV care. We will combine cost with effectiveness data from Aim 1a into a Markov model to project the health impact (HIV deaths and morbidity averted) and financial costs of the intervention compared to standard of care and estimate the cost-effectiveness and budget impact of ATP-YES implementation. This implementation science study focuses on sustainable implementation of an evidence-based intervention through youth-led data-driven intervention adaptations. The project aligns with existing MoH infrastructure and has potential to impact many YLH in Kenya and in similar settings.

NIH Research Projects · FY 2025 · 2024-09

I aim to become an independent researcher who studies parenting in diverse cultures via multiple methods and who builds, tests, and evaluates culturally sensitive preventive interventions for ethnically diverse families. This project will build on my expertise in parental psychological control (conceptualization, measurement, and mechanisms), my skills in quantitative data analyses, and my experience with questionnaire data collection. Additional training in family observations and interviews and solidifying my expertise in Latinx parenting (K99) will equip me to test my culturally sensitive mechanisms of PPC longitudinally (R00) and develop and evaluate culturally sensitive preventive interventions for culturally diverse families (future R01). My efforts to promote equity based on my background—coming from poverty, being a first-generation college student, having recovered from physical disabilities, and being a woman—make me eligible for the Maximizing Opportunities for Scientific and Academic Independent Careers program to enhance workforce diversity. Parental psychological control (PPC)—a set of intrusive parenting behaviors that emotionally manipulate children to obey their parents—has been associated with diverse negative developmental outcomes reported in more than 770 papers. However, the lack of culturally sensitive measures and of the mechanisms of PPC limits our understanding of if and how PPC impairs children’s development in diverse cultures. Although behaviors ethnically diverse families consider to be intrusive may differ from what white American families consider intrusive, this cultural variability of intrusiveness has been neglected in the PPC research literature. Drawing from my Two Facet Parental Psychological Control conceptual framework, I will measure what Mexican immigrant families believe to be intrusive (K99). Drawing from the Family Stress Model and the Integrative model for studying children’s developmental competencies of minority children, I will test a culturally sensitive mechanism of PPC in a longitudinal study (R00) with my refined PPC questionnaire from K99. In the K99 phase, I will observe and interview families and administer my PPC questionnaire to families to adapt my questionnaire to Mexican immigrant families. I will include fathers, who have been excluded from most PPC research, and adopt mixed methods to use interview and observation results to generate culturally sensitive items and refine my items. In the R00 phase, I will test longitudinally whether parents’ enculturative stress and beliefs about traditional gender roles (e.g., machismo, marianismo) predict PPC and whether that PPC then predicts children’s poor health. With this training, I will later examine culture-specific and unique impacts of PPC in diverse cultures. My results will provide a reproducible methodology for other researchers to create culturally sensitive measures of PPC based on what people in those cultures believe to be intrusive, which will provide a foundation for culturally sensitive preventive interventions to improve ethnically diverse children’s health and well-being. This project closely fits NICHD’s mission “to ensure the independence and well-being ofall people.”

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT We have entered an exciting era for PrEP with two additional non-oral products, a monthly dapivirine vaginal ring and a bi-monthly injectable cabotegravir, with several more options in various stages of clinical development. While the effectiveness of these interventions is now well established, uptake and persistence on PrEP depend not only on client-level factors but also on how well opportunity costs and health system barriers can be navigated by potential PrEP clients. Thus, taking these novel PrEP interventions to full scale will require simplifying and diversifying models for delivery, to achieve options that are accessible, scalable, and meet the needs of clients and health systems. Since 2020, in collaboration with the Kenyan Ministry of Health we have demonstrated PrEP can be delivered in African family planning clinics (FP) using existing staff and infrastructure in a programmatic stepped-wedge cluster-randomized trial (FP-Plus project), significantly increasing the proportion of general population women screened for PrEP from 3% to 93% and PrEP initiations among eligible women from <3% to 46%. We have also learned that there are several key health system barriers, such as heavy workload and lengthy clinic visits that burden the health system and limit expanded delivery at scale up. Within the FP-Plus project, we piloted model that allows HIV testing (HTS) counselors to screen and determine PrEP eligibility and that it both reduced clinic time by 60% and resulted in higher PrEP initiations and early PrEP continuation versus comparable control clinics maintaining usual care. We hypothesize that PrEP care can be done by HTS providers, in a single HIV testing encounter with clinician oversight as needed, in a way that will be more time- efficient and client-centered and will be acceptable, scalable, and readily transferable to other African settings. With an interdisciplinary team and our deep knowledge of the Kenya health system, we will use a participatory research approach with key stakeholders to co-develop and refine the core components of a ‘scalable unit’ composed of a simplified HTS counselor-led PrEP care intervention and an MOH feasible technical advisory and provider training support delivery at scale (Aim 1). We will then road test the effectiveness and impact of HTS counselor-led PrEP care to catalyze expansion of PrEP delivery at scale in 20 Kenyan health facilities representing a spectrum of clinical contexts likely to occur at full scale implementation (Aim 2). Lastly, we will use mixed methods to triangulate multilevel determinants of delivery at scale, including behavior science studies to understand and incorporate women perspectives, explore partner and community influence, and barriers to PrEP access and use; clinic and provider capacity to deliver multiple PrEP products; and key stakeholders’ power, interests, and perspectives (Aim 3). We have already demonstrated that PrEP can be delivered in African health facilities; this work will boldly extend that further, aiming for simplified facility-based PrEP delivery with greater clinic efficiency, diminished client burden, and greater public health impact of PrEP at population level.

NIH Research Projects · FY 2025 · 2024-09

The United Nations Joint Programme on HIV/AIDS describes current global HIV data as frightening. In the landmark year 2020, all global targets for HIV treatment and prevention were missed. During the past two years, multiple overlapping crises have made the situation even worse, with a reversal of previous progress in many areas of HIV treatment and prevention. Key populations have been disproportionately affected. Compared to other groups, women who engage in sex work tend to have lower ART uptake, poorer adherence, and worse treatment outcomes. They are frequently stigmatized, difficult to reach, and often do not benefit from treatment and prevention efforts targeted to the general population. Despite several clinical trials of interventions to improve the low rate of reaching an undetectable viral load (VL) in women with HIV who engage in sex work, none has demonstrated efficacy, underscoring the need for evidence-based interventions (EBIs) to support antiretroviral therapy (ART) adherence in this key population. To address this important HIV treatment and prevention gap, we used an iterative development process in collaboration with women who engage in sex work to create Motivation Matters! (MM!), an interactive mHealth intervention grounded in the Theory of Information, Motivation, and Behavior. We generated preliminary data on efficacy and participant-level feasibility and acceptability of MM! in a small randomized controlled trial (RCT). In the population of women engaged in sex work who were viremic at baseline, undetectable VL at month six was achieved in 74.3% (26/35) of intervention and 46.2% (12/26) of control participants (relative risk [RR] 1.61, 95%CI 1.02-2.55). These promising preliminary results informed this proposal for a hybrid type 1 effectiveness-implementation trial to test the effectiveness of MM! for achieving undetectable VL in women with HIV who engage in sex work. In parallel, we will evaluate key implementation, service, and client outcomes including intervention fidelity, feasibility, acceptability, appropriateness, cost, safety, patient-centeredness, engagement, and satisfaction to guide scale-up of MM!. Our aims are: 1) To conduct a RCT to compare the safety and effectiveness of Motivation Matters! vs. standard of care (SOC, control) for achieving undetectable viral load in women with HIV who engage in sex work and are initiating ART, 2) To conduct a mixed-methods study, organized within the framework of the Implementation Research Logic Model (IRLM), to examine patient-centeredness (service outcome) and key implementation outcomes including fidelity, feasibility, acceptability, appropriateness, and cost of MM!, and 3) To conduct a mixed-methods study, organized within the IRLM framework, to evaluate participants' satisfaction, engagement, and treatment related knowledge, motivation, and behavior. A definitive trial demonstrating the effectiveness of MM! would shift the clinical practice paradigm for supporting ART adherence in this key population by providing a simple and inexpensive EBI to improve rates of undetectable VL. Implementation research conducted in parallel will guide scale-up to achieve population-level impact if this is warranted based on our data.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT HIV and TB are leading and linked global epidemics. Household members of people with TB have an elevated prevalence and incidence of both TB and HIV. HIV pre-exposure prophylaxis (PrEP) reduces HIV acquisition by >90%, and both WHO and the Uganda Ministry of Health recommend PrEP as part of a comprehensive prevention package for HIV-negative persons with substantial exposure to HIV. New implementation approaches are needed to ensure that PrEP reaches all people who could benefit. A promising implementation approach to increase PrEP access is through household-based TB contact investigation, which is a leading strategy to decrease TB morbidity and mortality, particularly in high-incidence settings like Uganda. Care models that integrate HIV testing in household TB contact investigation are being evaluated. However, PrEP has not been integrated into TB household contact investigation in high-prevalence settings. Recently, we found that couples identified in households affected by TB in Kampala, Uganda were twice as likely to be serodifferent for HIV than couples in the general population (16% vs. 8%), suggesting that people living in TB-affected households may benefit from PrEP. Multiple studies have shown that household-based linkage to PrEP is feasible and effective in high HIV-burden settings, including among HIV serodifferent couples and pregnant people. We therefore propose to adapt the proven intervention of PrEP to a new setting of household TB contact investigation and evaluate its implementation, effectiveness, and costs using the RE-AIM implementation framework, a widely used framework for evaluating how proven interventions perform in a new delivery context. We hypothesize that integrating HIV prevention into household TB contact investigation will be a feasible, acceptable, effective, and cost-effective strategy for expanding access to status-neutral HIV services, including HIV self-testing and linkage to antiretroviral therapy and PrEP. In Aim 1, we assess the implementation and effectiveness of home-based HIV self-testing and PrEP initiation versus standard clinic referral for PrEP during household TB contact evaluation in Uganda. We use a household-randomized trial design and test the hypothesis that home-based PrEP initiation will increase PrEP uptake and retention compared to clinic referral. In Aim 2, we use qualitative methods to examine the processes of implementing HIV self-testing and PrEP during household TB contact investigation. In Aim 3, we estimate the cost-effectiveness of the strategy to integrate home-based HIV testing and PrEP with household TB contact investigation to assess its sustainability. This work is impactful because understanding how to offer HIV self- testing and PrEP in the setting of household TB contact investigation will facilitate increased use of PrEP, an underutilized innovation for HIV prevention, by leveraging existing health programs.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Women known to be at high risk for breast cancer have opportunities to reduce their risk through primary and secondary breast cancer prevention, including risk-reducing medications and supplemental screening beyond mammography. However, breast cancer risk models used to identify women eligible for risk reduction have only modest accuracy for predicting individual- level breast cancer risk and perform even less well in Black and Hispanic women compared to White women. Mammography-based AI algorithms have the potential to improve breast cancer risk prediction, with early studies suggesting image-based AI technologies outperform traditional clinical risk factor-based models commonly used in current practice. Multiple commercial mammography-based AI breast cancer risk algorithms will soon obtain U.S. Food and & Drug Administration approval for clinical use. Although promising, these models have limited performance data in real-world screening settings and there is a critical need for rigorous, independent evaluation prior to their adoption in clinical practice. The goal of this proposal is to use a large, diverse screening population to examine whether mammography-based AI breast cancer risk models can improve clinical risk prediction and reduce the inequities associated with currently used models. The accuracy and performance of four commercial mammography- based AI breast cancer risk algorithms will be evaluated using mammograms and cancer outcomes for women undergoing routine screening mammography at seven facilities across the Breast Cancer Surveillance Consortium. Model performance will be evaluated across race and ethnicity groups and compared to currently used clinical risk-factor based models. Finally, an established and externally validated breast cancer simulation model will be used to estimate the population-level health impact of adoption of AI-based breast cancer risk models for targeted risk reduction approaches. Overall, this work will provide robust performance and patient outcomes data that will guide physicians and policymakers for more precise applications of AI to identify women most likely to benefit from risk reduction measures beyond mammography and ultimately improve population-level breast cancer outcomes.

NIH Research Projects · FY 2024 · 2024-09

SUMMARY Increased attention must be given to the health of women living with HIV (WLHIV) across all stages of their lives, especially in sub-Saharan Africa and countries like Kenya where girls and women have the highest HIV prevalence and rates of new infections. Emphasis on women’s health is critical because WLHIV face unique health challenges and are often disproportionately affected by co-morbidities, especially as they age. It is essential that institutions build the in- country capacity to design and conduct research that will improve health of WLHIV. This is the primary goal of the parent D43 Fogarty-funded program, led by Drs. Elizabeth Bukusi (Kenya Medical Research Institute [KEMRI]) and Carey Farquhar (University of Washington [UW]), is entitled Women and HIV: Translation of Research into Practice (WHIV). In this application, we propose to complement what we are doing in the parent award and provide funding, mentorship and support for recent graduates of the D43 program who are on the path to becoming independent investigators. From 2015 to the present, our WHIV Fogarty training program has supported 27 researchers as they earned advanced degrees at the UW and University of Nairobi (23 MPH, 4 PhD). We have found that post-graduate funding is essential to ensure the success of our recent graduates as they transition to initiating independent research on HIV and women’s health. For this supplement we solicited concept notes from all eligible trainees and identified 4 MPH graduates to compete with full proposals for two fellowship positions. Our Training Advisory Committee will select the two awardees who will receive stipend and research support for their studies. They will also receive high-quality mentorship from experienced teams of KEMRI and UW mentors and participate in online research seminars, manuscript and grant writing workshops, and regular meetings with the MPIs, their peers and their mentors to review their research progress and discuss important career development topics. The WHIV D43 has used this approach with post-doctoral fellows to fill funding and mentorship gaps after graduation and will build on that successful experience.

NIH Research Projects · FY 2024 · 2024-09

Project Summary Dental decay and tooth loss are common problems. Bridges and implants are the primary treatment options but cannot completely restore the tooth biology and function. Although using cells from embryo to rebuild a functional bioengineered tooth has been demonstrated in animals, little is known in how to use a cell source to regenerate teeth in humans. Human induced pluripotent stem cells (hiPSCs) hold tremendous promise to regenerate teeth because of their near-unlimited regenerative capacity that can produce almost any tissues in the body. However, stem cell-based therapy has been hindered by our limited ability to provide an adequate microenvironment for stem cell renewal and differentiation and lack of understanding on the key signals required to regulate cell fate and cell-cell interaction during tooth development. The proposed research aims to develop a well-defined, feeder-free 3D material microenvironment for regulating self-renewal and differentiation of hiPSCs into odontogenic epithelial stem cells (OESCs) and neural crest cells (NCCs), and to co-culture OESCs with NCCs for tooth regeneration. The proposed 3D construct is made of a hybrid scaffold of chitosan and alginate (CA), two natural polymers that have a proxy structure of glycosaminoglycans, a major component of the native extracellular matrix (ECM). Natural polymer-based materials are clinically preferable over synthetic polymers or protein-based materials due to their excellent biocompatibility, biodegradability, and minimal immunogenicity. In addition, unlike synthetic polymers, The CA scaffold can be readily decomposed in cell-compatible solutions thus posing no harm to grown stem cells facilitating subsequent use and analysis. The specific aims of the proposed research are to (1) investigate how material composition and mechanical properties regulate stem cell renewal and if CA scaffolds optimized for stem cell renewal can support long-term growth of OESCs and NCCs in vitro; (2) differentiate hiPSCs into OESCs and NCCs, and identify proper reciprocal interactions of epithelial-mesenchymal stem cells for odontogenesis by co-culturing OESCs with NCCs in CA scaffolds; (3) enable odontogenic differentiation of hiPSCs and tooth tissue formation in an orthotopic mouse model. Successful completion of the proposed research would make a profound impact on stem-cell biology and technology and on human tooth tissue regeneration. Studies of tooth formation from human pluripotent stem cells will enhance the research community’s understanding on the fate decisions of tooth-specific lineages in odontogenesis and the epithelial-mesenchymal interactions required during tooth development.

NIH Research Projects · FY 2025 · 2024-09

Low back pain is the #1 contributor to years lived with disability (CLBP; pain persisting for ≥3 months). An obstacle to reducing the societal burden of CLBP is that most treatments have only small effects (~5-10% improvements in functional limitations and pain) when compared to a control treatment. Lumbar radiofrequency ablation (LRFA) is a minimally invasive procedure that is widely performed for CLBP. It can be used in patients for whom CLBP is isolated to the lumbar facet joints, defined by pain relief (“positive responses”) after local anesthetic medial branch blocks (MBBs) to the medial branch nerves. LRFA applies a thermal lesion to these nerves, temporarily reducing or eliminating CLBP. Unlike most CLBP treatments, LRFA can result in large improvements in properly selected patients. However, LRFA is neurodestructive, has potential adverse effects, and there is conflicting evidence regarding its effectiveness as seen in randomized controlled trials (RCTs). Experts have noted that those RCTs showing no effects of LRFA may be explained by (1) poor LRFA technique insufficient to adequately lesion the medial branches, and (2) suboptimal clinical selection criteria for identifying LRFA candidates. The most stringent evidence-based guidelines for LRFA technique and patient selection are those of the Spine Intervention Society (SIS). The SIS guidelines mandate various aspects of technique to optimize medial branch lesioning and consequent improvements in CLBP. They also include stringent clinical screening criteria for determining appropriate LRFA candidates, such as requiring ≥80% pain improvement to define positive MBB responses, and 2 separate sets of comparative MBBs with low anesthetic volume (<0.5cc). A definitive RCT of LRFA vs. control has yet to be conducted. Despite this, LRFA using conventional electrodes (LRFA-C) and new technological modifications to LRFA are now commonly used. These modifications are intended to make the procedure easier to perform and faster than LRFA-C. Among these modifications, LRFA using multi-tined electrodes (LRFA-M) has shown the greatest promise. However, there are no RCTs examining whether LRFA-M improves clinical outcomes compared to a simulated LRFA control procedure, or whether it is actually easier or faster to perform than LRFA-C. We propose A Superiority Trial of Lumbar Radiofrequency Ablation for Low back pain, or “ASTRAL”: a definitive, double-blind, 3-arm, multicenter trial to examine the effectiveness of LRFA-C and LRFA-M, each compared to a simulated ablation control procedure (simulated LRFA). ASTRAL will use the SIS criteria for LRFA technique and patient selection. Aim 1 is to compare the effectiveness of LRFA-C with simulated LRFA for improving back-related functional limitations. Aim 2 is to compare the effectiveness of LRFA-M with simulated LRFA for improving back-related functional limitations. Secondary aims will compare LRFA-C and LRFA-M with regards to procedure duration, radiation dose, and patient pain intensity during the procedure.

NIH Research Projects · FY 2024 · 2024-09

Project Summary/Abstract Here, we propose a training program with two years of training to prepare the candidate for a successful transition to independence, in the field of developing machine learning integration algorithms to predict undercharacterized genomic and proteomic data. The training plan is designed to guide the candidate's scientific and professional development, under the men-torship of Dr. Noble and guidance from five advisory committee members (Drs. Christine Disteche, Jay Shendure, Brian Beliveau, Mike MacCoss, and Sheng Wang) at the University of Washington. The committee will help the candidate extend their knowledge of proteomics, spatial imaging, and machine learning development. The proposed research focuses on developing semi-supervised machine learning integration tools that can predict the various types of single-cell profiles (e.g., chromatin accessibility, spatial locations, proteomics) from known measurements (e.g., gene expression). In Aim 1, we propose to computationally fill in the gap of single-cell time series snapshots to infer continuous cellular profile changes, by building a conditional variational autoencoder model with continuous time representations. The model will enable us to infer temporal maps of single cells in conditions with sparser time points captured (e.g., a mouse mutational strain collected in another experiment, human embryonic development, chromatin accessibility measurements). In Aim 2, we will develop a semi-supervised joint machine learning model stitching together the conditional variational autoencoder model and graph neural network to predict the physical locations of cells with dissociated gene expression and chromatin accessibility measurements. In Aim 3, we will combine the semi-supervised framework with deep tensor factorization and use genomics and bulk assays to infer single-cell proteomics profiles and identify genome-scale protein markers in single cells with only gene expression profiles. The research plan will generate computational tools to project single cells to their spatiotemporal contexts and understand the protein mediators. The tools will be generally applicable to studies of complex biological systems (e.g., embryonic development) and diseases (e.g., cancer). With the rapid development in single-cell time-series, spatial imaging, and proteomics, we expect our methods to have increasing power for biological knowledge detection.

NIH Research Projects · FY 2024 · 2024-09

Intimate partner violence (IPV) is a critical determinant of health, affecting over 40% of women and men in the US. IPV is particularly prevalent in Alaska and among American Indian and Alaska Native individuals. Given the widespread prevalence, impact on communities, and associated adverse outcomes, prevention strategies are urgently needed. Public health nurses (PHNs) can play a key role in IPV prevention, particularly in rural and underserved communities. These nurses work “upstream” to prevent and mitigate risks for underlying challenges to health and have unique skills in communication, collaboration, and applying evidence-informed approaches. Alaska has a unique geography and largely centralized public health system with a statewide infrastructure to deploy prevention practices. In their 2018-2021 strategic plan, Alaska’s statewide Section of PHN, within their Department of Health, made IPV a priority focus area. The Alaska Section of PHN is currently recentering their prevention efforts and updating their strategic plan. To guide their strategic planning process, we propose a practice-based research partnership between academic researchers at two leading research institutions and Alaska’s statewide Section of PHN to advance the use of high-impact, evidence-informed IPV prevention practices throughout the state. With input from Advisory Board members representing various organizations in Alaska, a team of interdisciplinary researchers and practitioners with expertise in IPV prevention, public health systems, practice-based research, mixed methods, and implementation science will initiate an Implementation Mapping process that combines quantitative data from existing sources (i.e., administrative data documenting PHN activities across the state) with newly acquired qualitative data from focus groups with PHNs and other state public health leaders. Specifically, we will: (1) describe the array of IPV practices delivered by PHNs throughout the state; (2) identify factors related to effective implementation of IPV practices delivered by PHNs; and (3) develop implementation strategies for PHNs to overcome common barriers to effective implementation of evidence-informed IPV practices using established implementation science frameworks: RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) and the Consolidated Framework for Implementation Science (CFIR). Identifying and implementing IPV prevention practices that are evidence-informed, feasible, relevant, and contextually appropriate is critical to the advancement of IPV prevention led by PHNs in Alaska. Findings from this solution-oriented study will benefit state and national organizations engaged in IPV prevention with rural and underserved communities and support further research regarding IPV prevention and PHN practice.

NIH Research Projects · FY 2026 · 2024-09

Building on our previous work, we are proposing an innovative dual-mode breast cancer scanner combining positron emission tomography (PET) and x-ray tomosynthesis (XT). Patient-specific evaluation of breast cancer therapy has become a compelling application of quantitative positron emission tomography (PET) imaging. With the advent of neoadjuvant therapies, it has been shown repeatedly over the last decade by at least 11 studies that molecular imaging with clinical PET scanners can be used to gauge response of breast tumors to therapies within days. In this approach, a window of opportunity between diagnosis and surgery allows early evaluation of the effectiveness of the planned adjuvant therapy before breast cancer resection. After a baseline PET image followed by a subclinical dose of the planned therapy, a second PET scan can be used to evaluate treatment response. If there is no response then there is time to test second-line and other alternative therapies and to guide the selection of an effective post-surgical adjuvant therapy. Dedicated breast-imaging PET scanners have been proposed and evaluated since the late 1980s. Despite the sustained level of interest, clinical breast PET imaging with whole-body (WB) PET scanners has had little adoption, a reflection of the challenges of using breast PET imaging in the diagnostic setting. Our approach instead is to focus on the quantitative assessment of response to breast cancer therapy, a unique advantage of PET imaging. However, this advantage is lost when imaging small objects (< 2 cm) in whole-body (WB) PET scanners due to limited resolution. This has created a mismatch between current technological capability and clinical need: WB-PET is accurate down to roughly 2 cm, but lesions <2 cm in size are the most prevalent at breast cancer diagnosis. Thus a quantitative breast imaging high-resolution PET/XT scanner will enable patient-specific optimization of therapy in early-stage breast cancer. Our three aims are: (1) Development and construction of the PET/XT scanner. (2) Develop and implement the necessary quantitative data correction algorithms for the PET/XT rectangular geometry, and integrate them with accelerated image reconstruction. (3) Perform initial imaging studies with 10 breast cancer patients immediately after their scheduled clinical WB PET/CT imaging. Comparisons of the PET/XT and PET/CT images will be used to design a follow-up clinical trial. The PET/XT system will be useable immediately in local clinical trials evaluating new breast cancer therapies. Initial patient studies will also provide essential data for designing follow-up clinical trials evaluating translation to clinical practice.