University Of Washington

NIH Research Projects · FY 2025 · 2024-06

Project Summary The ability to produce spatially and contextually dependent motor responses depends on the nervous system’s capacity to spatially localize tactile signals. How these computations are accomplished and how the diversity of neuronal cell-types contribute to network function is not well understood. This project will investigate how patterns of synaptic connectivity between diverse cell-types in the nervous system contribute to the spatial localization of tactile stimuli. The Tuthill lab is a collaborative and multifaceted team studying proprioception and sensorimotor processing in Drosophila melanogaster. This project will integrate information from different parts of the sensorimotor pathway while focusing on neural circuits involved in tactile information processing. Specifically, it will investigate how tactile sensory information from the leg is represented topographically in the ventral nerve cord (VNC) of the fly. This will be done by mapping the morphologies and projection patterns of tactile mechanosensory neurons using spatially selective genetic labeling techniques. Moreover, the fine morphology and synaptic connectivity patterns of individual sensory neuron axons will be reconstructed using volumetric electron microscopy image data. To characterize important cell-types in the tactile circuit, interneurons in the VNC that receive synaptic input from the tactile mechanosensory neurons will also be reconstructed. This will involve predicting the cell-type identity of these cells based on morphology, synaptic connectivity, and local shape features, all of which can be derived from large scale electron microscopy. This will shed light on the diverse neuronal types involved in tactile sensory networks as well as the anatomical features that define such types. Finally, theoretical modeling techniques will be applied to elucidate how the architecture of tactile circuits define the spatial representation of tactile sensation and how that may predict the spatial acuity of the fly in response to stimulation. This involves developing a model that represents tactile mechanosensory neurons from different areas on the leg and their downstream partners in the VNC. Constrained by the synaptic connectivity, this model will predict the spatial resolution with which flies can distinguish tactile stimulation on the leg. Overall, this project will examine how individual connections between neurons contribute to tactile sensory encoding and elucidate how deficits in the tactile circuit may affect spatial localization.

NSF Awards · FY 2024 · 2024-06

This project develops a critical technological capability that does not currently exist — the ability to accurately deploy a large number of sensors to otherwise inaccessible locations from aerial platforms. Specifically, it creates fully functional, battery-free microfliers that communicate with each other to self-organize and coordinate their descent, enabling precise deployment of wireless sensor networks over large spatial scales. Such microfliers could be transformative for large-scale distribution and automated deployment of wireless sensors across applications like environmental monitoring, disease management, and other domains which require deploying sensors across large areas. This interdisciplinary project spans origami design, low-power actuation, power-harvesting, wireless networking, localization, and distributed control and computing to create networked battery-free microfliers that can in an energy-efficient manner actuate, communicate, and coordinate their in-air descent, achieving targeted, large-scale sensor deployment. This interdisciplinary research develops a series of enabling technologies towards the goal of creating a network of microfliers that can coordinate their deployment. This includes novel designs of the origami structures, sensors, actuators, and power harvesting that allow microfliers to change their shape and examine how these changes affect their flight dynamics. The research develops techniques for fine-grained control over the microfliers' fall behavior in mid-air, enabling a new capability for modulated descent that balances between power-intensive flight and passive falling. Additionally, the project develops novel methods that enable fliers to navigate in controlled directions and localize their 3D positions in a power-efficient manner. The research team develops battery-free distributed networking protocols that enable the microfliers to communicate with each other during flight. This effort explores various techniques, including battery-free network synchronization, location-aware frequency allocation and scheduling, height-area power adaptation algorithms, and methods that enable microfliers to communicate during descent across neighbors to self-organize and achieve targeted deployment. 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 2026 · 2024-06

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. MODIFIED TITLE: The impact of early experiences and parent sensitivity on infant cellular aging: A randomized controlled trial. Modified Project Summary The aim of the proposed randomized controlled trial (RCT) is to test if an evidence-based home visiting model, Promoting First Relationships® (PFR), that improves parents’ sensitive and responsive care, will protect young infants from the effect of accelerated cellular aging. During the first years of life, children are particularly susceptible to the impact of early life experiences that shape long term health outcomes and overall aging. One mechanism that has not yet received systematic exploration in young children, in the context of a randomized control trial (RCT), is the study of telomere length and epigenetic age clocks. Both telomere length and epigenetic aging clocks are unique markers of cellular aging, including pediatric samples. Cellular aging is a marker of early disease process. This RCT will provide a home visiting program hypothesized to buffer cellular aging in a pediatric sample of children under the age of one. The setting for this study is unique. We have partnered with WakeMed primary care in North Carolina, a busy pediatric practice that utilizes an integrated care model. We will recruit a sample of 250 parents and their infants receiving supportive primary care from WakeMed. Parents will be randomized to Usual Care or to PFR-in Primary Care (PFR-PC), a 10-week home visiting program with follow-up PFR-PC content during well-child visits. We will measure parents’ telomere length at baseline and child’s telomere length and epigenetic age clocks at baseline and one-year post-intervention. Aim 1 will evaluate three under-studied heritability and intergenerational predictors of cellular aging in young children, namely parental telomere length at baseline (i.e. heritability), parental childhood experiences, and parental age at conception (i.e., intergenerational factors). Aim 2 will evaluate the impact of early life experience on changes in cellular aging. We will test if current parental experiences predict child cellular aging between baseline and 12-months post-intervention, controlling for heritability and intergenerational effects. Aim 3 will test whether PFR-PC reduces accelerated cellular aging and improves parenting sensitivity and child outcomes one-year later. Finally, an exploratory aim will evaluate PFR-PC implementation (dosage, quality, acceptability, satisfaction, and provider fidelity). The current proposal moves the integrated care model one step further. Early interventions are key approaches to addressing health outcomes, especially when integrated into primary care settings that are low cost, disseminatable, and grounded in strong theoretical premises related to cellular aging.

NIH Research Projects · FY 2025 · 2024-06

Project Summary/Abstract Cognitive behavioral therapy (CBT) is the first-line psychological treatment for anxiety and obsessive compulsive (OC) disorders, yet approximately half of patients who receive CBT fail to achieve sustained clinical remission. Such failures are widespread but poorly studied and contribute to the escalating public health burden of anxiety. To date, no reliable biomarker capable of detecting CBT non-response exists. In this R01, we seek to fill this gap by collecting a battery of clinical, behavioral, self-report, and neural measurements before, during, and after CBT in a large cohort of patients with anxiety and OC disorders and healthy controls. Using these data, we will employ state-of-the-art machine learning techniques to build a model of CBT non- response and to test the hypothesis that early changes in a specific biomarker, self-focused attention (SFA), will represent a sensitive predictor and potential mechanism of CBT non-response. Prior research from our group has identified a promising neuroimaging-based biomarker of SFA, characterized by abnormal resting state functional connectivity between regions of the default mode network (DMN) and dorsal attention network (DAN) in a transdiagnostic sample. Trait SFA showed sustained reductions by 6 weeks into treatment, which tracked with clinical improvement, suggesting potential corresponding neural changes at that time. A common limitation of prediction studies is that they typically assess predictors only at baseline, which provides limited understanding of processes contributing to non-response and leaves unaddressed the question of what can be done for those predicted to not respond. Given that for anxiety and OC disorders, substantial improvement during CBT rapidly diminishes if not achieved early in treatment, we hypothesize that early changes in DMN- DAN connectivity may represent a mechanism of non-response and contribute to an early warning system that can be used to identify individuals at risk for suboptimal CBT response. This study will first establish the reliability and construct validity of DMN-DAN connectivity as a measure of SFA, which is distinct from related cognitive constructs, such as rumination, worry, and more general attentional mechanisms, such as attentional control and orienting, in a subgroup of 50 patients and 50 matched healthy controls. Next, we will provide 12 weeks of standard CBT for 110 patients with anxiety and OC disorders. Neuroimaging data will be acquired at baseline, week 6, and post-treatment to assess changes in functional connectivity throughout treatment. As predictions of CBT response are unlikely to be a function of SFA alone, we will develop supervised machine learning models that accommodate the hypothesized DMN-DAN connectivity measure, plus other data-driven features, to predict response at post-treatment. Since our goal is not to use MRI scans clinically, the use of machine learning to identify the strongest predictors of CBT non-response from a large set of multimodal features throughout CBT may reveal potential proxy measures that do not require neuroimaging. This study will reveal potential mechanistic indicators of CBT non-response that can guide treatment selection and planning.

NIH Research Projects · FY 2024 · 2024-06

ABSTRACT Among Alaska Natives in Alaska, Tuberculosis (TB) remains endemic in communities and is a leading cause of morbidity and mortality. Alaska Native communities continue to have the highest rates of TB disease in the U.S., and most TB cases occur in villages that remain far from health centers. The approach for diagnosing TB, which includes airlifting people with TB-related symptoms to regional centers for chest radiography and sputum collection, is difficult and expensive to implement effectively. Through our research in TB-endemic countries, we have identified screening and diagnostics testing modalities that are well-suited for efficient TB case finding in remote communities of Alaska. First, portable chest x-ray devices capture digital images that can be analyzed by computer-aided diagnostic (CAD) artificial intelligence programs for real-time interpretation. Second, as collecting sputum specimens has been a major diagnostic barrier for community-based diagnosis, we have recently demonstrated the high accuracy of tongue swab sampling for nucleic acid amplification testing of Mycobacterium tuberculosis (Mtb) among adults in South Africa. We also have strong data, using cultured Mtb specimens, demonstrating high accuracy on next-gen, high-throughput molecular testing systems, which have automated processes for analyzing thousands of samples at lower costs compared to conventional lab-based PCR systems. The objective in this application is to leverage our existing health infrastructure in south-western Alaska, expertise in clinical TB and diagnostic testing, and strong relationships with Alaska Native communities, to evaluate two novel community-based screening and diagnostic tools in TB-endemic regions of the United States. Our central hypotheses are: 1) portable chest x-ray devices using CAD interpretation will be accurate and feasible to implement in Alaska, and 2) tongue swab testing will be accurate when tested on an automated, high-volume molecular platform, as compared to conventional sputum-based molecular testing. We will test our hypotheses through the following two specific aims: (1) to determine if a portable, digital chest x-ray with real- time CAD can be accurate for TB screening, and feasible for use in community settings, within TB-endemic regions of Alaska; and (2) demonstrate the accuracy of tongue swab sampling with molecular testing using an automated high-throughput system, compared to current sputum-based molecular testing, among adults and children (≥5 years old) who have presumed pulmonary TB disease in Alaska. The research will be innovative by expanding the possible tools for community-based screening and diagnostic testing in TB-endemic communities in Alaska and elsewhere. This proposal is highly responsive to PAR-20-214, which seeks novel “Research to Improve Native American Health.” These results will inform a subsequent clinical research trial to evaluate the clinical impact and cost-effectiveness for conducting community-based TB screening and testing in TB-endemic regions of Alaska.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY/ABSTRACT This application evaluates an integrated brief intervention to reduce alcohol and cannabis use and consequences and improve sleep among young adults (YA) with comorbid heavy episodic drinking (HED), cannabis misuse, and sleep impairment. HED in YA is an important public health problem; consequences include accidental injury and death, academic/work problems, unsafe and unwanted sex, and development of alcohol use disorders. Many YA with HED also use cannabis and experience increased harm as a result. Sleep impairment is common and problematic among YA, identified as one of 5 leading barriers to academic success for students and an important risk factor for mental health problems and suicide in YA. More than 75% of YA report frequent daytime fatigue, 27% extreme distress related to sleep problems, and more than 1 in 4 are at high risk for insomnia. Alcohol use has been linked to insomnia in adolescent, YA, and older adult populations, with bidirectional causal links between alcohol use and impaired sleep. Comorbidity of HED and sleep impairment is associated with increased consequences of alcohol use and exacerbates risk of accidents (including automobile accidents), impaired decision-making, and work and academic difficulties. Similar bidirectional relations exist with cannabis use and sleep, and co-use of these substances may be particularly harmful for sleep. Despite these risks, alcohol and cannabis prevention programs rarely target sleep directly, and the majority of YA sleep interventions either focus on sleep hygiene broadly in the absence of specific strategies to improve sleep or reduce alcohol/cannabis use, or have insufficient sample size and duration to truly evaluate impacts on sleep or related comorbid alcohol or cannabis use. Building on our successful R34 intervention development project, the current study addresses these gaps by evaluating efficacy of integrating a brief sleep intervention (BBTI) with an efficacious brief alcohol and cannabis intervention (BASICS/Cannabis BMI) to increase magnitude and duration of effects on sleep and alcohol and cannabis misuse among a diverse community sample of YA with comorbid insomnia, HED, and cannabis use. Given bidirectional influences between sleep impairment and alcohol/cannabis misuse leading to significant public health challenges for this population, an efficacious integrated treatment is imperative. Impact will be evaluated in a RCT comparing efficacy of telehealth-delivered, integrated BASICSSLEEP to BASICS/BMI only (BASICS+), BBTI only (SLEEP), and Attention control (AC). Surveys and daily diaries will assess alcohol, cannabis, and sleep at baseline, post-tx, 3-, 6-, 12-, and 18-months. Specific aims are: (1) Evaluate comparative efficacy of BASICSSLEEP, BASICS+, and SLEEP in reducing alcohol/cannabis use and consequences and improving sleep; (2) Evaluate moderators of efficacy for integrated and monotherapies; and (3) Use diary data to evaluate temporal sequencing of effects and duration/decay over time. Findings will remedy important gaps in the literature and result in a scalable, accessible new resource to address this important and costly comorbidity.

NIH Research Projects · FY 2026 · 2024-06

Abstract/Summary Microvascular (MV) changes occur early in the Alzheimer’s disease (AD) brain. Loss of MV basement membrane (BM) integrity due to alterations in Collagen IV (Col IV), a major component of BM, in particular predisposes the MV to complications such as microhemorrhages. In the MV of both AD and the related condition of congophilic amyloid angiopathy (CAA), levels of Col IV vary and deposition of amyloid beta (Ab) is in close spatial proximity, but specific interactions between Col IV and Ab are not known. Notably, we recently found that the Ab binding antibody, lecanemab (BAN2401), causes degradation of MV Col IV. Thus, we hypothesize that Ab deposition induces structural and/or enzymatic processes that result in MV BM Col IV destabilization, and that subsequent removal of Ab by lecanemab results in Col IV breakdown, causing MV dysfunction. Brain Col IV is restricted to the vascular BM, and requires models that retain native Col IV and Ab to advance understanding of MV extracellular matrix (ECM). We propose 3 feasible aims to elucidate the interactions of Ab and Col IV in AD. Since little is known about the associations of Ab and Col IV in AD, Aim 1 will define the ultrastructural/spatial relationships among Ab, Col IV, and mediators of Col IV degradation in MV of AD/CAA and control brain sections, and in matched viable human brain MV (huMV). Aim 2 will use the 5xFAD mouse model of MV Ab to determine if/how Ab deposition, and subsequent Ab removal, affects Col IV and subsequent MV function in a mouse model of microvascular Ab. Aim 3 leverages a unique repository of viable human brain MV from AD/CAA and controls to define how modifying Ab by 2 different methods: the Ab binding antibody, lecanemab, and breaker peptides, a small molecule non-antibody mediated method of removing Ab, effects changes in Col IV and the neurovascular unit (NVU). Impact: Completion of this project will advance the understanding of brain MV Col IV interactions with Aβ that are likely important in mediating MV dysfunction in the context of AD/CAA progression. In addition, our project offers mechanistic insight on the adverse effects of Aβ-lowering therapies, which is needed for advancements to improve their safety.

NIH Research Projects · FY 2026 · 2024-06

Abstract. Keratoconus (KC) is the most common and one of the most serious forms of corneal ectasia. Corneal thinning and deformation of corneal geometry leads to its near-conical shape. Corneal shape and thickness are currently used to characterize ecstatic changes, and Optical Coherence Tomography (OCT) is the most accurate tool for that. Although corneal shape can be used to calculate refractive power, it cannot be used alone to predict disease progression. In fact, elastic moduli changes in the cornea are a driver of ectasia. Corneal collagen crosslinking (CXL) is a minimally invasive procedure that can potentially slow the progression of ectasia [1-4]. UV light modifies the microstructure of cornea soaked in riboflavin and forms additional chemical bonds between collagen fibers in the stroma leading to increased corneal stiffness. However, there is currently no instrument that can provide noncontact, accurate assessment of corneal anisotropic elastic moduli. Indeed, the cornea is a bounded medium of highly organized collagen fibrils resulting in its highly anisotropic mechanical behavior, requiring detailed techniques and models to map its elastic moduli. The goal of this project is to develop a non-contact, non-invasive clinical tool based on Optical Coherence Tomography and Elastography (OCE) to simultaneously map geometry (curvature and thickness) and image elastic in- and out-of-plane mechanical moduli of cornea for longitudinal pre-and post-operative diagnostics of KC progression and evaluate CXL surgery outcomes. We hypothesize that quantifying corneal elasticity in vivo will enable significant innovation, providing a basis to build an individualized biomechanical model of the eye, monitor progression of KC and other ectatic changes in the cornea, guide customized treatment plans, and both predict and evaluate refractive surgery outcomes. SA1 will focus on optimizing our unique AµT-OCE system for in vivo elasticity measurements in KC patients, building it on a slit-lamp based platform and combining it with OCT topography. In SA2, we will map baseline elastic properties in rabbit cornea pre- and post-CXL to confirm that elastic property changes due to the procedure can be quantified. Leveraging the results of SA1, SA3 will focus on baseline moduli in healthy volunteers matching the most likely demographic of KC patients to determine whether moduli depend on race and IOP and define diagnostic criteria for KC. Finally, in SA4 we will perform cornea moduli mapping in KC patients longitudinally pre- and post-CXL to comprehensively compare them to those in normal subjects. This project builds on the rigor of our previous research where (i) we invented a fully non-contact system to launch mechanical waves in the cornea and track their propagation with fast OCT [5, 6]. (ii) We showed that the cornea is highly anisotropic and developed a proper model of corneal biomechanics [7, 8]. (iii) We tested our approach in ex vivo and in vivo studies and validated our results with mechanical tests [7-10]. We also obtained statistically significant preliminary data for CXL treated human cornea ex vivo [9].

NIH Research Projects · FY 2025 · 2024-06

Abstract Early initiation of antiretroviral therapy (ART) during primary HIV infection leads to clear public health benefits by preventing onward HIV transmissions. However, it is not clear how the timing of early ART initiation affects longer-term individual outcomes, such as chronic immune activation. Chronic immune activation during HIV infection leads to immune dysregulation and exhaustion that contributes to disease progression and other clinical problems. Heightened immune activation continues even after ART suppresses viral loads below the limit of detection. Our group previously demonstrated that one pathway involved in immune activation, expression of interferon stimulated genes (ISGs), is persistently upregulated during untreated and treated HIV infection. Building on those results, we hypothesize that (1) effective antiretroviral treatment does not completely reverse chronic ISG activation in people living with HIV, (2) chronic activation of the IFN system will be lower in people with HIV (PWH) who started ART early, and (3) higher IFN system activation correlates with a larger proviral reservoir. Identifying ISG pathways that remain elevated following several years of ART could identify targets for preventing or treating co-occurring inflammatory and degenerative diseases, which are increasing in prevalence as more and more PWH have remained on ART for decades. To evaluate these hypotheses, we will use a highly unique set of archived samples, with longitudinal samples from individuals prior to HIV infection, during primary infection, and after treatment initiation. These samples come from a study of early ART initiation in which 1) individuals without HIV were followed monthly with serology and RNA testing to detect HIV infections shortly after acquisition, and 2) participants diagnosed with HIV were randomized to begin ART immediately or to defer ART for 24 weeks. They were followed with frequent visits and sample collections for up to 4 years. In the proposed study, we will measure expression of ISGs in 40 participants (20 from each ART arm) before HIV infection, after HIV diagnosis but before ART and at 6, 30 and 48 months after ART is started. Using these data, we will determine whether ISG expression remains elevated after 48 months of ART relative to pre-infection samples from the same participant. Second, we will evaluate if reduction of ISG expression following ART is different among those in the immediate vs. the deferred ART initiation arms. Lastly, we will assess whether ISG activation correlates with the size of the latent HIV reservoir, as has been suggested by animal models but remains unknown in humans.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY Alzheimer’s Disease (AD) and Related Dementias (ADRD) are a growing concern in our aging population. The identification of modifiable risk factors is critical. Growing evidence links ADRD to traffic-related air pollution (TRAP), a complex mixture of gasses and particles that includes ultrafine particles (UFP, ≤ 100 nm diameter), black carbon (BC), oxides of nitrogen (NOx), fine particles (PM2.5) and other pollutants. The impact of TRAP mixtures as a whole (vs individual pollutants) on ADRD, the most relevant pollutants, and critical exposure periods, however, have not been identified to support future evidence-based interventions and regulations. Moreover, most epidemiologic air pollution studies have investigated clinical cognitive outcomes; few have investigated neuropathologic changes more closely tied to mechanisms. UFPs may have an increased neurotoxic potential because of their small size. UFP health studies are limited because UFPs are not regularly monitored, and they require novel monitoring techniques. The Adult Changes in Thought (ACT) study is one of the largest, most extensive community-based autopsy cohorts in the world. My team previously developed the first-of-their-kind, UFP/TRAP exposure surfaces using an innovative mobile monitoring design in 2019 for this cohort. I will apply my expertise in exposure science developing long-term TRAP models and UFP monitoring campaigns along with new training in ADRD neuropathology, exposure mixtures, and advanced epidemiologic methods to address the following important gaps. In Aim 1, I will evaluate associations between exposures to UFP/TRAP mixtures and late-life ADRD neuropathological changes at autopsy and determine whether these effects are magnified in women, apolipoprotein E (APOE) ε4 carriers, or individuals with lower socioeconomic status. In Aim 2, I will collect additional UFP data and develop the first long-term UFP exposure surfaces. In Aim 3, I will evaluate long-term UFP/TRAP exposures and ADRD neuropathologies; identify the exposure periods that may be most relevant for the development of neuropathologies; and address potential survival biases in autopsy studies – a concern that has received scant epidemiologic attention but may be a concern when the exposure of interest (e.g., air pollution) increases risk of death (i.e., autopsy) at younger ages when neuropathologies are naturally less severe. My training plan, which consists of an excellent mentorship team of international experts, specific training goals, professional development, and transition to independence will position me to successfully develop the skills and experiences needed to lead this study. I will be uniquely qualified to develop a career independently leading novel and original studies in the fields of ADRD neuropathologies and environmental exposure mixtures.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY Alzheimer’s Disease (AD) and Related Dementias (ADRD) are a growing concern in our aging population. The identification of modifiable risk factors is critical. Growing evidence links ADRD to traffic-related air pollution (TRAP), a complex mixture of gasses and particles that includes ultrafine particles (UFP, ≤ 100 nm diameter), black carbon (BC), oxides of nitrogen (NOx), fine particles (PM2.5) and other pollutants. The impact of TRAP mixtures as a whole (vs individual pollutants) on ADRD, the most relevant pollutants, and critical exposure periods, however, have not been identified to support future evidence-based interventions and regulations. Moreover, most epidemiologic air pollution studies have investigated clinical cognitive outcomes; few have investigated neuropathologic changes more closely tied to mechanisms. UFPs may have an increased neurotoxic potential because of their small size. UFP health studies are limited because UFPs are not regularly monitored, and they require novel monitoring techniques. The Adult Changes in Thought (ACT) study is one of the largest, most extensive community-based autopsy cohorts in the world. My team previously developed the first-of-their-kind, UFP/TRAP exposure surfaces using an innovative mobile monitoring design in 2019 for this cohort. I will apply my expertise in exposure science developing long-term TRAP models and UFP monitoring campaigns along with new training in ADRD neuropathology, exposure mixtures, and advanced epidemiologic methods to address the following important gaps. In Aim 1, I will evaluate associations between exposures to UFP/TRAP mixtures and late-life ADRD neuropathological changes at autopsy and determine whether these effects are magnified in women, apolipoprotein E (APOE) ε4 carriers, or individuals with lower socioeconomic status. In Aim 2, I will collect additional UFP data and develop the first long-term UFP exposure surfaces. In Aim 3, I will evaluate long-term UFP/TRAP exposures and ADRD neuropathologies; identify the exposure periods that may be most relevant for the development of neuropathologies; and address potential survival biases in autopsy studies – a concern that has received scant epidemiologic attention but may be a concern when the exposure of interest (e.g., air pollution) increases risk of death (i.e., autopsy) at younger ages when neuropathologies are naturally less severe. My training plan, which consists of an excellent mentorship team of international experts, specific training goals, professional development, and transition to independence will position me to successfully develop the skills and experiences needed to lead this study. I will be uniquely qualified to develop a career independently leading novel and original studies in the fields of ADRD neuropathologies and environmental exposure mixtures.

NSF Awards · FY 2024 · 2024-06

This award is for Oceanographic Instrumentation (OI) for R/V Thompson, a 274-foot general purpose, global class research vessel, and R/V Rachel Carson, a newly outfitted 72-foot coastal research vessel, both operated by the University of Washington (UW) as part of the U.S. Academic Research Fleet (ARF). UW will develop an underway CTD system and will acquire 2 CTD probes to be used with it. Also, UW seeks to install a 150 kHz Acoustic Doppler Current Profiler (ADCP) to complement the existing ADCP systems of different operational frequency; it will also purchase an additional Seabird SBE911plus sensor for use with the existing CTD rosette system. The principal impact of the present proposal is under Merit Review Criterion 2 of the Proposal Guidelines (NSF 23-525). It provides infrastructure support for scientists to use the vessel and its shared-use instrumentation in support of their NSF-funded oceanographic research projects (which individually undergo separate review by the relevant research program of NSF). The acquisition, maintenance, and operation of shared-use instrumentation allows NSF-funded researchers from any US university or other organization access to well-maintained, high-quality, calibrated instruments for their research. It ensures the collection of high-quality oceanographic data in support of science, reduces the cost of that research, and expands the base of potential researchers. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-06

Project Summary/Abstract Substances of abuse alter neural circuitry that result in the progression towards a substance use disorder (SUD) in a subset of individuals. Currently, the United States is faced with an epidemic of SUD causing immense human suffering and high overdose rates. Understanding the changes in neural circuitry that underlie the transition to SUD-like behaviors, particularly in behaviors that have high risk such as escalated drug intake, is key to designing and implementing new therapeutic techniques to combat this epidemic. The midbrain dopaminergic system and particularly its projection to the Nucleus Accumbens (NAc) has been heavily implicated in drug consumption and is believed to be involved in the addictive liability of drugs and the progression to compulsive drug taking. Importantly, previous results from the Phillips lab demonstrated that escalation of drug intake results from a decrement of the phasic dopamine signal to drug associated cues. The driving force behind this degradation of phasic dopamine response related to drug consumption is unknown. However, other neuromodulatory systems have also been implicated in drug consumption, such as corticotropin releasing factor (CRF), and are capable of modulating the dopamine system. The overarching hypothesis of this proposal is that CRF receptors in specific subpopulations of the NAc contributes to escalation of drug intake through negatively modulating dopamine signaling. This hypothesis will be addressed through two independent aims. Aim 1 will test the necessity of CRF receptor 1 in the NAc in the escalation of drug taking via bilaterally knocking out CRF receptor 1 in NAc subpopulations using CRISPR/SaCas9 technology prior to a long access self-administration regime. Aim 2 will test the modulation of phasic dopamine response via CRF receptor 1 in the NAc during escalation of drug taking via unilaterally knocking out CRF receptor 1 and bilaterally measuring dopamine signaling in the NAc during long access self-administration via fiber photometry coupled with a dopamine sensor. The results from this proposal will 1) outline the role of NAc CRF receptors and 2) further investigate the contribution of dopamine modulation, both in the progression of SUD-like phenotypes. Uncovering the neural mechanisms that drive SUD-like drug consumption will provide therapeutic targets to combat SUD and related harms.

NIH Research Projects · FY 2025 · 2024-06

Alcohol use disorders (AUDs) in older adults age 65+ are a substantial and rapidly growing clinical problem. About 40% of older adults are current drinkers, 5.6 million have recently engaged in binge drinking and 1.2 million have a diagnosable AUD. This has been characterized as a “silent epidemic” because AUDs in older adults are vastly underdiagnosed and undertreated in health care. This problem will likely broaden as the number of older adults is expected to increase from 54 million in 2019 to 77 million by 2034. Inadequate access to care for AUD may be a key reason for undertreatment. This is particularly relevant for older adults enrolled in Medicare Advantage (MA) plans, who are subject to rules set by insurers regarding care utilization. These rules include restrictions to receiving care from providers within plan networks. There is a substantial gap in rigorous evidence characterizing the accessibility of providers of AUD care within MA plan networks, and quantifying the effect of inadequate access on older adults' utilization of AUD care. These insights support the long-term goal of our research, which is to guide payers and health systems increase the uptake of care for AUD through rigorous evidence on the effects of provider networks and other managed care approaches. To advance these goals, this R21 project will examine quantify and examine the effects of access to AUD care among older adults enrolled in MA and will accomplish the following three specific aims: 1) describe geographical variation in diagnosis of AUD and unmet treatment need among older adults, 2) descriptively characterize access to providers of services for AUD among older adults, and 3) estimate the relationship between access to care and use of care for AUD. Research in all aims will be conducted using extensive Medicare administrative and claims data, which tracks enrollment in MA and the health service use of Medicare beneficiaries nationally. In Aim 1, geographical variation in AUD diagnosis will be quantified using spatial mixed effects regression models. Exploratory analyses in Aim 2 will quantify access to providers of AUD care across several measures by utilizing comprehensive data on provider networks made available through the Robert Wood Johnson Foundation. Multivariable regression models will be applied to identify individual and local area factors associated with greater access to care. In Aim 3, econometric models for health care utilization will be applied to quantify the relationship between use of AUD care and access measures generated in Aim 2. Products from this study will provide timely data-driven insights for health care stakeholders responsible for ensuring individuals' ability to access care for AUD meets adequate standards. Also, insights identifying the dimensions of access to care that most strongly influence utilization will help stakeholders prioritize approaches to increase uptake of care for AUD. Finally, the current project will generate preliminary data for more complex studies that examine the effects of other managed care approaches that may hinger uptake of care for AUD using rigorous methods for causal inference using observational data.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY Although purine nucleotide homeostasis is critical to photoreceptor health, basic aspects of purine metabo- lism and its regulation in photoreceptors are unknown. Here, we analyze the critical role of inosine monophos- phate dehydrogenase 1 (IMDPH1) in retinal function and disease. IMPDH1 catalyzes and regulates a critical step in metabolic flow through the parallel de novo adenine and guanine nucleotide biosynthesis pathways. At least a dozen dominant missense mutations in IMPDH1 cause photoreceptor degeneration. We will leverage the recent advances we made with initial support from a two-year R21 award. We combined in vitro biochemical analyses of the human and zebrafish retinal IMPDH1 variants with in situ characterization of mutant forms of IMPDH1 in zebrafish, a well-established model for investigating the causes of photoreceptor degeneration. We showed that the structural and biochemical properties of human retinal variants are conserved in zebrafish. Im- portantly, our preliminary data also show that a transgenic zebrafish line expressing mutant IMPDH1 recapitu- lates the retinal degeneration seen in human disease. We propose to exploit our extensive collection of reagents and animal lines to define the structure, function, and metabolic role of IMPDH1 in healthy and dis- eased photoreceptors. We use a multidisciplinary approach that combines characterization of IMPDH1 structure and function using cryo-electron microscopy and biochemical dissection with cell biological and metabolic strat- egies in intact retinas.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY Syphilis has been a scourge for thousands of years. It has been impossible to eradicate due to biological and societal barriers. Despite curative therapy and public health work, incidence is rising in underrepresented minorities, men who have sex with men, women, and children. An effective syphilis vaccine will be a key tool for control and eradication. During infection, Treponema pallidum (Tp) bacteria are largely cleared from primary and then secondary infectious lesions by immune mechanisms, including antibody-mediated phagocytosis by IFNγ-activated tissue macrophages. Prior efforts to create a syphilis vaccine focused on antibodies against rare outer membrane proteins. These only generate partial protection in rabbits and have not advanced to human trials. Notably, these candidates did not specifically target T-cell responses. The premise of this K08 application is that inclusion of T cell antigens will drive effective antibody responses and macrophage activation, and should be a goal for vaccine design. We hypothesize that there are population prevalent Tp T cell antigens. Prior to my work, there are no reported human Tp T cell antigens with epitope validation. Aim 1 focuses on acquired immunity, including identification of dominant/prevalent CD4 T cell antigens. I will use a suite of methods established in my mentor’s lab to detect, enrich, and expand Tp-specific CD4 T cells from blood. We have also shown that Tp-specific CD4 T cells are naturally enriched in situ in small biopsies of secondary syphilis lesions. My established IRB protocols and subject referral pathways have allowed me to demonstrate that Tp-specific T cells remain in skin for at least 6 months after therapy. CD4 T cells from blood and biopsies will be screened with a large panel of rationally chosen recombinant Tp proteins and T cell reactivity thoroughly validated. Syphilis lesions are rich in B cells that secrete antibodies (plasma cells, PC). Aim 1 will examine the hypothesis that lesion PC secrete Tp-specific IgG. While Tp is canonically an extracellular pathogen, not expected to elicit peptide-specific CD8 T cells, abundant CD8α-expressing cells do occur in lesions. If Aim 2 confirms the presence of CD8αβ T cells with hypervariable T cell receptors in lesions, Aim 1 will examine their fine specificity for potential vaccine use. Aim 2 focuses on the innate immune response to Tp in active and healed syphilis lesions. Immunohistochemistry and single cell RNAseq will examine the hypothesis that parenchymal dermal cells express interferon and ISG genes in syphilis rashes, and that innate leukocytes are also involved in the inflammatory reaction. Aim 2 Approaches will also yield IgG and CD4 T cell TCR sequences suitable for synthetic reconstruction of antibodies and TCR-bearing reporter cells, cutting-edge technologies in use in my mentors’ labs, to further address Aim 1 acquired immunity hypotheses. Overall, knowledge of Tp T cell antigens will significantly improve our ability to design next- generation candidate vaccines against syphilis.

NIH Research Projects · FY 2025 · 2024-06

Project Summary/Abstract Infection with Plasmodium parasites leads to over 240 million cases of malaria and 700 thousand deaths annually, the majority of which are children under the age of five. Vector control has reduced transmission of Plasmodium, though a protective vaccine is required to reduce disease burden further. Currently deployed vaccines focus on the liver stage circumsporozoite protein (CSP) and offer moderate protection in Plasmodium- naïve individuals. However, vaccine efficacy and durability severely decline in individuals who have previously been infected with Plasmodium. Understanding how Plasmodium infection influences the pre-vaccine CSP- specific memory B cell pool is essential to identify why our current vaccinations are ineffective in endemic areas. Previous research has demonstrated that antibody responses towards two domains of CSP, the immunodominant repeat region (RR) and the non-dominant C terminus (CT), may be protective against infection. In contrast, other data suggest that the highly repetitive sequence of the RR may instead be a mechanism of immune evasion. The high avidity of this region may drive short-lived humoral responses or concentrate responses to the RR rather than perhaps more functional regions of CSP. We generated unique tetramers that allow us to isolate and track RR and CT-specific B cell responses during infection and/or immunization. In a murine model, we found that Plasmodium infection preferentially expands B cells specific to the RR at the expense of CT-specific B cells. In contrast, vaccination alone expands B cell populations specific to both domains. We hypothesize that Plasmodium infection induces a predominantly RR-specific pre-vaccine memory B cell pool that, due the high avidity of the region, will differentiate into short-lived plasmablasts upon a subsequent vaccination rather than reseeding memory pools. In this proposal, we will characterize the CSP- specific memory B cell pool generated during infection or immunization in a murine model and relevant human clinical trial samples. We will also identify the impact of previous infection on the response to a subsequent vaccination. Lastly, we will use novel, modified vaccination strategies to improve vaccine efficacy and durability in previously infected models. Understanding how to induce a larger breadth of B cell responses or induce longer lived RR-specific cells is important to improve vaccine efficacy in individuals previously infected with Plasmodium.

NIH Research Projects · FY 2026 · 2024-06

ABSTRACT For more than 100 years much of oculomotor research in primates has been guided by Hering's law, which states that any eye movement generated by the brain will be sent equally to the two eyes so that they move as a yoked pair. Refixations between targets in different directions involve saccades, which are conjugate movements that have peak velocities of hundreds of degrees per second. Refixations between targets at different distances require vergence eye movements, which slowly rotate the eyes by equal amounts in opposite directions. For gaze shifts between targets that differ in both direction and distance, vergence velocity is substantially higher during the saccade. The neural basis for this effect has been the subject of intense debate for more than 35 years. According to one view, consistent with Hering's Law, the extremely high intrasaccaddic vergence velocity results from a non-linear interaction between saccades and vergence. Alternatively, the vergence angle changes rapidly during the saccade because the saccadic system programs unequal saccades. This latter view would be inconsistent with Hering's law, since it necessitates the generation of unequal saccadic commands. For this reason, virtually all of the relevant neurophysiological studies have targeted brain areas involved in the generation of saccadic eye movements. The existing literature has yielded conflicting results, which is why this problem remains controversial. The experiments in this proposal take a novel approach, primarily by targeting brain areas involved in the generation of vergence eye movements during both slow vergence and disjunctive saccades.

NIH Research Projects · FY 2026 · 2024-05

Project Summary/Abstract This is a multi-PI project in which the 3 PIs each have a set of unique, but complimentary, cutting- edge technologies, patient resources, and computational tools that together enable us to fill a key knowledge gap: what are the upstream pathways that drive the chronic production of type I interferons (IFN-Is) in systemic lupus erythematosus (SLE)? Our work with focus on innate immune cells (neutrophils and monocytes) and skin biopsies from SLE patients (compared to healthy donors) obtained at the University of Washington and the University of Michigan, respectively. These samples will be subjected to ultrasensitive protein detection and protein- bound nucleic acid sequencing at Rockefeller University, as well as joint experiments in the first two labs. We anticipate that the synthesis of data from these approaches will be transformative for our understanding of SLE pathogenesis and the molecular mechanisms of lupus flares. Our aims are: AIM 1. To identify the NA(s) that triggers IFN-I production in SLE neutrophils and monocytes. Because SLE is a systemic disease involving numerous cell types, including immune cells, we focus this aim on neutrophils and monocytes. This choice is in part based on many recent papers indicating that they play an important role in SLE and in part because our preliminary data show that neutrophils are much altered in this disease, contain all the components for nucleic acid sensing and IFN-I production, and are the lineage with the highest retrotransposon expression. Monocytes likely play a (similar?) role in SLE. In this Aim, we will focus on identifying the nucleic acid species that are associated with the nucleic acid sensors that drive IFN-I using ultrasensitive detection methods. AIM 2. To identify the pathogenic DNA species that triggers IFN-I production in lupus skin. The skin is a key location of pathology in SLE patients. Ultraviolet (UV) light triggers flares of rashes and systemic disease in SLE patients, yet the reasons for this are unknown. IFN-Is are chronically upregulated in SLE epidermis, drive inflammatory responses in the skin, and are dysregulated after UV light exposure such that more IFN-I is produced in SLE vs. healthy control skin. The reasons for increased IFN-I production in SLE skin remain undefined yet are critical targets for novel therapeutic development and flare prevention. In this Aim, the macromolecular aggregates of nucleic acid sensors and the associated nucleic acids will be identified in keratinocytes before and after UVB exposure and the source of the pathogenic nucleic acid(s) determined.

NIH Research Projects · FY 2026 · 2024-05

ABSTRACT Despite the effectiveness of antiretroviral treatment (ART) at treating HIV, it fails to completely eradicate the viral reservoir. HIV reactivation occurs naturally, as evidenced by occasional low-level viremia (“blips”) observed in patients on ART. Studying the anatomical sites of HIV reactivation and the molecular mechanisms driving these blips can provide essential information for the development of HIV cure strategies. Non-human primate studies, autopsies, and clinical trials indicate that the gastrointestinal (GI) tract contains up to 98% of the HIV reservoir and that its immunophysiology could be especially conducive for HIV reactivation. In our previous work, we found that the epithelium of the intestinal mucosa contains a population of cells producing extremely high levels of type I/III interferon-stimulated proteins, among them, IFN-stimulated gene 15 (ISG15). These specialized enterocytes in the gut express glycoprotein 2, suggesting that some of these epithelial cells with heightened immunity are microfold cells (M cells). Type I IFN stimulation drives bystander T cell proliferation in vivo, which likely include latently infected cells, thus contributing to reservoir persistence. There is also evidence that type I IFN efficiently reactivates HIV-1 in vitro and ex vivo. Furthermore, mouse studies indicate that blocking type I interferon signaling diminishes immune activation, restores T cell function, and reduces the size of the HIV reservoir. Taken together, the data suggest that the GI tract, and particularly M cells, may contribute to HIV persistence and reactivation. Our overarching hypothesis is that immunologically hyperactive microfold (“M”) cells in the gut create a microenvironment that fosters proliferation of latently infected bystander CD4+ T cells, sporadic HIV reactivation from these cells, or both. We will investigate our hypothesis by ex vivo studies of mucosal GI tissues, including from people living with HIV (PLH), and in vitro M cell cultures to model and manipulate their effect on HIV latency. In Aim 1, we will investigate whether the interaction with M cells (ISG15high enterocytes) increases immune activation of bystander CD4+ T cells and macrophages using a single-cell spatial transcriptomics/proteomics approach. In Aim 2, we will test the hypothesis that T cells/macrophages containing HIV-1 proviral DNA/mRNA are found in high number in the vicinity of M cells using duodenal and rectal biopsies from a clinical study of 40 PLH on stable ART. We will quantify HIV-1 DNA and mRNA copies by digital PCR, determine T cell clonality by spatial transcriptomics and analyze the spatial relationship of HIV- 1 DNA+ and mRNA+ cells by DNA/RNAscope. In Aim 3, we will use in vitro models to test the hypothesis that M cells drive T cell proliferation and HIV reactivation via their increased activity of type I/III IFN pathways. This study will provide key information about the intestinal microarchitecture of the HIV reservoir that is necessary for the development of novel latency reversal agents or strategies to target latently infected cells via M cells.

NIH Research Projects · FY 2025 · 2024-05

Project Summary/Abstract Parasitic helminths infect ~25% of the global population, mostly colonizing the gastrointestinal tract. Emerging clinical evidence suggests that helminth infections, although typically non-pathogenic per se, may promote certain viral (e.g., HIV) and bacterial (e.g., M. tuberculosis) infections by dampening protective inflammatory immune responses. Recent studies in mice have recapitulated this phenomenon, as helminth infections were found to impair Th1 and CD8+ T cell responses against several enteric viruses, leading to dramatically increased viral replication in the intestine. Helminths induce a strong “type 2” immune response mediated by the characteristic cytokines IL-4 and/or IL-13. In prior work, helminth-mediated suppression of the host’s antiviral program required type 2 immunity, as co-infected IL4Ra-KO mice (which cannot respond to IL-4 and IL-13) mounted robust antiviral responses and efficiently controlled viral replication. Thus, the classic “type 1 vs. type 2” immune dichotomy paradigm has been implicated in helminth promotion of viral infection. Seeking to expand on these findings in a model of enteric adenoviral infection, we infected mice with Heligmosomoides polygyrus (“H.p.” - a model of human chronic hookworm infection), followed by oral gavage of mouse adenovirus 2 (“mAdV2”, which models acute adenoviral gastroenteritis). At early (day 3) and late (day 14-21) time points after viral infection, mice co-infected with H.p. + mAdV2 had dramatically increased viral titers in feces and small intestine tissue compared with mAdV2 infection alone. Tuft cells can sense helminth infections and initiate type 2 responses, but mice lacking tuft cells (Pou2f3-KO) showed similar viral enhancement upon H.p. co-infection as compared to WT mice. Surprisingly, all tested components of type 2 immunity were dispensable for viral enhancement, as mice deficient for IL-4Ra, IL-5, IL-25 and IL-33R all failed to control mAdV2 when colonized with H.p. Interestingly, infection with an unrelated helminth, Nippostrongylus brasiliensis, also enhanced mAdV2 infection. Thus, in contrast to other viral infections, intestinal helminths promote mAdV2 infection independent of type 2 immunity. This project aims to determine the mechanism of helminth-mediated mAdV2 enhancement by testing three non-mutually-exclusive hypotheses. In Aim 1, we will test the hypothesis that helminths blunt the anti-mAdV2 adaptive immune response, with a particular focus on IFNg-producing CD4s recruited to the intraepithelial compartment (as recently described) and helminth-mobilized Tregs. In Aim 2, we will assess whether helminths promote mAdV2 infection by impairing early interferon responses. In Aim 3, we seek to determine whether helminth secretory products, which modulate host immunity and epithelial cells independent of type 2 signals, are responsible for mAdV2 enhancement. If successful, this project will elucidate a novel mechanism of helminth-virus crosstalk with potential implications for human health.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY/ABSTRACT The 29.3 million patients receiving care in US Federally Qualified Health Centers (FQHCs) have much lower cervical cancer screening rates than national averages: Only 53% of eligible patients were up-to-date in 2021 and the COVID-19 pandemic exacerbated these disparities. Self-sampling for human papillomavirus (HPV) is an evidence-based cervical cancer screening method with high potential to reduce screening barriers. Self- sampling kits can be distributed at clinics or mailed to patients' homes. Despite widespread international adoption, HPV self-sampling is nascent in the US. Little data is available to inform implementing this preventive service in low-resource settings such as FQHCs. Our two-phase pilot and pragmatic trial will adapt and evaluate two programs to integrate HPV self-sampling into FQHCs. Our trial accounts for the context, capacity and resources of FQHCs, and leverages FQHC-Medicaid partnerships to promote this preventive care service. Phase 1 will be a milestone-driven planning phase. We will use community-based participatory research and stakeholder input to adapt and pilot-test 2 multilevel interventions in 2 FQHCs for distributing HPV self- sampling kits: in clinics and in clinics plus direct mailing. Phase 2 will be a cluster-randomized pragmatic trial in 42 Oregon and Washington FQHC clinics to evaluate the comparative effectiveness and cost-effectiveness of the interventions. Clinics will be randomized to Usual Care (UC), in-clinic distribution (Clinic Only), or in-clinic plus mailed distribution (Clinic + Mail). For in-clinic distribution, providers will offer self-sampling at in-person or telehealth encounters. The mailed component will be administered by Medicaid health plans. The primary outcome is the proportion of eligible patients (30-64 years, due/overdue for routine screening) who complete screening. Co-primary comparisons are (1) UC vs Clinic Only and (2) Clinic Only vs Clinic + Mail. To minimize bias, each comparison includes distinct but overlapping patient populations. Comparison 1 includes all patients (Medicaid and non-Medicaid) with a clinic encounter during the 12-month study period. Comparison 2 is restricted to Medicaid patients who are enrolled with the clinic, but does not require a clinic encounter during the 12-month study period. Cost-effectiveness will compare the Clinic Only HPV self-sampling intervention relative to UC, and Clinic + Mail relative to Clinic Only. We will use the RE-AIM framework and PRISM to assess provider, clinic and health plan acceptability and evaluate adaptations to the implementation strategies through mixed methods. Our pragmatic trial will be the first in the US to determine the effectiveness and cost- effectiveness of HPV self-sampling for increasing cervical cancer screening in FQHC settings. Results from our comparisons and evaluation of implementation strategies will inform broad-scale implementation of HPV self- sampling across FQHCs and other safety-net clinics in the US to reduce cervical cancer screening disparities.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY Over 3 million adolescents are diagnosed annually with major depressive disorder (MDD). Adolescent MDD predicts lifelong risk of chronic medical conditions, psychosocial disability, and death by suicide. Current evidence-based practices for adolescent MDD, such as standard cognitive behavioral therapy, are time and resource intensive while still leaving some adolescent MDD symptoms, including sleep disturbance and fatigue, unresolved. Capitalizing on adolescents’ near ubiquitous use of technologies, including smartphones and wearable devices, this proposal aims to develop an innovative and scalable digital tool (i.e., Sidekick) that will deliver a just-in-time adaptive intervention for adolescent MDD treatment within outpatient primary care. This R61/R33 will test whether Sidekick engages core target mechanisms of sleep and physical activity for improving adolescent MDD and functioning. The R61 phase will expand an existing digital platform by developing and optimizing Sidekick’s intervention algorithms, conducting user testing, and testing whether Sidekick engages core treatment mechanisms (i.e., sleep duration and physical activity levels). Smartphones and smartwatches will collect passive data and ecological momentary assessments on sleep and physical activity. Sidekick will process these streams of data to identify periods where adolescents need just-in-time support to increase physical activity and improve sleep. Aim 1 will focus on developing and refining the algorithm that individually tailors intervention type and delivery timing. Aim 2 will consist of a micro-randomized trial with 30 adolescents receiving collaborative care for MDD to test whether youth demonstrate improved sleep (e.g., more sleep for insomnia, less sleep for hypersomnia) and increased physical activity when they receive (vs. do not receive) a Sidekick tailored intervention. Once we satisfy our “go” criteria of engaging sleep and physical activity targets, the R33 phase will conduct a moderately sized randomized control trial of 70 youth receiving collaborative care for MDD. Aim 3 will examine whether youth who receive Sidekick in combination with collaborative care vs. collaborative care alone demonstrate greater improvements in sleep, physical activity, MDD symptoms, and psychosocial functioning. To better prepare for a larger clinical trial, Aim 4 will assess whether Sidekick is feasible, acceptable, appropriate, usable, and engaging across all phases of the study. If successful, this project will have a significant, lasting impact on the field of adolescent mental health by creating a digitally delivered, just-in-time adaptive intervention that can overcome substantial barriers in accessing evidence-based interventions and assisting adolescents in their daily contexts where support is most needed. This research will set the stage for a series of R01s testing Sidekick in expanded settings and as an evidence-based therapy enhancement tool for other mental health problems that may benefit from in-the-moment physical activity and sleep support, like suicidality, inattention, and executive functioning difficulties.

NIH Research Projects · FY 2026 · 2024-05

Project Summary/Abstract The goal of most cancer treatments is to induce the apoptotic death of tumor cells; in many cases these treatments also induce substantial off-target apoptosis in healthy tissues. Even in the absence of therapy, the majority of prospective metastatic cells die by apoptosis, resulting in the early metastatic niche being rich in apoptotic cell material. While numerous studies have focused on the features of tumor cells that allow them to survive and metastasize in the face of such treatments, less attention has been paid to the influence of dying cells themselves on cancer progression. The work proposed here will investigate the hypothesis that apoptotic cells drive efficient metastatic spread of healthy cancer cells, because they initiate a cascade of platelet recruitment, coagulation, and myeloid cell reprogramming at metastatic sites. We will address this hypothesis by focusing on three Aims: First, we will address the role of phosphatidylserine exposure on apoptotic cells in recruiting platelets and promoting tumor cell survival within the intravascular niche upon arrival of metastasizing cells to the lung. Second, we will examine the interface between apoptotic cells, cancer cells, and the myeloid immune network of the lung, during extravasation and establishment of the metastatic niche. Third, we will study the effects of apoptotic cells on spontaneous metastasis from a primary tumor, and test whether blocking pro-metastatic features of apoptotic cells can reduce metastasis in this setting. While our work is focused on the fundamental processes by which apoptotic cells influence metastasis, we suggest that it may point toward therapeutic combinations that prevent metastasis.

NIH Research Projects · FY 2026 · 2024-05

Abstract Understanding how T cell receptors (TCRs) see tumor antigens presented by MHCs is necessary to fully understand how the immune system recognizes tumor antigens, and to reap the full potential of antigen-specific immunotherapy. To achieve this goal, a quantum leap forward is required in which the revolutionary advances in machine learning are combined with a large volume of structure, function, data on matched TCR-pMHC pairs. The development of accurate predictors of TCR-antigen recognition will be dependent on the creation and integration sequencing-based datasets with high-throughput structural and functional insights. Our proposal, submitted as a CRUK/NCI Grand Challenge team (MATCHMAKERS) will combine researchers with expertise in immunology, methods development, structural biology, and computation to enable generalized prediction and design of TCR recognition. This work will be spread across four Work Packages (WPs): WP1: Large-scale generation of TCR-pMHC pairs from naturally occurring sources. We will build datasets of naturally occurring TCR-pMHC pairs. Our team will use an array of approaches to collect these datasets, from humans and from mouse models, and in the context of both cancer and immunity more generally. WP2: Ultra-high throughput TCR-pMHC matching using molecular engineering. Efforts to create general models will require a broader array of data than feasible to collect from natural TCR systems. We will use an array of synthetic approaches developed by our team to comprehensively match TCRs with pMHCs to train computational models. WP3: Large-scale structural and biochemical analyses of TCR-pMHC interactions. A key to our team’s vision is to match interaction datasets with high throughput structural and functional insights. A deep understanding of how the TCR contacts with MHC helices control function and orientation will be essential for training and testing computational models. WP4 AI-based prediction and design of TCR-pMHC interactions. We will integrate our data to train next- generation algorithms capable of generally predicting and designing TCR-pMHC interactions. These predictions will proceed through a reiterative testing and feedback circuits for further model optimization.