University Of Washington

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract Cancer metastasis occurs when cancer cells spread to distal organs from their site of origin, and it is the leading cause of death in patients with solid cancers. When cancer spreads to the lung, various types of innate immune cells either help or inhibit this colonization process. Monocytes are one of the earliest cell types to flood the lung during the beginning of metastasis. These monocytes eventually become tumor-supporting metastasis-associated macrophages (MAMs), and many studies in the field have reported that monocytes and MAMs actively aid metastatic cancer to infiltrate the lung and take residence there. My project aims to understand how monocytes differentiate into MAMs; in particular, what signals and factors are critical for this transition to occur in the lung. Furthermore, from my preliminary data, I have identified a time window during which monocytes have undergone clear phenotypic changes but have not yet fully developed into MAMs. Interestingly, this transition period also coincides with the anti-tumor activity of other immune cell types, such as natural killer (NK) cells. Therefore, I aim to study the interactions between pro-tumoral monocytes and anti- tumoral NK cells during the first several hours of cancer metastasis to the lung. By understanding how the mechanisms that underlie these interactions help to increase the odds of metastatic establishment in the lung, I will be able to contribute valuable insights towards novel therapeutic efforts to prevent metastasis.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Alternative splicing (AS) is a major driver of protein isoform diversity and is regulated in a highly cell type-specific manner. A better understanding of the cell type-specific splicing code will not only provide novel insights into the role of alternative splicing in disease and development but will also result in novel genetic tools for perturbing and interrogating cell types of interest. Synthetic splicing constructs have been successfully used to target activation of reporter and therapeutic genes to cancer cells carrying mutations in splice factors or to make gene therapies conditional on a small molecular trigger. Existing examples highlight the potential of AS as a programmable control mechanism but do not provide a clear path towards engineering splice regulatory sequences that can be used to target gene expression to any desired cell type or state. Here, we propose to combine synthetic biology with machine learning to generate highly cell type-specific splicing constructs. Building on our earlier work, we will first quantify cell type-specific AS using splicing massively parallel reporter assays (MPRAs). We will focus on exon skipping and intron retention because they are among the most common forms of AS and can be highly cell type-specific. For each type of AS, we will create libraries with hundreds of thousands or even millions of reporters with variation targeted to regions of interest. We will then measure AS for these libraries in a panel of cell lines and cultured primary cells (Specific Aim 1). Next, we will use these data to train machine learning models that can accurately predict AS isoform abundance from reporter gene sequence. We will systematically compare different network architectures and approaches including convolutional and recurrent neural networks. We will then combine models with sequence design approaches previously developed in the lab to generate synthetic sequences with enhanced target cell specificity. We aim to show that we can generate reporter constructs that are specific to any cell type in our panel. We will validate predictions experimentally and use resulting data to iteratively improve model predictions (Specific Aim 2). Finally, we will generalize our approach to an experimental setting that more accurately reflects the diversity and complexity of cell types encountered in multi-cellular biological systems. Specifically, we will perform splicing MPRAs in organotypic developing rat brain slice culture. We will optimize conditions for library delivery to slice culture and we will similarly optimize approaches for reading out splicing MPRAs at the single cell level. We will combine the resulting data with the generative models from Specific Aim 1 to design reporter constructs that precisely target protein expression to cell types of interest (Specific Aim 3). We believe that this work will result in novel genetic tools for biology research and provide a path towards gene therapies with increased specificity and reduced side effects.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY | ABSTRACT Proteins act as the effector molecules of cells – carrying out most of the structural, regulatory, and enzymatic functions. Proteins themselves are often regulated through direct interaction with ligands, including metals, lipids, other proteins, and drugs. These protein-ligand interactions are fundamental to diverse biological processes. Yet, technologies to explore these interactions are limited in terms of both throughput and their ability to scale. The limits of these technologies are in part highlighted be the fact that for nearly 30 years, proteomics and genomics technologies research have been unable to fully characterize the functions of the 20,000 protein coding genes in human cells. To address this, we propose to build a cornerstone technology suite for high-throughput, proteome-wide protein-ligand interaction profiling. In this work we will demonstrate the development and implementation in a focused way to highlight the potential of this technology to bring robust quantitative approaches to study ligand binding at scale. Our technological innovations center on using high-throughput methods to detect protein- ligand interactions across the entire proteome in a single analysis. To do this, we will measure the change in thermal stability of proteins induced by binding to a ligand. We measure this thermal stability as a relative difference in protein abundance using sample multiplexing based on tandem mass tags (TMT). Sample multiplexing enables quantitation of up to 18 samples’ proteomes simultaneously. Sample multiplexing with TMT increases sample throughput, reduces missing values across samples, and enables complex experimental designs – e.g., time courses, dose dependency, and knockout-rescue experiments. Over the course of the proposed work, we will build new proteomics technologies to harness the benefits of proteome-wide thermal stability assays and TMT quantitation to characterize protein-ligand interactions. The combination of (1) intelligent mass spectrometric data acquisition, (2) proteome thermal stability profiling, and (3) sample multiplexing will enable us to decipher the complex interplay between proteins and ligands across the proteome. With an eye towards translational research, we will focus at first on small-molecule drugs as ligands as we can acquire diverse libraries with known primary protein targets. These data and methods will be used to reveal the functional and secondary effects of ligand perturbation of the proteome by leveraging matched whole proteome and gene expression profiles to determine to what extent specific drug-protein- engagement drives cellular responses.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Brain-computer interfaces (BCIs) hold great promise to restore movement to paralyzed people. But BCIs cannot yet provide reliable performance across the long timespans and varied settings needed for real- world applications. Maintaining robust BCI performance over many days is challenging because brains are highly plastic. Plasticity during extended BCI practice leads to changes in how neural activity relates to move- ments—the brain’s encoding of BCI movement. How the brain’s encoding changes is influenced by the decod- ing algorithm used by the BCI to map neural activity into movement. These interactions create complex dynam- ics where methods that improve performance in the short term may produce problems longer-term. Indeed, our preliminary data suggests current adaptive decoding methods used to maintain performance over time lead the brain to form encoders where very few neural signals control movements, which make BCI vulnerable to cata- strophic failure with loss of a single neural signal. The long-term vision of this proposal is to expand the engi- neering tools available to produce robust, high-performance BCIs by building tools that account for and even leverage plasticity. To enable this vision, this proposal will test the overarching hypothesis that decoder-en- coder interactions can be used to jointly optimize BCI performance and robustness. We focus on robustness of BCI systems to signal loss and changes in task context. We will use an animal model where monkeys move cursors with activity from motor cortices, which has repeatedly informed clinical BCIs. We will leverage novel micro-electrocorticography implants that allow us to longitudinally monitor and manipulate cortical dynamics to advance our understanding of plasticity in multi-day (10 days) BCI training. We will test our overarching hy- pothesis across three aims. If our hypothesis is true, there must be relationships between decoders and prop- erties of encoders that are related to robustness. Aim 1 will determine whether decoders influence how infor- mation is structured in an encoder, which influences how robust BCIs are to signal loss. Aim 2 will determine whether decoders influence the specificity of learned encoders to BCI movements, which influences how ro- bust BCIs are to changes in tasks. Finally, if our hypothesis is true, it requires computational tools that can opti- mize multiple goals in a BCI. Aim 3 will test a novel decoder training paradigm we developed that can consider multiple objectives. We will compare our novel method to established single-objective methods to determine whether multi-objective methods can improve robustness without compromising performance. Across all aims, we will perform offline analyses and online perturbations to measure robustness to signal loss and changes in neural state and behavioral task. Together, these studies will identify how critical plasticity computations can be influenced through the decoder. Pairing this with tests of novel decoding methods will establish new frame- works to build encoder-informed decoders and pave the way for BCIs that can leverage brain plasticity.

NIH Research Projects · FY 2026 · 2023-09

ABSTRACT Language discordance in prehospital emergency care can deny patients live-saving clinical care and build distrust with the emergency medical system. When non/limited English proficient (LEP) patients call 9-1-1, they are more likely to experience delays, less likely to receive and perform pre-arrival instructions and more likely to experience adverse health outcomes and unscheduled emergency department return visits than their English- speaking counterparts. With 25 million LEP individuals in the United States we need a better understanding of the gaps in prehospital emergency care and modify the system to optimize care delivery for LEP populations. In hospital and clinic settings, the gold standard for overcoming language discordance is the use of professional interpreters, which has shown to improve care delivery, patient satisfaction and health outcomes. While over- the-phone interpreter (OPI) use in the 9-1-1 Dispatch emergency setting can be critical to facilitating assessment and pre-arrival instruction delivery, suboptimal utilization (over, under or delayed utilization of OPI) can result in worsened outcomes. This may explain some of the differences seen in research showing that 9-1- 1 calls with LEP callers more frequently result in triage errors, increased time to dispatching response, and that pre-arrival instructions are often delayed and/or not performed by LEP callers. We propose a multi-method study, guided by the Feldman-Stewart et al. (2005) provider-patient communication framework, to increase our understanding of the complex interaction between LEP callers, dispatchers and interpreters during the first critical minutes of emergency care. This study has three aims and one sub-aim: 1) Identify call characteristics that are associated with use of OPI and associated communication and care delivery outcomes during real-life 9-1-1 calls with LEP callers. 1a.) analyze three-way communication patterns between dispatcher, caller and OPI in a sample of Spanish and Chinese (i.e., Mandarin/Cantonese) 9-1-1 calls with OPI. 2) Identify key dispatcher attributes associated with use of and time to OPI during simulated scenarios (developed based on information collected in Aim#1), with LEP Spanish and Chinese mock callers. 3) Translate and disseminate the results of the study via training opportunities and policy recommendations identified by emergency medical services (EMS) and community stakeholders, using a participatory Delphi technique. Our research group has contributed significantly to the existing research on prehospital care for LEP populations. We bring our vast knowledge of the complexity of communication in an emergency setting and a 30-year history of collaborative work with EMS and community partners to shed light on OPI use in prehospital care and guide translation of findings into policies and training on OPI use in prehospital care delivery.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY During development, a series of extracellular signals lead to the formation of different cell-types by inducing the differential expression of many genes. Although all genes experience the same signal, the expression of some genes is increased, some reduced, and others stay the same. Therefore, the gene expression profile that is characteristic of any cell-type must result from each genomic locus interpreting the signal in a distinct manner. The loss of faithful signal interpretation by genomic loci is pathogenic in many contexts including cancer and neuropsychiatric disease. Thus, an understanding of how individual genomic loci interpret extracellular signals is a fundamental yet unresolved problem. The challenge in understanding cis-regulation in response to extracellular signals is two-fold. First, any manipulation of the signal (concentration, duration, identity) leads to myriad pleiotropic effects in trans that confound interpretation. Second, multiple cis-regulatory elements (CREs) work together across large genomic windows to specify the expression of their target gene. Even in this post-CRISPR era, it has remained challenging to simultaneously manipulate multiple CREs across these large genomic regions to deconvolve their relative contributions to target gene regulation. This proposal seeks to solve these challenges using a combination of synthetic biology and single-cell sequencing. At the HoxA cluster, extracellular signals such as retinoic acid (RA) and Wnt induce the establishment of distinct transcriptional, epigenetic and topological domains that are stably inherited through cell divisions. In Aim1, we will rewire the HoxA cluster to respond to an extracellular signal that is completely orthogonal to the rest of the genome. This will enable the independent manipulation of transcription factor binding in cis and changes to the trans-regulatory environment to determine their relative contributions in establishing and maintaining the HoxA response to differentiating signals. We are unlikely to glean generally applicable principles of gene regulation from studies of a single locus. In Aim2 we will develop a technology that uses single-cells as individual experiments to massively increase the scale at which interactions between CREs can be uncovered at any locus. This technology will be applied to dissect the regulatory landscapes of genes involved in neuronal cell-type specification. We will then use the large dataset to develop a predictive model of cis-regulation at other loci.

NIH Research Projects · FY 2025 · 2023-09

Single-cell genomics technology has advanced at a blistering pace. The throughput of single-cell transcriptome sequencing has increased by four orders of magnitude in the past five years alone, enabling our group and others to catalog all of the cell types in a whole embryo within a single experiment. In parallel, assays for diverse aspects of the epigenome, including chromatin accessibility, DNA methylation, and histone modifications have been adapted to work in single cells and at scale. Furthermore, multiplexing techniques have raised the prospect of using single-cell genomics not only to catalog cell types, but to comprehensively study the effects of myriad perturbations of embryonic development, or to characterize the evolution of disease pathogenesis at whole-animal scale and molecular resolution. In principle, single-cell genomics could serve as an extraordinarily high-content means of phenotyping, but the volume and richness of datasets produced by such experiments poses new, daunting computational and statistical challenges. A lack of software tools for comparing specimens profiled as part of single-cell RNA-seq or ATAC-seq experiments constitutes a critical gap in the field. This proposal aims to fill that gap with software tools that will allow users to characterize how disease progression, genetic or chemical perturbations, or environmental effects alter the proportions and molecular states of cells in complex tissues or whole embryos. In order to establish the accuracy of our tools and the physiological relevance of their predictions, we will extensively validate their output through analysis of existing and newly generated single-cell sequencing data using the very tractable zebrafish embryonic development system. In our first Aim, we will develop software for detecting shifts within cell populations across healthy and pathological molecular states. In our second Aim, we will develop software for identifying genes that mediate or regulate cell-state transitions during development or disease pathogenesis. In our third Aim, we will develop methods for defining how chromatin states at regulatory DNA control transcriptional states. Upon completing these aims, we will have delivered new, widely applicable software for analyzing single-cell genomics experiments. We will also have produced new datasets that will serve both as a reference map for vertebrate embryogenesis and a platform for further development of tools for genetic analysis by our group and others. Our experiments will also yield new insights as to how vertebrate genomes encode developmental programs.

NIH Research Projects · FY 2025 · 2023-09

Abstract Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe joint pain and debilitating inflammatory flares. There are currently no safe and effective treatments that achieve long-term remission, and therefore, RA patients are twice as likely to become chronic opioid users than non-RA pain patients. Maladaptive immune cell function is the underlying cause of RA which leads to joint inflammation and activation of nociceptor sensory neurons that trigger pain. Nociceptors, in turn, can regulate immune responses in tissues via peripheral vesicle release. Joints without sensory innervation are protected from arthritis, underscoring the key role of sensory neurons in controlling both pain and inflammation. Therefore, the neuroimmune axis is an excellent potential avenue, to treat RA. However, our understanding of the diverse sensory neurons and immune cells in the joints, how they interact with each other, and how these interactions change over the course of RA is limited. This proposal is a five-year plan of research, training, and career development focused on studying the role of neuroimmune interactions in RA pain and inflammation. In the two-year mentored phase, I will map the receptor-ligand interactions between sensory neurons and immune cells at a single-cell resolution in healthy and inflamed joints to identify neuroimmune pathways linked to arthritis, and also determine which neurons drive pain in response to immune ligands in arthritis. I will accomplish this by utilizing innovative approaches to construct receptor-ligand cell-cell interactomes, assess pain behavior in mice using machine learning and inhibit nociceptor activity in a spatially and temporally controlled manner. This scientific training will complement the career development activities selected to enhance my skills in scientific communication, leadership, mentorship, and ethics of scientific conduct. The insights and skills gained during this training will guide my research in the independent phase, elucidating how nociceptor-immune interactions contribute to the chronicity of RA. This research will uncover the biological mechanisms of joint inflammation and guide the development of novel neuroimmune-based therapies. I have assembled a diverse group of highly accomplished mentors who will ensure that I receive extensive training in pain neurobiology and in the assessment of sensory neuronal function in mice. My training will be further enhanced by the unique scientific environment of the Harvard Medical School and Boston Children’s Hospital research community, which is geared towards unifying my expertise in immunology and sensory neuroscience and enabling my successful transition into an independent academic position as a pain researcher.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Sexual assault is a persistent public health problem that affects a substantial proportion of college women and is often associated with increases in heavy drinking to cope with post-assault distress. Survivors often recover within social networks such as sororities where heavy drinking is normative, and recovery alongside heavy drinking peers can exacerbate survivors’ drinking to cope. To address this problem, the current application involves the development of a novel intervention designed to promote effective support of survivors within social networks of sororities. Support behaviors incompatible with heavy drinking are expected to increase perceived support among survivors and reduce alcohol use and related consequences among all intervention recipients. The research plan involves: (1) developing a new web-based intervention in collaboration with community stakeholders, (2) testing the feasibility of the intervention within a pilot cluster randomized trial, and (3) examining network characteristics associated with adoption of support behaviors. This Mentored Clinical Scientist Research Career Development Award (K08) will provide Dr. Anna Jaffe with the research support and training needed to become an independent researcher in the field of alcohol research. Dr. Jaffe has a strong foundation researching the intersection between alcohol use and sexual assault, but requires additional training to become an intervention researcher capable of contributing to broad change by leveraging technology to administer brief interventions within social networks. To facilitate this training, Drs. Mary Larimer, Christine Lee, and Cynthia Stappenbeck will provide mentorship in intervention development and evaluation with relevance to alcohol use, peers, and sexual assault. Additionally, Drs. Nancy Barnett and Tyler McCormick will provide mentorship in social network methodology and related statistical analyses. The University of Washington is an ideal environment for conducting this research and obtaining the content, methodological, and statistical expertise necessary to develop an independent career in alcohol intervention research. The proposed project will provide pilot data to support a R01 submission to test the intervention on a larger scale and evaluate the spread of supportive behaviors through social networks. This highly innovative research plan is consistent with NIAAA strategic goals in the creation of a low-resource technology-based intervention that has the potential to significantly impact public health by improving peer support to survivors of sexual assault and reduce heavy drinking on a broad scale.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Preterm birth remains a major cause of mortality and morbidity globally and in the United States. Fortunately, over the past several decades, mortality has decreased such that survival is now over 90% in high income countries. Unfortunately, commensurate improvements in neurodevelopmental outcomes of extremely preterm infants (EP, born <28 weeks’ gestation) remain elusive, with more than 60% of survivors developing at least one disability such as cerebral palsy, autism, ADHD, or cognitive, hearing, or visual impairment. There are no targeted neuroprotective interventions for preterm infants in current clinical use, driving a significant clinical need to develop therapies that reduce the mortality and long-term morbidity seen in EP infants. To evaluate promising therapeutics in the preterm infant, we have developed complementary in vitro and in vivo techniques in the developing ferret. Our preliminary data in the inflammation sensitized hypoxic-ischemic-hyperoxic (HIH) ferret model of preterm brain injury shows injury patterns and behavioral changes consistent with those seen in infants born prematurely. In cultured organotypic ferret brain slices exposed to oxygen-glucose deprivation (OGD), we have also shown regionally dependent injury, similar to the preterm human, and regional and treatment- dependent transcriptome changes associated with neuroprotection. The fact that we see regionally dependent responses to therapy suggests that an optimal therapeutic approach will require combinatorial therapies to provide global neuroprotection and improve long-term neurodevelopmental outcomes. This is particularly relevant considering the recent publication of the PENUT trial, which found no significant neuroprotective effect of erythropoietin (Epo) monotherapy – one of the most promising therapies in the pipeline – in EP infants. Organotypic brain slices can provide a platform to screen combinatorial therapeutics including their interactions. For example, our preliminary data in EP-equivalent ferret brain slices shows Epo in combination with the anti- inflammatory antibiotic azithromycin results in synergistic benefit in the subcortical white matter, a region that is specifically at risk in EP infants, but this combination does not result in benefit in all brain regions. Building on these findings, the objectives of our proposed research are to (1) determine the regional specificity and efficacy of multiple promising neurotherapeutics in vitro, (2) evaluate combined neurotherapeutics to optimize regional and global neuroprotection in vitro, and (3) develop a cocktail of neurotherapeutics optimizing neuroprotection in vivo in a ferret model of EP brain injury. Our overarching hypotheses are that: (1) neurotherapeutics that provide complementary region-specific neuroprotection in vitro will increase global neuroprotection in vivo, and (2) that compared to monotherapy, combining complementary neurotherapeutics will result in greater neuroprotection across the entire brain that persists into adolescence. Data resulting from this proposal could support a clinical trial in this population for which no specific neuroprotective therapies are currently available.

NIH Research Projects · FY 2024 · 2023-09

Project Summary/Abstract: Midbrain dopamine (DA)-producing neurons of the ventral tegmental area (VTA) play a critical role in modulating reward-seeking behavior. VTA-DA neurons are functionally and genetically heterogeneous, and genetic markers for neuropeptides and neuropeptide receptors can be used to isolate VTA subpopulations. Though distinct neuropeptidergic pathways have been shown to potently modulate DA neurons, the intracellular signaling pathways that act downstream of neuropeptide receptors are unknown. VTA-DA neurons that express the Gq-protein coupled receptor, tachykinin receptor 3 (Tacr3), are a minimally sufficient subpopulation of DA neurons that promote reward reinforcement behavior. Tacr3 activation has recently been shown to be dependent on transient receptor potential canonical (TRPC) channel signaling in the hypothalamus. TRPC type 6 (TRPC6) channels are enriched in DA neurons and are activated by stimulation of Gq-coupled receptor signaling. Therefore, I hypothesize that TRPC6 is likely the main type of TRPC channel in VTA-DA neurons that acts downstream of Tacr3 activation. To establish the role of TRPC6 in regulating the physiology and function of VTA-Tacr3 neurons, I propose to selectively mutate the Trpc6 gene to generate a loss of function in a cell-type specific manner within the VTA of adult mice using an advanced CRISPR/Cas9 genetic technology. I will perform ex vivo slice electrophysiology and slice calcium imaging (Aim 1), as well as in vivo recordings of calcium dynamics during a probabilistic discounting paradigm and progressive ratio motivational task (Aim 2). Determining the function of TRPC6 in VTA-Tacr3 neurons will provide important insights into the therapeutic potential of this understudied ion channel in the central nervous system.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY The purpose of this Ruth L. Kirschstein National Research Service Award (NRSA) Individual Pre-Doctoral Fellowship in Nursing Research (F31) application is to provide research training for Ms. Frazier, a third-year doctoral student at the University of Washington School of Nursing. The long-term goal of this training is for this applicant to develop into an independent nurse scientist in a research-intensive academic setting with a program of research dedicated to interventions that integrate biological and socioecological factors to reduce and ameliorate symptom burden in individuals living with atrial fibrillation (AF). As the U.S. population ages, the number of individuals with AF is rapidly increasing, with cases projected to more than double by 2030. Most individuals with AF experience bothersome and at times debilitating symptoms that significantly impair quality of life (QOL). Women with AF bear the burden of more frequent and severe AF symptoms and lower QOL. While prior studies have consistently identified gender differences in AF symptom and QOL outcomes, the multilevel factors contributing to such differences in women and men are largely understudied. The applicant proposes a cross-sectional study (N=124) that employs both quantitative (Aims 1 and 2) and qualitative (Aim 3) methods to elucidate social factors and novel biological markers that contribute to differences in AF symptoms and QOL in women and men with AF. The specific aims are to: 1) Compare epicardial adipose tissue volume, adipokines (leptin and adiponectin), AF symptoms, and QOL between women and men with AF; 2) Examine for associations linked to potential intermediating pathways between epicardial adipose tissue volume, adipokines (leptin and adiponectin), AF symptoms, and QOL for women and men with AF; and 3) Explore perceptions of social factors (social support, living situation, and social network interactions) and their influence on AF symptoms and QOL for women and men with AF. Through advanced coursework and direct research experience, qualitative and quantitative methods, focused analysis of gender and social contexts in AF, and discovery of highly relevant links among biological markers of and AF-related outcomes, this award will provide a firm foundation for the long-term goal to develop behavioral interventions and upstream solutions to improve symptom experiences and QOL in women and men with AF.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY The purpose of this Ruth L. Kirschstein National Research Service Award (NRSA) Individual Pre-Doctoral Fellowship in Nursing Research (F31) application is to provide research training for Ms. Yoo, a beginning second-year doctoral student at the University of Washington (UW). The long-term goal of this training is for Ms. Yoo to develop into an independent researcher at a research-intensive academic setting with a program of research focused on improving health outcomes of persons with inflammatory bowel disease (IBD) through the development of self-management strategies that address biological and socio-ecological factors. The costs of care and prevalence of IBD, a chronic gastrointestinal (GI) disease, have been rising in the United States. IBD symptoms (e.g., diarrhea, abdominal pain) negatively impact quality of life, work productivity, and school attendance; thus, there is a clear need to explore behavior modifications (e.g., behavior-influenced sleep-wake cycles) to mitigate the symptoms of those with IBD. Although animal models have shown the adverse effects of disrupted sleep-wake cycles on the GI system (e.g., intestinal dysbiosis), there is little research that focuses on the impact of inconsistent sleep-wake cycles on IBD health outcomes as well role of external socio-ecological factors (e.g., work and family obligations) on sleep-wake cycles of those with IBD. The aims of the proposed study that employ both quantitative and qualitative methods are to understand the relationship between rest- activity rhythm (RAR) characteristics and social jetlag with fatigue, sleep quality, GI symptoms, and disease activity, and identify the social and societal factors that impact sleep-wake cycles. Unlike most IBD sleep studies, this study will use objective actigraphy to measure RARs and social jetlag, and a qualitative portion will provide additional insight from IBD participants on socio-ecological factors that impact sleep-wake cycles which quantitative measures cannot fully capture. The socio-ecological model of health and sleep will guide the research project to consider the societal, social, and individual level impacts of sleep-wake cycles on IBD outcomes. The principal investigator will collect prospective data on 24 IBD participants from the University of Washington Medical Center's gastroenterology clinic and leverage existing data on 26 IBD participants from a previous study focused on nighttime sleep outcomes, resulting in a total of 50 participants. This award will prepare a pre-doctoral trainee through advanced coursework and direct research experience, qualitative and quantitative methods, focused analysis of RARs, and discovery of the relationships among three different concepts related to sleep-wake cycles and IBD-related health outcomes. The findings generated from this investigation will provide foundational knowledge for building a new program of research in self-management and symptom science in IBD.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT Hearing loss is among the leading causes of disability worldwide, with the highest burden in resource limited settings (RLS). Children are disproportionately affected, given the detriment to a child’s neurocognitive and social development, yet the impacts can be mitigated if detected and treated early. Nearly 60% of hearing loss in children is due to preventable factors, and identification is the first step in addressing hearing loss. High income countries have implemented universal newborn hearing screening (UNHS) programs with a goal of diagnosing hearing loss and starting early intervention in the first few months of life. Few comparable programs exist in low and middle income countries, given such barriers as limited access to trained personnel and high cost of hearing screening equipment. We propose to optimize a low-cost smartphone otoacoustic emissions (OAE) device for hearing screening and study the implementation in an RLS. The smartphone OAE is comparable to conventional hearing screening equipment in US trials and now must be evaluated where it can have the greatest impact. The aims of the R21 are to optimize the OAE device in various clinical settings and patient ages in Kenya. We will evaluate potential impact of noisy clinical environments, assess consistency of screening, and compare usability in frontline and lay health facility workers, with a deliverable of a low-cost, user-friendly OAE that is a feasible tool in a low- resource clinical setting. Work will begin to integrate hearing screening results from the smartphone OAE directly with electronic medical records systems in Kenya. The R33 will further establish implementation outcomes and validity of the smartphone OAE device in a UNHS program, and will provide an in-depth evaluation of the implementation strategy and task-shifting in the Kenyan context. In parallel, the R33 will deploy the smartphone OAE in a longitudinal study of suspected (HIV exposure) and known (otitis media with effusion) risk factors for hearing loss. The longitudinal study will leverage an additional innovative lay-person friendly smartphone tool that can be used to monitor for middle ear fluid, an important companion for hearing screening in children that typically relies on expensive, skill intensive equipment. The research team includes medical providers, public health researchers, computer scientists and the Technical Working Group for Ear and Hearing Care in Kenya’s Ministry of Health, a collaboration that will support program sustainability when the project is complete. The project establishes a foundation for smartphone OAE in UNHS programs, high-risk infant surveillance, ototoxicity monitoring, and future research to understand and improve ear and hearing care in RLS. The outcomes of this work align with the goals of the WHO World Report on Hearing, which strives for all people, including those with hearing loss, to have access to high-quality services without experiencing financial hardship by 2030.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract There are ~7000 recognized rare diseases, which affect 5 - 10% of the U.S. population. The Undiagnosed Disease Network (UDN) is motivated by the dual goals of providing a diagnosis to patients who have undergone a protracted unsuccessful diagnostic odyssey and by the opportunities for scientific discovery that these unique patients offer. The UDNs impact also extends to systematizing the diagnostic approach to the undiagnosed patient. Our Pacific Northwest UDN site has served our region, and recently much of the Western United States, bringing a conclusion to the journey of our patients. Our group has deep and broad expertise across all the relevant areas required for the evaluation and diagnosis of adult and pediatric patients who have had a previously unproductive clinical odyssey, to identify novel disorders, and to advance the broader goals of the UDN. Foremost, we have a diverse team of physicians and an established record in the characterization of new genetic disorders and the identification of their genetic mechanisms. We leverage our unique existing regional medical and educational infrastructure, unique genomic strengths, and providers in the states of Washington, Wyoming, Alaska, Montana, and Idaho to identify patients in need and provide regional care. Our clinicians include members with nationally recognized expertise in neurogenetics, adult and pediatric genetics/genomics, immunology, internal medicine, pediatrics, neurology, teratology, human development, dysmorphology, and neonatology. We have national expertise in genomic sequencing and annotation, copy number variant technology, data-sharing, clinical informatics, bioethics, molecular diagnostic testing, and statistical genetics; covering disciplines such as: bioethics, pharmacogenetics, genomics, environmental genetics, translational bioinformatics, health care outcomes, and policy. We serve a critical regional need.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Major hallmarks of aging and neurodegeneration include cognitive decline, altered body composition, dysregulation of circadian rhythms, and changes in neuroendocrine systems. The hypothalamus is the brain region that harbors a diversity of neuronal subtypes that coordinate these important functions. Yet, the extent to which changes in the hypothalamus underlie functional decline in normal aging and neurodegeneration is not well understood. Intriguingly, interventions targeting the hypothalamus can significantly extend lifespan in mice, with a discrepancy in females versus males. Moreover, alterations in sleep and body weight can occur prior to the onset of neurodegeneration, for example in Alzheimer’s Disease (AD). One challenge in understanding the aging process is that it is highly heterogeneous, meaning that different cell-types age differently. For example, in brain aging, within individuals, the immune cells (microglia) age very differently from neurons. Moreover, across individuals, women are more susceptible to age-associated neurodegenerative diseases such as Alzheimer’s disease (AD) than men. However, the selective vulnerability of different cell-types in the brain in aging and AD, and the cell-type specific mechanism underlying female bias in brain aging are largely unknown. For the F99 phase of this proposal, in Dr. Webb’s laboratory at Brown University, I will build on my foundational work in which I defined the cell-type transcriptional changes that occur in the aging female mouse hypothalamus. I will perform machine learning analysis to identify signatures of cell vulnerability and resilience with age and extend this work to a model of neurodegeneration (AD mouse models and human post-mortem tissue). Understanding the selective vulnerability in aging and AD can help develop precise interventions to specifically target the vulnerable neurons to slow down brain aging and promote health span. For the K00 phase of this proposal, I will seek to understand the epigenetic mechanisms regulating sex-differences in brain aging. My previous analysis found increased expression of Xist, the master regulator for silencing one of the two chrX in females in eutherian mammals, in aging and AD brain. Given that chrX is enriched for neural and immune genes and the known loss of heterochromatin in aging, I hypothesize that Xist is required for maintaining chrX silencing to protect neurons in brain aging. I will test this hypothesis by epigenetically activating or silencing Xist in induced neurons derived from aged fibroblasts to determine the impact on neuronal aging, and in vivo to reveal the cell-type specific response to the chrX-specific perturbation. This work will contribute to the understanding of the heterogeneity, especially cell-type specific and sex-specific vulnerability, in normal brain aging and AD. Further, it will lead to the discovery of novel biomarkers to assess age and AD status at single cell resolution, which will contribute to the development of cell-type specific interventions. To successfully complete these goals, I will gain extensive training from a team of experts in computational biology, biology of aging, neurodegeneration, and neuroscience.

NIH Research Projects · FY 2024 · 2023-09

ABSTRACT Hearing loss is among the leading causes of disability worldwide, with the highest burden in resource limited settings (RLS). Children are disproportionately affected, given the detriment to a child’s neurocognitive and social development, yet the impacts can be mitigated if detected and treated early. Nearly 60% of hearing loss in children is due to preventable factors, and identification is the first step in addressing hearing loss. High income countries have implemented universal newborn hearing screening (UNHS) programs with a goal of diagnosing hearing loss and starting early intervention in the first few months of life. Few comparable programs exist in low and middle income countries, given such barriers as limited access to trained personnel and high cost of hearing screening equipment. We propose to optimize a low-cost smartphone otoacoustic emissions (OAE) device for hearing screening and study the implementation in an RLS. The smartphone OAE is comparable to conventional hearing screening equipment in US trials and now must be evaluated where it can have the greatest impact. The aims of the R21 are to optimize the OAE device in various clinical settings and patient ages in Kenya. We will evaluate potential impact of noisy clinical environments, assess consistency of screening, and compare usability in frontline and lay health facility workers, with a deliverable of a low-cost, user-friendly OAE that is a feasible tool in a low- resource clinical setting. Work will begin to integrate hearing screening results from the smartphone OAE directly with electronic medical records systems in Kenya. The R33 will further establish implementation outcomes and validity of the smartphone OAE device in a UNHS program, and will provide an in-depth evaluation of the implementation strategy and task-shifting in the Kenyan context. In parallel, the R33 will deploy the smartphone OAE in a longitudinal study of suspected (HIV exposure) and known (otitis media with effusion) risk factors for hearing loss. The longitudinal study will leverage an additional innovative lay-person friendly smartphone tool that can be used to monitor for middle ear fluid, an important companion for hearing screening in children that typically relies on expensive, skill intensive equipment. The research team includes medical providers, public health researchers, computer scientists and the Technical Working Group for Ear and Hearing Care in Kenya’s Ministry of Health, a collaboration that will support program sustainability when the project is complete. The project establishes a foundation for smartphone OAE in UNHS programs, high-risk infant surveillance, ototoxicity monitoring, and future research to understand and improve ear and hearing care in RLS. The outcomes of this work align with the goals of the WHO World Report on Hearing, which strives for all people, including those with hearing loss, to have access to high-quality services without experiencing financial hardship by 2030.

NIH Research Projects · FY 2024 · 2023-09

SUMMARY: Cannabis use in the US has alarmingly quadrupled in recent years: from 8.9% in 2016 to 17.5% in 2019 in individuals of age 12+ that used Cannabis in the last year. Thus, it is critical that we better understand the bioactivity of ∆9-tetrahydrocannabinol (THC), the primary intoxicating compound in Cannabis. THC activates cannabinoid receptors 1 (CB1R) and impairs several behaviors, including spontaneous locomotion. While it is known that THC reduces spontaneous locomotion in mice, the neural-circuit basis and involvement of the endocannabinoid (eCB), 2-arachidonoyl glycerol (2-AG), of this response remains largely unexplored. Using a novel 2-AG sensor (eCB2.0) expressed in the prelimbic cortex (PrL) neurons, we discovered a tight correlation between increase in 2-AG levels, calcium transients and initiation of spontaneous locomotion. Remarkably, both 2-AG and GCaMP6f calcium transients were significantly greater in THC-treated mice compared to vehicle- treated mice, and the number of initiated locomotion events greatly reduced as a function of the hypolocomotion response. Our hypothesis is that 2-AG activates CB1R’s on select PrL GABAergic interneuron subpopulations, which disinhibits the glutamatergic activity within the PrL to control the initiation of spontaneous locomotion, and THC potentiates this mechanism. ■ Aim 1 will determine how THC preferentially modulates the physiological activity of select GABAergic subpopulations and glutamatergic neurons in the PrL. We will use RNAscope in situ hybridization to map CB1R expression in GABAergic interneurons (GABA-IN’s) in the PrL. Combining GABA-IN-Cre lines with viral techniques and channel-rhodopsin assisted circuit mapping with slice electrophysiology, we will determine how 2-AG’s action at CB1-R in PFC changes synaptic transmission and how this is impacted by THC. ■ Aim 2 will utilize in vivo fiber photometry and optogenetic manipulation of GABA-IN-Cre and VGLUT-Cre mice expressing cre-dependent GCaMP6f or eCB2.0 in mouse PrL to record changes in neuronal activity and 2-AG levels of inhibitory and excitatory neurons during spontaneous locomotion of mice treated with increasing doses of THC. We will determine the specific 2-AG signaling components involved in this response using selective pharmacological inhibitors. We will also virally express a CRISPR-CB1R construct to eliminate CB1R from GABA- IN’s and glutamatergic neurons to establish the involvement of this target. Based on this premise, we will test the hypothesis that select subpopulations of GABA-IN’s mediate changes in PrL activity associated with increase in 2-AG levels and control of spontaneous locomotion. To determine the necessity and sufficiency of PrL activity in THC treated mice, we will optogenetically stimulated or inhibited GABA-IN’s and glutamatergic neurons and measured changes in spontaneous locomotion in vehicle and THC-treated mice. This exploratory R21 grant proposal provides an ideal mechanisms and scientific foundation for studies aimed at deciphering the mechanisms by which eCBs modulates PrL activity and how THC impairs locomotor behavior.

NIH Research Projects · FY 2025 · 2023-09

Alcohol and cannabis are the most misused psychoactive substances in the United States, particularly among young adults (aged 18 to 30 years). Personally relevant stressful experiences are potentially key social determinants of drug use, and a substantial body of research has shown the deleterious impact of negative interpersonal encounters on young adults. Studies have also linked these stressful experiences to alcohol and cannabis use and their co-use, but this link is almost exclusively based on findings from correlational studies that use retrospective reports of interpersonal experiences. There is a lack of knowledge on the effects of indirect (i.e., vicarious) exposures to these negative interpersonal exchanges—daily burden that is more commonly experienced than direct interpersonal exchanges. There also have been a few experimental studies examining these personally relevant stressful experiences’ effects on drug use; such research is necessary to help establish a causal link between these stressful experiences and substance use. Establishing this causal link with a rigorous design and scientifically valid measurements will incrementally advance addiction research. The main objective of the proposed research is to examine the effects of personally relevant stressful situations on alcohol and cannabis use and co-use. Other objectives are to evaluate the indirect pathways explaining this link by way of acute stress, rumination, and coping motives, and to evaluate the buffering role of resilience factors. We propose a novel between-group experiment that uses virtual reality to subject research participants (N = 456, 18-30 years) to different stressful situations. Using validated, semi-structured scripts in experimental simulations, virtual reality has the unique advantages of immersing research participants in realistic environments and personally relevant interpersonal exchanges to promote ecological and internal validity of the findings. We will assess participants’ acute stress and coping motives to use alcohol or cannabis, or both, in real time, and assess their anger rumination and alcohol and cannabis use and co-use status 24 and 48 hours following the lab procedures. This application aligns closely with NIDA’s funding priority on polysubstance use.

NIH Research Projects · FY 2024 · 2023-09

ABSTRACT International and South African guidelines recommend TB preventive therapy (TPT) for people with HIV (PWH) and other people at high risk for TB, including close contacts of people with TB. Despite the evidence for reduced morbidity and mortality for people with HIV (PWH) who receive TPT, and guidelines recommending use, there remains a substantial gap between people recommended to receive and people who actually receive and complete a course of TPT. The 2022 WHO Global TB Report highlighted the growing gap in access and provision of TPT, which has been aggravated by the COVID-19 pandemic. Bridging this gap is a South African and global priority. With the recent availability and evidence for newer, shorter regimens of TPT, a transformation of HIV care delivery models (in part forced by the COVID-19 pandemic) and evolving national guidelines for TPT, it is increasingly urgent to explore new patient-friendly models of TPT delivery in order to inform programmatic guidance that results in greater uptake, adherence, and completion of TPT. HIV care has benefited from the expansion of “differentiated care delivery” models, which encourage community-delivered care, infrequent clinic/facility visits, limited laboratory monitoring, and task-shifted treatment models to deliver comprehensive HIV care to stable adults in community settings. Emerging demonstration projects have found that HIV preventive medication, or PrEP, can be safely and effectively delivered by pharmacists rather than clinicians. These successful models for differentiated HIV treatment and prevention delivery may be able to be translated to include TB preventive therapy. The availability of safe, effective, short-course TB preventive therapy with limited monitoring requirements suggests that similar community-based models may be adapted to provide this similarly essential preventive treatment. We will explore two approaches of adapting HIV differentiated services to TB prevention. We hypothesize that people who receive community-delivered TPT have higher rates of completion of a course of TPT than people who receive standard-of-care clinic-based TPT. We will conduct a randomized controlled trial of community vs. clinic-based TPT delivery among people participating in a community-based TB screening program in South Africa, and explore participant reasons for completion and noncompletion with qualitative research. We will also conduct preliminary research on the feasibility and acceptability of task-shifted TPT delivery, engaging clinic- based pharmacy assistants to provide TPT to low-risk clients. Through formative research, qualitative interviews with nurses, clinic operational managers, and workflow mapping exercises, we will identify barriers and facilitators for pharmacy assistant task-shifted TPT delivery. Together, this research will establish the foundation for subsequent larger trials of patient-centered, differentiated TPT delivery approaches to increase TPT uptake and completion in South Africa and ultimately decrease morbidity and mortality from TB.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Obstructive hypertrophic cardiomyopathy (HCM) causes significant symptoms and morbidity due to left ventricular outflow tract obstruction (LVOTO). Interventricular septal (IVS) reduction procedures for LVOTO such as alcohol septal ablation and surgical myectomy relieve symptoms and reduce sudden death risk, but are often initiated late in the disease process due to their peri-operative risk, anatomic constrains, complications (particularly atrio-ventricular (AV) block) and limited efficacy. Our laboratory has developed an attractive approach to IVS reduction therapy (SRT) and obtained preliminary large animal data using a high- intensity ultrasound (HIU) catheter system for the treatment of oHCM, severe LVOTO and its consequences. HIU has distinct benefits over existing SRT methods in that it: 1) is less invasive (delivered via a femoral venous approach to the right ventricle (RV)). 2) selectively ablates the mid-myocardium while sparing the sub-endocardium (which contains the His- Purkinje system), thereby reducing risk of AV block. 3) does not rely on unpredictable anatomic availability of septal perforator coronary artery branches. This proposal will further develop HIU IVS reduction by optimizing lesion size and depth, avoiding the near-field subendocardium, tracking catheter location/orientation/contact, confirming effective formation non- invasively, and initiating regulatory work to position us for first-in-human studies with a subsequent award. In Aim 1, we will use acoustic simulations to design, fabricate and validate optimal HIU transducers and catheters in ex-vivo models. Aim 2 will develop and test several advanced catheter design features that will confirm transducer-tissue contact, track catheter location in real time, and confirm effective IVS ablation after HIU sonication is performed. Aim 3 will study fully-developed HIU catheters in-vivo to determine ability to reduce IVS thickness (and local myocardial mechanics) over 30 day survival. The assembled team includes exerts in therapeutic ultrasound, acoustic physics, echocardiography, cardiac MRI, large animal research methods, research sonographer, and an HCM clinical researcher who will help with eventual translation of this work to first-in-man studies. Regulatory consultants will ensure that animal studies are performed in a Good Labor and Practices (GLP)-compliant manner, positioning our group for an Investigational Device Exemption for an Early Feasibility Study with subsequent awards.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY/ABSTRACT K99 training: The goal of the proposed K99/R00 Pathway to Independence Award is to provide Dr. Jonas Dora with training needed to launch his career as an independent scientist. Following his PhD in cognitive psychology, Dr. Dora has already started to make important contributions to the field of alcohol use research as a postdoctoral research fellow in the Department of Psychology at the University of Washington. The proposed K99 training period builds on Dr. Dora’s PhD background and his current training in the study of alcohol use in natural environments. The K99 phase will provide a period of intensive training in the combined study of alcohol use with experimental, ecological momentary assessment, and computational approaches, and will position Dr. Dora to make substantial contributions to the field of alcohol research over the course of his career. Dr. Dora will learn from the proposed mentor (Dr. Kevin King), local collaborators (Drs. William George, Mary Larimer) and external collaborators (Drs. Matt Field, James Murphy, Katie Witkiewitz), who are leading experts in the field of alcohol use research using both experimental and ecologically valid approaches, as well as the advanced computational modeling of behavioral and subjective data. In addition, Dr. Dora will attend courses, scientific conferences, and workshops to meet his training objectives. The University of Washington is a world-class research institution that provides an optimal environment, the necessary resources, and a stimulating intellectual space to facilitate successful completion of this project. K99 research: Together with his mentor and collaborators, Dr. Dora will conduct controlled experiments in a simulated bar environment as well as studies in people’s natural drinking environment to test the idea that negative and positive reinforcement of alcohol can be observed when heavy drinkers with and without symptoms of alcohol use disorder (AUD) make decisions between alcohol and substance-free reinforcers. R00 research: Dr. Dora will translate the K99 research using a task involving hypothetical choices between alcohol and substance-free reinforcers into an ecologically valid test of the hypothesis that positive and negative affect differentially motivate real-world value-based decisions to consume alcohol (vs regulate affect via alternative emotion regulation strategies) in heavy drinkers with/without symptoms of AUD in everyday life. Significance: By combining methods from cognitive psychology and alcohol use research, this research will provide a novel test of the idea that alcohol use is reinforcing in the face of positive and negative emotions, and in that way will advance NIAAA’s strategic aim to identify mechanisms that contribute to AUD. By studying alcohol use as a form of value-based decision-making, the insights from this project will suggest new possibilities to target people’s emotions in the prevention and treatment of alcohol use disorder.

NIH Research Projects · FY 2025 · 2023-09

Mobile manipulators that can navigate and physically interact with their environment have the potential to assist people with motor limitations in carrying out activities of daily living independently. Despite this great potential, robots that can be safely deployed in the homes of these users do not yet exist. Until recently one of the key reasons for this gap was the lack of available hardware platforms, but the release of Stretch – a new low-cost, light-weight, inherently safe, and highly capable mobile manipulator – has greatly reduced the barrier to in-home deployments. A second key reason is the difficulty of robust autonomy given the vast variations across home environment. A practical, near-term solution is to have robots teleoperated by the user, which is also preferred by users in the target group who want to keep control over the robot. However, most existing teleoperations interfaces are not accessible to users with motor limitations who might have restricted input. This project aims to tackle this challenge by developing new systems and algorithms that enable adaptive accessible teleoperation interfaces for mobile manipulators. The ability to adapt to the unique requirements and preferences of these users while enabling the safest and most efficient operation of the robot is critical to our proposed solution. The project involves the development of an integrated system called AccessTeleopKit implanted on the Stretch robot platform, and shared as open-source software. New algorithms for automatically customizing interfaces in AccessTeleopKit based on user input ability assessment, and automating repetitive parts of common tasks from user demonstrations as they teleoperate the robot will be developed. Contributions also include conceptual frameworks to represent teleoperation interfaces as mappings between user inputs and robot control outputs with Finite State Machines; and the heuristically assessing the accessibility of a teleoperation interface for users with different abilities. Evaluation will involve user studies and multi-phase long-term deployments of the robots in five homes facilitated by occupational therapists and will contribute new empirical findings about the usability, utility, and acceptance of assistance robots in the home. New guidelines for occupational therapists to use teleoperated robots in their practice will also be created.

NIH Research Projects · FY 2025 · 2023-09

Project Summary: The goal of the proposal is to develop a Bayesian statistical framework for mortality estimation from disparate data sources. Using this framework we will produce a suite of principled methods to be used in those situations in which vital registration data are lacking. We will emphasize efficient implementations that can be used by researchers in low- and middle-income countries (LMICs), who may have limited computing resources. In Aim 1, we will develop guidelines on a general statistical framework for mortality estimation. Aim 2 will focus on subnational child mortality with particular emphasis on the under-5 mortality rate (U5MR), which is a key indicator of the health of a population, and the neonatal mortality rate (NMR). Excess mortality estimation during the Covid-19 pandemic, by month, at the country level, will be the subject of Aim 3. We will disseminate results widely and provide software and training in the developed methods. We will produce yearly estimates of U5MR and NMR at the geographical level at which health decisions are made. To achieve this goal, household survey, VR and census data must be combined in a coherent way. Census data on child mortality typically provide summary birth history (SBH) data, which consist of mother's age along with the number of children born and the number who died, but without the times at which those events occurred. We will develop a framework for combining the different data sources, which will entail dealing with the design issues in the household survey, accounting for unknown birth and death times in the SBH data, and estimating the completeness of the VR data (births and deaths). We will also incorporate demographic information via a form of Bayesian benchmarking. Effective and appropriate use of the models will require rigorous model assessment, careful interpretation of results and meaningful and informative graphical summaries. We will develop robust models to evaluate the excess mortality, i.e., the difference between the deaths ob- served in the pandemic and those expected if the pandemic had not occurred. We will model the expected deaths, and incorporate the uncertainty in this endeavor in the excess mortality calculation. Completeness of mortality counts, that is, under-reporting and delays in reporting, will also be considered. For countries who do not report deaths in the pandemic, we must predict the mortality count using available country-level covariate data, and we will adopt flexible yet interpretable regression forms, and acknowledge uncertainty in the covariate data. We will produce user-friendly software for the methods, along with vignettes and training materials, including short courses. The endpoint is to have software that can be used by researchers in LMICs. All aims will be informed by the collaborative team's close links with the United Nations Inter-agency Group for Child Mortality Estimation (for the subnational child mortality aim) and the World Health Organization Division of Data, Analytics and Delivery for Impact (for the excess mortality aim). Together we will develop methods to highlight disparities and inform interventions.

NIH Research Projects · FY 2026 · 2023-09

I am a mid-career nephrologist, a newly promoted Professor, the holder of Arthur Stach Endowed Professorship and the Director of Nephrology Clinical and Research Education in the Division of Nephrology at the University of Washington (UW). I have been a NIDDK-funded physician-scientist since the completion of my fellowship in 2010; and have an active patient-oriented research program that focuses on the intersection of kidney and cardiovascular disease. My work encompasses epidemiological studies, mechanistic studies, and clinical trials all focused on the pathophysiology, diagnosis, risk stratification and treatment of hypertension, heart failure and cardiac arrhythmia in patients with chronic kidney disease, acute kidney injury and kidney failure (treated with dialysis or kidney transplant). I am currently the PI of three NIH R01s, the co-Director of the UW Nephrology NIDDK T32, co-I on two NIH U01s and the PI of two NIH administrative supplements. One of the greatest joys and privileges of my career to date has been the opportunity to serve as mentor. My success as a mentor is measured by my mentee’s success. My current and previous grants have provided numerous rich opportunities for training for post-doctoral students, residents and fellows. I have been a mentor for 24 talented individuals since 2010, Of these, 63% of my mentees remain in academia and continue in scholarship or research. The work of these mentees has been productive, yielding >40 first author publications and ten NIH or foundation grants. It is well known that advances in NIDDK-focused diseases are in crisis as fewer physicians and scientists choose to pursue research careers. Mentorship is a critical factor cited by students for inspiring their interest in scientific careers. Locally, the UW, located in Seattle, WA, is unique in its mission to attract trainees from across a five-state region of Washington, Wyoming, Alaska, Montana and Idaho. Coupled with established outreach programs at UW and the sizable pool of post-doctoral trainees, there is tremendous opportunity to cultivate the next generation of NIDDK scientists in this region. This award will provide key resources, training and professional development that will enhance my ability to serve as an effective mentor for post-doctoral trainees.