University Of Washington

NIH Research Projects · FY 2026 · 2024-07

ABSTRACT Hepatitis C virus (HCV) infection is a widely prevalent bloodborne infection, with approximately 71 million global (2.4 million in USA) chronic infections worldwide. HCV infection is frequently asymptomatic and many of those infected are unaware of their illness. Untreated HCV infection may lead to chronic liver disease, such as hepatocellular carcinoma, and accounts for an estimated 1.1 million annual global deaths (14,000 USA). Within the last six years, direct acting antivirals (DAAs) have demonstrated high cure rates (90-95%) across all genotypes in less than 12 weeks of all-oral treatment. These highly effective therapeutics offer a path toward ending the HCV epidemic as drugs become more affordable and global health efforts prioritize expanded access. The rollout of DAAs relies on diagnostic testing to identify HCV cases and rapidly link eligible patients to treatment options. In most clinical settings, current HCV testing protocols use a rapid antibody test to diagnose past or current cases of HCV. While rapid HCV antibody tests are easy to use and widely available, current HCV nucleic acid amplification tests (NAATs) require venipuncture blood samples and central laboratories where tests are run by trained technicians on complex, expensive equipment, causing delayed test results and loss to follow-up. Recent initiatives by the Whitehouse White House’s HCV Elimination Program, WHO, MSF Access Campaign, and NIH (NOSI: NOT-AI-23-001) have encouraged the development of point-of-care (POC) HCV NAATs to provide accessible and rapid diagnosis of chronic HCV and aid in the rollout of DAAs. Decentralized, clinic-based HCV NAATs offer a streamlined approach to patient care where a single test may be used to diagnose HCV, identify active viremia, and later confirm a cure. There is an abundance of commercial POC NAAT tests for respiratory diseases, such as influenza or SARS-COV-2, but due to the significant technical challenges of detecting low viral titers in blood samples, there are no available capillary whole blood rapid POC NAATs for HCV that meet target product profiles. We have developed a new approach for an integrated POC NAAT for detecting HCV from whole blood. Our proposed HCV test is a significant departure from most existing POC tests that use classical extraction methods (solid phase extraction), multiple buffer exchanges, reaction chambers, PCR amplification, and robotics for physical actuation to automate and miniaturize laboratory-based PCR workflows. Here, we propose an innovative paper-based device with novel whole blood sample preparation and electrophoretically-mediated RNA purification, amplification, that is capable of simultaneously extracting and amplifying viral HCV RNA from whole capillary blood using reverse transcription recombinase polymerase amplification. The test cartridge consists of a paper and plastic device with no moving parts and provides results in less than 30 minutes. This low complexity diagnostic test is intended to be CLIA-waived and uses a disposable cartridge model with costs less than $5 and a benchtop reader costing less than $500, enabling expanded use in resource-limited clinics.

NIH Research Projects · FY 2025 · 2024-07

ABSTRACT Medicaid is the largest payer for mental health care in the US, providing coverage for more than a quarter of those with serious mental illness. Yet, despite a greater burden of mental illness and more chronic physical disease, Medicaid enrollees have especially high rates of unmet care needs due to low behavioral health provider participation in Medicaid networks and fragmented payment and delivery systems. Community Health Centers (CHCs) make up a critical component of the safety-net for low-income and underserved populations. CHCs have been at the forefront of medical home demonstrations and have increasingly integrated behavioral health services and personnel into comprehensive primary care practices. While a confluence of federal and state policy initiatives, as well as efforts on behalf of advocacy groups and professional associations, have prioritized initiatives to integrate behavioral health with primary care for Medicaid enrollees, uptake of evidenced-based models has been hampered by administrative and payment hurdles. To date, little is known about the extent of integrated behavioral health among CHCs, including which patients have access to integrated services, how integration is associated with outcomes, and how policies like state Medicaid benefit design may be promoting clinical integration in CHCs. The proposed study will leverage a novel practice-level dataset collected by the research team linked to national Medicaid claims and a variety of publicly available data sources to examine the drivers and consequences of integrated behavioral health in CHCs. We will field a survey among a nationally representative sample of CHC delivery sites to assess the current landscape of integrated behavioral health using a validated instrument, determine the organizational and state-policy factors associated with greater integration in these settings, and assess the extent to which clinic-level integration improves access to care, quality, and health spending for Medicaid enrollees with mental illness. Further we will develop and disseminate a new claims-based measure of behavioral health integration that will efforts to track integrated behavioral health in CHCs and permit future research and policy evaluation without the need of surveying clinics directly. Through this work we seek to provide timely and generalizable data on how efforts to integrate care in CHCs are delivering value for state Medicaid programs. We expect this work to inform resource allocation and policy decision-making to enhance access to evidenced-based systems of care for enrollees with mental illness.

NIH Research Projects · FY 2025 · 2024-07

The annual “Principles of STI and HIV Research and Public Health Practice” course was launched by the University of Washington in 1993 to provide an intensive overview of skills and foundational knowledge required for research careers in the field of STI/HIV. Since then, it has evolved into a globally-recognized cornerstone of STI/HIV research training with over 3,500 participants trained to date from over 25 countries and 6 continents. The proposed R13 is for partial support of the course / training conference for the next five years. The course objectives are to train early-stage STI/HIV investigators from interdisciplinary backgrounds to: (1) Describe the biologic, clinical, epidemiological and social/behavioral aspects of STI of contemporary public health importance; (2) Identify outstanding scientific questions and develop a research design or program evaluation to answer these scientific questions; (3) Gain experience applying different strategies from research and/or public health program evaluation to answer emerging questions in the field of HIV/STI; (4) Gain experience working on a multidisciplinary team of STI/HIV researchers and practitioners and provide opportunities for social interaction and networking; (5) Discuss the different opportunities and career paths available in STI/HIV research and practice fields for US domestic and international public health; and (6) Provide opportunities for professional networking with peers and course faculty To meet these objectives, the course takes an interdisciplinary approach and provides early-stage investigators with tools for continued learning, collaboration in multidisciplinary teams, and maintaining a broad scope of investigative possibilities. This course offers a unique opportunity for state-of-the-art introductory training in behavioral, clinical, epidemiologic, statistical, implementation, and basic science research on STI/HIV through a practically-oriented overview of concepts and skills common to these broad disciplines. Course proceedings are disseminated on a UW website, which contains speakers' slides, lecture recordings, and discussion boards. The course is evaluated each year, and updates to subsequent course agendas are informed by participant feedback and Curriculum Committee recommendations to ensure the course is up-to-date, relevant, and employs active learning techniques. Participant feedback is extremely positive, demonstrating that the “Principles Course” remains a critical resource for training the next generation of HIV/STI researchers and public health practitioners.

NIH Research Projects · FY 2024 · 2024-07

SUMMARY/ABSTRACT This proposal is a request to purchase and install pen housing for groups of nonhuman primates. These pens will be used primarily to house harem breeding groups of pigtail macaques (Macaca nemestrina). The Washington National Primate Research Center (WaNPRC) manages the largest domestic breeding colony of the pigtail macaque, M. nemestrina, to provide animal models for use in biomedical research. To save costs, the bulk of the breeding colony is housed at the WaNPRC’s Arizona Breeding Colony (ABC). However, this requires that animals be transported to Seattle for research assignments. Some research projects require the use of pregnant animals or pre-weaned juveniles, and it is necessary to breed animals in Seattle to meet these needs. Currently this breeding is performed in a timed-mating pair-housing situation. Installation of breeding pens in Seattle will increase production and efficiency while improving animal welfare. Housing animals in harem groups will eliminate the need for monitoring female reproductive cycles, scheduling mating days, and introducing breeding pairs. Housing the breeding animals in pens rather than individual cages improves overall animal welfare in two ways: Socialization in groups provides significantly improved psychological well-being when compared to single housing or even pair housing, and the increased total space (horizontal and vertical) in pens compared to cages improves both physical and psychological well-being. The cost of pens is significantly lower than the cost of cages per sq ft of floor space. In summary, this project will: 1) Increase efficiency of Seattle breeding program. 2) Improve animal welfare by increasing socialization and housing space. 3) Increase animal availability and decrease lead time for initiating research projects.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY/ABSTRACT The University of Washington (UW) Molecular Biophysics Training Program (MBTP) is designed to train predoctoral students to apply state-of-art physical and quantitative approaches to the investigation of biomedically relevant systems at molecular and cellular levels. As manifested by the COVID-19 pandemic crisis, basic and translational research in almost all biomedical areas necessitate the adoption and implementation of rigorous and quantitative biophysical methods to dissect the fundamental mechanisms of molecular and cellular biology and to develop effective therapeutics against a variety of existing and emerging human diseases. This requirement calls for a highly trained workforce proficient in research methods at the intersection of physics, chemistry, engineering, and biology. The overarching objective of MBTP is to meet these needs by enhancing the research experience and training of holistically selected UW predoctoral students interested in molecular biophysics and preparing them for a productive career in health-related research in academia, government, and the private sector. Each year MBTP trainees are chosen through a rigorous selection process that identifies promising graduate students from a large pool of talented and diverse applicants admitted to UW through five interdisciplinary programs and nine departmental programs. During their graduate career, 10-12 MBTP trainees are provided with at least two years of mandatory structured activities to expose them to a wide range of biophysical methods, techniques, and research topics that go beyond their home graduate program. These training activities include, but are not limited to, a structural biology and biophysics graduate level course, a bi-weekly student research presentation series, a peer-organized student journal club and discussion group, an annual retreat trainee-centered retreat, and interactions with a larger local biophysics community. These activities are further supplemented with lectures and courses required or supported by MBTP and related UW departments. MBTP plays a special role at UW by actively nucleating a cross- departmental biophysics community. It fosters close interactions among trainees and their peer pre- doctoral students, who share common interests in molecular biophysics, but are otherwise separated by departments and graduate programs. By taking advantage of a growing body of UW faculty with biophysics background, MBTP creates a unique platform, where trainees learn about modern biophysical techniques, sharpen their communication skills, build and extend their professional network, establish and enhance their science identity and self-efficacy. The training program has a strong record of success and impact as evidenced by the diverse research-related career choices trainees make after they leave graduate school.

NIH Research Projects · FY 2025 · 2024-07

Project Summary/Abstract The goal of this proposal is to develop a platform created from advanced biomaterials that enable novel investigations into the physiochemical roles of the tumor microenvironment (TME) on the origins of colorectal cancer. Colorectal cancer is a leading cause of cancer deaths in the U.S. and is increasing in incidence. Virtually all of these tumors arise from adenomas or polyps whose progression to cancer is driven by physical and chemical changes within the TME in concert with genetic mutations. Although much is known about the genetics of colon cancer, relatively little is understood about how the physicochemical properties of the surrounding TME matrix impact the process of cancer initiation. Current evidence does suggest that these TME alterations are critical to adenoma formation and progression to cancer. To advance our understanding of this process, an interdisciplinary group of internationally renowned investigators with expertise in materials science, bioengineering, optical platforms, intestinal stem cell biology and oncology has been assembled to create a 4D-tunable hydrogel to study how these TME alterations impact the development of colorectal cancer. Advanced light-activated hydrogels and their fabrication in forming an accurate model of the colonic architecture at the micron scale will be extensively optimized and characterized. The light activatable biomaterials with controllable physiochemical properties will then form a foundational component of a colon microphysiologic system (MPS). Human intestinal cells will reside on the new biomatrix scaffolding possessing photo-controlled stiffness in both space and time and supporting formation of chemical gradients. To take full advantage of the new biomaterials tool set, a customized light-sheet platform and imaging cassette compatible with application of gradients of growth factors and oxygen will be developed to support the living colonic tissue on this bioengineered scaffold. The platform will enable high-quality imaging of large numbers of colonic crypts to generate data sets of sufficient size for statistical comparisons and hypothesis testing. This humanized, architecturally and physiochemically accurate biomaterials platform will then be used to reveal key characteristics of the TME’s influence on the hallmarks of cancer demonstrating the utility of these advanced biomaterials in studies of colon and other cancer types.

NIH Research Projects · FY 2025 · 2024-07

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The University of Washington (UW) Medical Scientist Training Program (MSTP) was established in 1970 and is the only MD-PhD program in the Pacific Northwest, comprising a quarter of the nation’s land mass. Our program has thus far produced over 300 graduates, most of whom have been employed in scientific research throughout their careers. Our goal is to build an educational pipeline leading to the development of a highly well qualified group of trainees and equip them with the skills, mentorship, role models, and motivation required to advance the frontiers of biomedical science and technology. Among multiple accomplishments, students and graduates of our program created the Apple Macintosh computer and one of the first enzyme replacement therapies for metabolic disease, have provided fundamental insights into the nature of stem cells, the sequence and structure of the human genome, and have led similarly successful MD-PhD programs elsewhere, thereby exponentially amplifying our program’s impact on training the next generation of physician-scientists. Our competitive program has grown to comprise approximately one-fifth of all medical students in Seattle. For each offer of admission, we receive over 23 training grant-eligible applications. Our trainees carry out their PhD research with UW faculty mentors at the UW, Fred Hutchinson Cancer Research Center (Hutch), Seattle Children's Hospital Research Institute, and Benaroya Research Institute. Current trainees' PhD departments and programs include Molecular and Cellular Biology, Neuroscience, Genome Sciences, Bioengineering, Computer Science, Molecular Engineering, Chemistry, and Epidemiology. They are mentored by a highly trained group of 81 well-funded and distinguished faculty drawn from across ranks, who emphasize and practice responsible, reproducible science. Our program integrates medical and graduate education, while reducing redundancy. Mean time to completion is on a shortening trajectory, with minimal attrition. Graduates published a mean of 6.7 peer-reviewed papers, including 2.8 as first-authors, many of which are exceptionally impactful. Nearly all graduates go on to research-related residencies at leading institutions, predominantly in fields conducive to long-term retention in research. We continually evaluate our outcomes, measure our progress toward its overarching objective of producing physician-scientists pushing the envelope at the interface of science and medicine, and iteratively evolve our program to stay at the forefront of evidence-based innovations in training practices.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY Mycoplasma genitalium is a sexually transmitted bacterial pathogen that frequently causes genital tract syndromes including urethritis in men and cervicitis, pelvic inflammatory disease, and infertility in women. Sensitive diagnostic tests have been approved in the US since 2019, however, few treatment options for M. genitalium are available. M. genitalium lacks a cell wall and has only a single membrane so antibiotics targeting peptidoglycan synthesis, or the bacterial outer membrane, are completely inactive. Doxycycline is only 30-40% effective in eradicating M. genitalium infections. The efficacy of azithromycin, the preferred therapy, has decreased in recent years and now more than 50% of US strains are resistant. In high-risk populations in the US and worldwide azithromycin resistance reaches 100%. More than 10% of strains are resistant to moxifloxacin, the recommended second line therapy, and resistance to both macrolides and fluoroquinolones is increasingly reported. No effective treatment options are approved in the US to treat these dually resistant infections. In addition, moxifloxacin is not approved for certain patient groups (e.g., pregnant women, adolescents <18 years old), and the FDA discourages fluoroquinolone use unless no other options exist because of potentially severe and permanent side effects. There is an urgent and immediate need to identify additional therapies with activity against M. genitalium. We determined that M. genitalium is susceptible in vitro to nitroimidazoles, consistent with a recently published clinical trial demonstrating that metronidazole reduced M. genitalium infection in women with PID, and contrary to the accepted view that these drugs are inactive against mycoplasmas. Building on our preliminary data we now propose to define the activity of nitroimidazole and nitrofuran antibiotics against M. genitalium in detail. We will assess the in vitro susceptibility to more than a dozen nitro group-containing drugs for which clinical safety and efficacy data are known, including several that are approved for other indications in the US and elsewhere in the world. The in vitro activity of these drugs will be compared in terms of minimum inhibitory concentration, time kill kinetics, post antibiotic effect, activity against biofilms, and spontaneous resistance rates to inform future clinical trials. Differences in strain susceptibility will be determined by measuring the potency of top performing analogs against our existing collection of clinical isolates. We found that nitroimidazole resistance is associated with mutations affecting an oxidoreductase gene suggesting a mechanism for the bioreductive activation of the prodrug that is necessary for its bactericidal activity. We propose to expand and confirm these findings by isolating additional resistant mutants and defining drug-enzyme interactions with wild type and mutant alleles of the purified oxidoreductase. This study will have direct translational impact by offering clinicians and their patients additional options for the untreatable M. genitalium infections that are increasingly reported.

NIH Research Projects · FY 2024 · 2024-07

Our current clinical approach to re-irradiation is not based on data. Guidelines vary widely and are not rooted in observed toxicities. A frequently cited reason for that is both the scarcity of existing outcome data, as well as its heterogeneity: there are multiple radiation courses per patient with variable time between treatments. It is correct that the lack of data is a severe problem, though one that will be solved given the steep increase in the number of re-irradiation cases and published data. What the current lack of data obscures is a much more fundamental problem: that even if we had enough outcome data, there is no conceptual framework or outcome model to fit that data to. The need for such an approach to guide clinical treatment of re-irradiation is urgent. While re- irradiation used to be rare, patient volumes are growing rapidly: studies report that already 1 in 6 patients that come for radiotherapy have received prior radiation to the involved or a nearby site. To overcome the challenges described above, we propose a novel approach to guide re-irradiation based on imaging the evolution of normal tissue damage and recovery. In this space, data is more plentiful, with imaging at defined, clinically relevant follow-up timepoints. Furthermore we can build on our success in describing and analyzing normal tissue response to radiation. To overcome the challenges described above, we propose a novel framework to guide re-irradiation based on two innovative concepts: 1) Quantifying the evolution of normal tissue damage and recovery after RT. The time factor that is so important in re-irradiation can be studied using the evolution of radiation-induced normal tissue damage on imaging. 2) Normal tissue radiosensitivity in an individual patient is conserved between RT courses. While this seems intuitive, it is not known if normal tissue response in patients correlates when re-irradiating them. We have unique preliminary indicating that there is a strong relationship, and proving this hypothesis would enable us to integrate the response to the first treatment into the planning of the second. Based on these two concepts we formulated our two independent aims. In SA1 we will describe normal tissue recovery based on follow-up imaging using imaging biomarkers of liver and lung injury after radiotherpay. We hypothesize that we can parameterize the dose-dependent recovery from radiation-induced injury using a single, patient-specific recovery parameter in normal liver (SA1a) and lung (SA1b) after radiotherapy. In SA2 we will explore feasibility of personalization of re-RT based on the observed normal tissue response at first RT. Our working hypothesis is that the observed radiation-induced image changes after the first RT predicts normal tissue response at second RT, when corrected for the initially given dose distribution. Upon completion of these aims we will possess a generalizable framework for re-irradiation that allows us to incorporate the patient’s individual response to the first radiation treatment, and the time that has passed since, into the planning of re-irradiation.

NSF Awards · FY 2024 · 2024-07

This project will center on the study of inverse problems, particularly those involving transport-type partial differential equations. The theory of inverse problems lies at the borderline between pure and applied mathematics, with connections to statistics, physics, engineering, and biology. The diverse array of applications which can be addressed via this theory include X-ray computed tomography, geophysical prospection, and parameter identification for partial differential equations. An effective approach to tackle such questions often involves the use of a geometric framework and geometric tools, facilitating the reconstruction of internal structure from local or boundary measurements. This project focuses specifically on geometric inverse problems. The relevant equations feature velocity fields capable of generating chaotic dynamics, an aspect which presents new challenges for the analysis. The project will also generate opportunities for research and professional training for graduate and undergraduate students. The project addresses several novel strands of research situated at the interface of geometric inverse problems, dynamical systems, microlocal analysis, and complex geometry. At its core, the planned research is motivated by the desire to comprehend and characterize distinguished solutions to transport problems, a pursuit with potentially far-reaching consequences including the resolution of certain longstanding geometric inverse problems. Among those are the determination of the range of the scattering relation (the first return map of the geodesic flow), deciphering the information encoded within the Ruelle zeta function at zero, and determining topological features of the underlying space from the periods of closed trajectories of the velocity field. The study of distinguished solutions to transport equations necessitates an in-depth analysis of X-ray transforms and the spectral theory of hyperbolic flows. 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 · 2024-07

PROJECT SUMMARY The primary goal of the Research Education Program in the Department of Otolaryngology-Head and Neck Surgery (OtoHNS) at the University of Washington (UW) is to provide every resident in our department with knowledge, skills, and inspiration to establish an independent and sustainable research program in an academic setting as a Clinician-Scientist. We also offer research training and education to medical students to encourage them to pursue academic careers in Otolaryngology. The long-term goal of our program is to increase the research contributions of Otolaryngologists and to hasten development of better treatment options for patients with disorders impacting communication. Our research training program has had outstanding outcomes under support of a NIDCD T32 Grant for 40 years. For example, 64% of the resident Participants in the past 15 years are in full-time academic positions. To continue these efforts, we request support for five Postdoctoral (resident) Participants and one Predoctoral (medical student) Participant. The OtoHNS Department contributes funds for this training and also offers 1-2 years of Post-Residency Fellowship to one resident in our Program to continue mentored research training, prepare a K Award application, and gain additional clinical training. We are dedicated to training diverse Participants. We evaluate Program outcomes using input from Participants, Preceptors, and an Advisory Board, and we use feedback to build best practices and meet the changing needs of Participants. We propose two major aims: mentored research training (Aim 1) and structured research education (Aim 2). For Aim 1, every resident receives intensive research training with an experienced, well- resourced Preceptor for 80% of their working hours during a one-year or two-year period, starting in the third year of residency. Before this, residents select a Preceptor, either amongst the 23 Preceptors we describe or another Preceptor who fits our strict criteria. Together, they define a research project and a training plan. During the R25-funded year(s), Participants conduct research in their Preceptor’s group, learning the critical skills needed for research success. Concurrently, residents attend structured research educational sessions (Aim 2) with OtoHNS faculty and Program Alumni who impart key research skills and provide guidance for career development in academic Otolaryngology. Residents spend 20% of the R25 year(s) in clinical training. After the R25-supported time, residents continue research activities, facilitated by a department-supported research rotation with minimal clinical activities. Medical student Participants engage in the same mentored research and educational elements as residents for 9 months, working closely with them. Our Program prepares Participants at both levels for successful careers in academic medicine.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY/ABSTRACT Bladder cancer is the 6th most common cancer in the US and the 4th most common cancer in males. Each year, more than 80,000 people in the US are diagnosed with bladder cancer and over 17,000 will die. The vast majority (74%) present with non-muscle invasive bladder cancer (NMIBC). NMIBC has the oldest median age at diagnosis, intensive surveillance requirements, high recurrence and progression rates (up to 80%), and one of the greatest lifetime treatment costs of all cancers. Treatment options following recurrence of high-grade NMIBC include either BST (bladder sparing therapies with significant risk of cancer recurrence and/or progression) or radical cystectomy (a life-altering bladder removal surgery with substantial short-term morbidity and mortality). However, patients, their caregivers, and clinicians must make this complex treatment decision based on limited evidence since bladder cancer research remains underfunded relative to other common cancers, bladder cancer epidemiology cohorts are uncommon, RCTs have proven challenging to conduct, and risk stratification models are inadequate. Thus, there is a critical need for high-quality research in recurrent high-grade NMIBC across the full spectrum of outcomes to inform treatment decision-making. A recently established and unique cohort can be leveraged to address these evidence gaps. Specifically, the PCORI- funded Comparison of Intravesical Therapy and Surgery as Treatment Options (CISTO) Study is a large pragmatic multisite study of patients with recurrent high-grade NMIBC patients who have selected BST or radical cystectomy to manage their cancer. The CISTO cohort is a unique resource in bladder cancer care and has potential to serve as the foundation for addressing critical questions relevant to optimal patient-centered management. However, longer-term follow up of the CISTO cohort is required to fully assess the comparative effectiveness and harms of management options for recurrent high-grade NMIBC. In addition, incorporating molecular factors associated with bladder cancer progression has the potential to improve clinical staging and augment risk prediction models. Finally, the financial impact of new BST options is an important consideration for patients with what is already one of the most expensive types of cancer to treat. Therefore, we propose the BEST CARE for Recurrent NMIBC study 1) To compare long-term outcomes (clinical and patient- reported) between patients undergoing BST or radical cystectomy, 2) To determine whether prediction of progression to muscle-invasive or metastatic bladder cancer is improved by molecular staging, and 3) To evaluate the impact of newly approved BST options on financial toxicity. We aim to fill substantial knowledge gaps about long-term oncologic and quality of life (QOL) outcomes, specifically addressing the continued role of radical cystectomy. If radical cystectomy is associated with better long-term clinical outcomes, less financial hardship, and similar long-term QOL as BST, in the context of additional information offered through molecular staging, this would be impactful to clinical NMIBC practice.

NIH Research Projects · FY 2024 · 2024-07

Abstract: The epidermis provides a critical barrier between the body and its environment; it is composed of multiple layers of keratinocytes that form robust connections by assembling desmosomes between neighboring cells. Breakdown of desmosomes induces separation between keratinocytes, called acantholysis, a hallmark of several skin blistering disorders, most notably Hailey-Hailey disease (HHD). This inherited disease manifests as recurrent skin erosions causing super-infections, chronic pain, and reduced quality of life for patients. The advent of biologic and molecular therapies has brought relief to many patients with inflammatory skin diseases, but comparable advances for HHD and other genetic cutaneous pathologies remain elusive. Despite linkage to the ATP2C1 gene more than two decades ago, there are no FDA-approved therapies for HHD and ablating Atp2c1 in mice did not replicate HHD, hampering translational work. ATP2C1 encodes a Golgi calcium ATPase SPCA1, but our limited understanding of how SPCA1 loss compromises skin integrity limits rational drug development for HHD. Using CRISPR/Cas9, we ablated ATP2C1 in human keratinocytes to build cellular and tissue models of HHD with the goal of delineating its pathogenesis and identifying putative drug targets. Our preliminary data show that SPCA1-deficient cells model HHD pathology with impaired cohesion in epithelial sheets and organotypic epidermis; this is consistent with our finding impaired expression and trafficking of adhesive proteins as well as abnormal cell morphology suggesting cytoskeletal dysregulation. To identify pathogenic drivers downstream of SPCA1 loss, we performed RNA sequencing. Our data revealed up- regulation of (1) Rho GTPase signaling and actin modifiers, which modulate cell-cell adhesion, and (2) stress- mitigating pathways, including autophagy, the unfolded protein response (UPR), and antioxidant metabolism. Our aims will determine how these cellular dysfunctions compromise keratinocyte cohesion and determine if targeting them can restore epidermal integrity in our HHD model. Aim 1 will test the hypothesis that SPCA1 deficiency compromises cell-cell adhesion due to faulty cadherin trafficking and impaired regulation of RhoA and actin. Aim 2 will test the hypothesis that up-regulation of autophagy, induction of the UPR, and dampening of reactive oxygen species (ROS) could restore tissue integrity in HHD. Combining our established systems for live cell and tissue imaging with novel biosensors, we will delineate the pathogenic signals downstream of SPCA1 loss. To validate the functional role of these pathways in adhesion, we will evaluate candidate drugs using a mechanical dissociation assay, then test if lead compounds restore integrity in our HHD tissue model. In sum, the proposed work leverages new human cellular and tissue models to identify pathways that drive epidermal breakdown in HHD. Results from the planned studies will provide a platform for future work to validate druggable targets in patient-derived cells and de-identified HHD biopsies with the ultimate goal of delivering lead drugs for clinical trials aiming to improve skin integrity in patients living with this rare disorder.

NSF Awards · FY 2024 · 2024-07

The University-National Oceanographic Laboratory System (UNOLS) is a consortium of 58 academic institutions with research and educational programs in the ocean sciences and dedication to the major shared-use facilities that support these programs. UNOLS Infrastructure is composed of a myriad of assets including ships and deep submergence vehichles, aircraft, and major instrumentation. Institutions or federal agencies own these facilities and it is through the UNOLS system that the community has access to them. Support for the UNOLS Office is traditionally provided by six Federal Agencies: National Science Foundation, Department of the Navy/Office of Naval Research (ONR), National Oceanic and Atmospheric Administration (NOAA), Department of the Interior/U.S. Geological Survey (USGS), Bureau of Ocean Energy Management (BOEM) and the U.S. Coast Guard (USCG). This project is for the University Washington to host the UNOLS Office. Under the guidance and leadership of the UNOLS Office, much of the work is done through the volunteers from the scientific community who serve on standing committees. The UNOLS organization, founded in 1971, has played an important role in coordinating and improving the operations of the nation's Academic Research Fleet. One of the important focus areas for UNOLS is to coordinate and schedule these national assets, to plan for the future, and to help identify and meet the scientific infrastructure requirements of the U.S. oceanographic research scientists, students and technicians. This enables the United States to make advances in science, education, and the public awareness of our natural environment. One of the critical functions that the UNOLS Office performs, through broad community involvement, is to assist in prioritizing the resources within the available budgets to ensure the advancement of the field of oceanography. It is through the UNOLS efforts that the office assists the National Science Foundation and other federal agencies with providing community feedback and input on the future direction of oceanographic research in the United States. Through various UNOLS meetings, workshops, reports, studies, and daily communication, UNOLS provides a conduit for open dialog between the agencies supporting this research and the scientific community being served. The NSF's mission to "promote the progress of science; to advance the national health, prosperity, and welfare; to secure the national defense" are all aided by the UNOLS Office's ability to bring together the scientific minds to identify what are the science questions that need to be answered, and then to provide the safe platforms to conduct this important work. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-07

This grant supports the development of extremely fast methods for large-scale computing with structured matrices that appear pervasively in applications such as imaging, control theory, and signal processing. The Investigator will leverage new ideas in rational approximation that explain the structures in these matrices and imply the possibility of superfast algorithms. The matrices of primary interest are those with special displacement structures, including Toeplitz, Vandermonde, Hankel, Cauchy, and Loewner matrices, as well as block variants of these matrices. Such matrices and related matrix equations are ubiquitous across the sciences, and improved algorithms are greatly needed to overcome computational bottlenecks that currently impede progress and limit the scale of investigable problems. Collaborating with domain experts, the Investigator will develop open-source software that solves these problems under broader assumptions and at larger scales than what is currently possible. In areas such as MRI imaging, geophysical imaging, Fourier imaging in astrophysics and scattering, and in climate modeling, these improvements will ultimately benefit the public with positive impacts on medical technologies and other technologies deployed in the interest of citizens. The goal and scope of the project is to advance scientific knowledge in two critical ways: (1) It will extend the applicability of rank-structured methods beyond what is currently possible and create new methods for working with rank-structured rectangular matrices. The solvers developed in this work are general and can be applied to any matrix with rectangular hierarchical structure. The work will develop general techniques for efficiently designing preconditioners, solving least squares and minimum norm problems, applying regularization, and solving constrained optimization problems that involve rectangular hierarchical matrices. It will inspire further research into both the design and application of direct methods in settings where previously they were too expensive or underdeveloped to consider. (2) This work tackles a collection of matrix families that lie at the heart of many applications. It supplies a new and general framework from which all of their compression properties can be theoretically understood. The foundation of that framework comes from rational approximation theory. 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 · 2024-07

PROJECT SUMMARY Vast numbers of mutations in human protein coding sequences have been identified by DNA sequencing, but for only a tiny percentage of these variants do we understand the biochemical basis for any defect. This project seeks to develop an approach to characterize the biochemical activities – for such activities as thermostability, post-translational modification, kinetics and catalysis – of protein variants at high throughput using the ease and scale of DNA sequencing. Knowledge of biochemical activities can be used to annotate clinically-relevant proteins, many of which have variants that are nearly all either unannotated or annotated as variants of uncertain significance for their effect on pathogenicity. In the proposed approach, each variant will be covalently linked in vivo to a unique RNA barcode by fusion to a tRNA modifying enzyme that recognizes and couples to a short stem-loop RNA sequence. The stem-loop will contain a barcode sequence that identifies the variant. The barcodes allow a pool of variants to be subjected to a biochemical assay, with the results read out by DNA sequencing of the barcodes. By developing this technology to express variant proteins in vivo, we allow these proteins to fold or become post-translationally modified in their native cellular environment; to bind to other cellular proteins or ligands; to become modified upon cellular perturbation; or to be synthesized in a variety of hosts, including human cultured cells. As proof-of-concept examples of the use of this method, in Aim 1, variants of dihydrofolate reductase will be assessed for thermal stability. The variants will be fused to the tRNA modifying enzyme and expressed in E. coli; the fusion proteins will be purified in a pooled format; and aliquots of the proteins will be heated to varying temperatures followed by purification of the soluble, undenatured protein (thermal proteome profiling). The number of sequence reads of the soluble fraction of each variant allows melting temperatures to be determined. In Aim 2, we will develop this method in mammalian cells to quantify the abundance of protein variants of thiopurine methyltransferase. In summary, we will develop a high throughput in vivo protein barcoding method to study fundamental biochemical properties of variant proteins that have so far remained inaccessible by current methods.

NIH Research Projects · FY 2025 · 2024-07

Abstract Spinal cord Injury (SCI) leads to sensorimotor paralysis for which there is currently no cure. Our previous work determined that optogenetic spinal stimulation, a relatively new method for stimulating the spinal cord, has robust neuromodulating effects that significantly increases axonal growth, neuro-vasculature and importantly, functional recovery in rats with sub-chronic cervical spinal injuries. However, recovery was less complete in rats with more severe injuries. With the overarching goal of identifying effective therapeutics for spinal injuries of varying magnitudes, the proposed study will further develop and optimize optogenetic spinal stimulation for the severely hemi-contused spinal cord. More specifically, in Aim 1 we will identify if increasing the number of weekly stimulation periods will promote significant recovery in rats with a severe cervical hemicontusion. We will increase stimulation sessions from 1x/week to 2,3 and 4x/week and investigate the effects on forelimb functional recovery of four behavioral tasks. In Aim 2, we will investigate the combinatorial effects of optogenetic spinal stimulation and Intracellular Sigma Peptide (ISP) on functional recovery in rats after severe cervical hemicontusion. ISP alleviates the inhibitory effects of chondroitin sulfate proteoglycans on axonal growth and new circuitry formation after SCI. We hypothesize that combining this peptide with optogenetic stimulation will increase the critical formation of new circuitry bridging the lesion site, helping to reconnect upstream neurons with downstream targets that will translate into improved functional recovery. This will be further explored in Aim 3, where we will identify the changes in circuitry that occur in response to optogenetic spinal stimulation alone or in combination with ISP delivery. This will be assessed by looking at spinally-evoked forelimb muscle activity in combination with the activity-sensitive viral vector CaMPARI2 to identify participating neurons, as well as additional tissue analysis using immunohistochemistry and RNAScope. Overall, the proposed study will further develop and optimize a new and powerful method for therapeutically stimulating the spinal cord and promoting significant functional recovery within the sub-chronic, severe SCI community. The findings from circuitry analysis will also provide important insights into future strategies for further improving functional recovery after SCI.

NSF Awards · FY 2024 · 2024-07

Controlling the false positive error in model selection is a prominent paradigm for gathering evidence in data-driven science. In model selection problems such as variable selection and graph estimation, models are characterized by an underlying Boolean structure, such as the presence or absence of a variable or an edge. Therefore, false positive error or false negative error can be conveniently specified as the number of variables/edges that are incorrectly included or excluded in an estimated model. However, the increasing complexity of modern datasets has been accompanied by the use of sophisticated modeling paradigms in which defining false positive error is a significant challenge. For example, models specified by structures such as partitions (for clustering), permutations (for ranking), directed acyclic graphs (for causal inference), or subspaces (for principal components analysis) are not characterized by a simple Boolean logical structure, which leads to difficulties with formalizing and controlling false positive error. A new perspective is needed to provide reliable inference in modern data analysis. The methods developed in this project have the potential to impact a wide range of fields as varied as image analysis, geosciences, computational genomics, and many others. The research will engage both graduate and undergraduate students and will be disseminated to a broader audience through the development of new courses. In this project, the PI develops a generic framework to organize classes of models as partially ordered sets (posets), which leads to systematic approaches for defining natural generalizations of false positive error and methodology for controlling this error. The project aims to use the poset framework to address the following questions: what attributes of the poset structure determine the power and computational complexities of false positive error controlling procedures? How can we exploit specific structures in posets to design powerful model selection methods? How do we provide false discovery rate guarantees over posets? Can we utilize the framework for learning rooted phylogenetic trees and performing highly correlated variable selection? 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 · 2024-07

Project Summary/Abstract Defensins are small, innate immune peptides with broad antimicrobial activity, yet some pathogens, including non-enveloped viruses, have evolved methods to evade or co-opt defensins to enhance their infectivity. Resistance or enhancement is most pronounced for enteric viruses, leading to the hypothesis that fecal/oral transmission facilitates viral evolution to escape defensin neutralization. The studies herein will determine the molecular, cellular, and evolutionary mechanisms of viral escape from defensin action. Using a library of chimeric defensin peptides, we will determine the structural and biochemical properties of defensins essential to their activity against human adenovirus, rotavirus, and human papillomavirus (Aim1). Testing defensins against representatives from multiple viral families will provide insight into which defensin structural elements are globally required for activity, versus which are pathogen-specific. To more clearly elucidate the drivers of viral resistance to defensins, we will leverage the biological diversity across enteroviruses (EVs) to study how defensin sensitivity is related to viral transmission (Aim 2). In parallel, we will determine the cellular mechanism of EV neutralization by defensins, as well as the mechanism of EV defensin escape (Aim 3). This work will provide insight into how viral pathogens bypass the host innate immune system to promote infectivity, expanding our understanding of the host/pathogen evolutionary arms race. Many of the viruses included in these studies cause serious human illnesses, and this work will also point to new routes for antiviral development. The proposed work is designed to provide training in several techniques of virology and cellular biology, including cell culture and viral assays; high-performance liquid chromatography and peptide purification; biophysical binding assays; cellular mechanism studies; as well as microscopy. In addition to scientific expertise, the proposed training plan also includes education in scientific communication; mentorship; responsible research conduct; diversity, equity, and inclusion; as well as a career development plan for becoming a successful independent researcher. This work will be conducted in the University of Washington Microbiology Department, which is a hub for infectious disease research. This richly collaborative environment includes several faculty members and core facilities that provide the necessary resources, equipment, and expertise to enable completion of the proposed training plan.

NIH Research Projects · FY 2026 · 2024-07

West Nile virus (WNV) is a flavivirus of global concern and serves as model flavivirus. WNV is transmitted to humans via the bite of an infected mosquito, and infection is accurately modeled in immunocompetent mice. During acute infection, WNV replicates in short-lived peripheral myeloid cells and can spread to long-lived parenchymal cells of many tissues unless restricted by the innate immune response. Those who recover from infection often experience long-term sequelae including persistent inflammation and cognitive decline. WNV can invade the central nervous system (CNS) and cause death. Both innate and adaptive immunity are essential for control of WNV and CNS invasion, but how these responses are initiated and programmed following myeloid cell acute infection are not well understood. Our studies show that the RIG-I-like receptors (RLRs), RIG-I and MDA5, play essential roles in recognition of WNV in myeloid cells. Our preliminary studies now indicate that RIG-I and MDA5 sense and bind to specific pathogen associated molecular pattern (PAMP) motifs within WNV genomic and replication strand RNA products to trigger the innate immune response in myeloid cells. Using novel RIG-I and MDA5 conditional knockout mice lacking either factor in myeloid cells, we reveal that the RLRs direct a myeloid cell response that serves to restrict systemic virus replication; myeloid cell signaling by RLRs directs an innate immune response that serves to suppress virus spread, induce type I and III interferons, and protect against CNS invasion. Immunological analyses indicate that RLR signaling in myeloid cells plays an impotent role to program the adaptive immune response for clearance of infection. Using an infected cell-reporter mouse model we have identified previously infected WNV-experienced cells including CNS neurons, following virus clearance. Functional genomics analyses of WNV-infected myeloid cells, and spatial transcriptional profiling of tissue regions of the WNV-experienced cells, show signatures of innate and adaptive immune programming that precede long-term inflammatory signatures of WNV sequelae. Thus, WNV PAMP sensing and innate and adaptive immune actions lead to outcomes of virus control and infection sequelae but the molecular mechanisms programming these outcomes are not defined. The proposed studies will investigate the hypothesis that RLR- mediated sensing of WNV within short-lived, replaceable myeloid cells initiates innate immune response that prevents viral spread and neuroinvasion, which parenchymal cells that survive viral infection can drive long-term inflammatory sequelae due to unresolved inflammatory signaling that remains after viral clearance. We will conduct the following Specific Aims: 1: Define the WNV PAMP ligands of RIG-I and MDA5, and determine PAMP- induced innate immune activation programs; 2: Determine the myeloid cell-specific role of RLRs in innate immune protection and immune programming against WNV infection. 3: Identify the determinants by which WNV infection promotes sequelae across tissues. This work will provide important insight into the virus and host features of immune programming and post-infection sequelae from infection by WNV and other flaviviruses.

NSF Awards · FY 2024 · 2024-07

This project aims to build a workbench for scientists and engineers to address numerical issues in real-world applications. Numerical issues are issues caused by the gap between mathematical (real) numbers and the number representations used on computers, like floating point. Ultimately, this gap makes it difficult for scientists and engineers to develop software that does numerical computation accurately and runs reliably and efficiently on a variety of hardware and software platforms. Over the years, the research community has studied these issues and developed a number of tools that make developing numerical software easier, but these tools have become difficult to use together. In this project, the investigators will develop a set of standards, benchmarks, and user interfaces to make these existing tools interoperable and thus easier to use in concert. The project’s novelties are a set of standards where floating-point computations can be connected to the hardware and software platforms they run on, along with observed bad inputs or bugs. The project’s impacts are its potential improvements to real-world software packages, making them faster and more reliable across a wide range of hardware and software. Additionally, the investigators plan a variety of community-building initiatives including a community meeting, workshops, and REUs to build further ties within the numerical research community and between that community and practitioners in industry, national laboratories, and academia. The project builds on the existing FPBench standardization and interoperability effort. That standardization effort largely focuses on unambiguously describing floating-point computations, but real-world numerical workflows must track much more information: representative inputs; platform characteristics; pointers into codebases; and error bounds, observed or proven. This project will extend the FPBench standard with new formats to record and transmit this additional information, and update a variety of existing, widely-used numerical tools to use the new format. The investigators will then collect more benchmarks from real-world applications, recording rich metadata descriptions using the new formats, and distribute the extended tools and new benchmarks. To tie these standards, tools, and benchmarks together, the investigators will develop a novel, task-oriented user interface for scientists and engineers dealing with numerical issues. This interface will dispatch individual tools and collect the information they generate (in the new standard formats) in a single database, transparently passing the necessary information to every tool and informing the user when running additional tools would be useful. 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 Acute respiratory distress syndrome (ARDS) is characterized by the acute onset of severe hypoxemia associated with bilateral pulmonary opacities on imaging that are not fully explained by cardiac dysfunction. ARDS has a major impact on global health, representing 10% of intensive care unit admissions, 23% of patients supported on invasive mechanical ventilation, and has an associated mortality of 35%. Despite this burden on public health, there are no disease-modifying therapies for ARDS that have shown efficacy. Alveolar macrophages (AMs) are an attractive therapeutic target for ARDS because they play a central role in almost all aspects of its pathophysiology. In animal models, different AM “subsets” can augment inflammation, clear debris/dead cells, halt inflammation, and coordinate responses from other cell-types (e.g. T cells). These distinct AM functions are largely determined by cell “ontogeny” (resident vs. recruited). Resident AMs (rAMs) are embryonically-derived and self-renew during life. In injury, blood monocytes are recruited to the lung and mature into monocyte-derived macrophages (MoMs) that replenish depleted rAMs. Preliminary data in this proposal and prior publications has identified AM subsets that are associated better (e.g. CD71HIPD-L1HI, CD123HI) or worse (e.g. CD163HI, CD14HI alveolar monocytes) ARDS outcomes. The functional roles of these different AM subsets in humans, and how ontogeny contributes to their development and fate, are not known. The primary objective of this project is to determine how AM subset ontogeny and function contribute to ARDS clinical outcomes. Aim 1 is a mechanistic aim that will leverage AM chimerism in lung transplant recipients to test the hypothesis that recruited blood monocytes can mature into either protective or harmful MoM subsets. Aim 2A is a translational aim that will perform intracellular cytokine staining, efferocytosis assays, and AM/T cell co-culturing on AM subsets collected from a multi-center cohort of subjects with ARDS to test the hypothesis that different AM subsets have highly distinct functional properties. Aim 2B is a clinical aim that will test for associations between AM subsets and patient-centered ARDS clinical outcomes. This project leverages a multi-disciplinary team of experts in ARDS, lung transplant, macrophage biology, immunology, and computational biology. Findings from this project will provide key insights into ARDS pathobiology, forming a basis for future interventional studies to determine how to target AMs in ARDS and other inflammatory conditions of the lung.

NIH Research Projects · FY 2025 · 2024-06

Critical health- and treatment-related outcomes such as adherence to antiretroviral therapy (number of doses taken out of those prescribed), substance-related problems (e.g., number of problems endorsed), and frailty (e.g., number of Fried Frailty Phenotype criteria experienced) frequently take the form of fractions or proportions. However, fractional and proportional outcomes generally have not been appropriately analyzed in the behavioral HIV field and health outcomes research more broadly, which may lead to invalid conclusions. For example, outcomes such as the proportion of prescribed doses taken are highly skewed with both floor and ceiling effects (i.e., at 0 and 1), which violate the assumptions of commonly used statistical models, such as linear regression. We propose the marginalized zero- and N-inflated binomial (MZNIB) model to assess the overall effects of covariates (e.g., treatment effects) on proportional outcomes. The MZNIB model produces regression estimates that share the familiar interpretation of logistic regression by focusing on the mean probability of the target outcome (e.g., medication adherence) across the entire population. The MZNIB approach provides a more straightforward estimation of an overall effect than traditional zero-inflated models or other alternatives, which produce multiple sets of estimates on fractional outcomes that distinguish, for example, between those who (1) potentially engage in the behavior (e.g., take HIV medication at least occasionally) and (2) never engage in the behavior. In clinical research, it is critical to quantify the overall effect as a benchmark to compare effects, identify reasons for heterogeneity in effects, and improve on effects. Lack of appropriate methods, especially for HIV research, remains a barrier to innovative treatment development and evaluation. To address this gap, this R21 study has three aims: (1) provide best practice recommendations via simulation study regarding when and how the MZNIB model would be preferred over existing approaches for evaluating medication adherence and other proportional outcomes with floor and ceiling effects, (2) produce tutorials for implementing the MZNIB approach to estimate effects of treatment and other predictors using real data from three HIV intervention/prevention trials and a large-scale HIV cohort study (Ns = {70, 73, 224, 9336}), and (3) develop and disseminate the first-ever open-source computational tool for the MZNIB model. This R21 study leverages an established research group with combined expertise in HIV, substance use, and frailty. Findings from this study will empower behavioral HIV research communities by introducing novel statistical models and explaining their assumptions, advantages, and disadvantages in one coherent analytic framework. Simulation studies, accessible tutorials, and substantive application papers that address fractional count outcomes will improve statistical inference and scientific rigor. In addition, we will develop computing tools for greater dissemination and implementation of the methods studied. The R21 will support extensions of the MZNIB model to clustered and longitudinal data, and additional computational tools in a future R01 study.

NIH Research Projects · FY 2025 · 2024-06

This project will enable high-sensitivity testing of noninvasive oral swab samples for diagnosis of active tuberculosis (TB). Pulmonary TB is usually detected by analysis of sputum, a viscous material from human airways. Sputum collection presents exposure risks and many patients cannot routinely produce sputum for testing, especially in community settings where most TB transmission occurs. In response to the need for alternative, non-invasive sample types, we have demonstrated that Mycobacterium tuberculosis (MTB) DNA can be detected on oral swabs (OS) by using quantitative PCR (qPCR) analysis. In TB OS, the tongue dorsum is gently scraped with a disposable swab. The process is painless and requires just seconds. “Sputum-scarce” people, who can have risk factors for TB but not yet symptoms, can easily be sampled. Self-sampling is straightforward. To further unlock the potential for this approach, the current project will develop and evaluate enhanced swab sampling methods, using new sample processing technologies combined with a unique set of clinical sample resources. Specific Aims are: 1) To develop and assess high-capacity OS testing for pulmonary TB; and 2) To develop and assess protocols for testing serially collected and pooled OS samples for TB screening. TB OS has the potential to simplify TB diagnosis, improve the care of many TB patients, and enable active case-finding strategies that will reduce TB transmission. Thus, this project could help transform the global fight against TB.

NIH Research Projects · FY 2025 · 2024-06

PROJECT SUMMARY Understanding sensory processing in the brain has been difficult due to the complex and variable nature of neuronal activity. The primary goal of this training proposal is to determine how visual encoding is modulated by fluctuating brain-wide activity. The primary visual cortex (V1) is thought of as the key locus of visual processing. Recent evidence suggests that visual information exists even outside of the traditional visual pathway. Additionally, sensory encoding in V1 is modulated by externally measured behavioral state and locomotion. It remains unclear how these variables are reflected in neuronal computations and to what degree they modulate visual processing and behavior. We hypothesize that trial-to-trial variability in V1 reflects the fluctuating activity of a distributed network of brain regions. In Aim 1, I will use Neuropixels 2.0 recordings to map diverse brain areas and assess their relationships with fluctuating sensory encoding in V1. Aim 2 will determine the fundamental underlying noise level of neurons in V1, providing a key metric for understanding the fidelity of visual encoding and for models used to analyze neural data. Together, these aims will advance our understanding of the nature of visual cortical encoding and the distributed network of brain regions that support visual processing and behavior. These results will improve our ability to create more effective brain-computer interface therapeutics, which currently rely on an incomplete understanding of information coding in the brain. During my tailored training period, I will learn Neuropixels electrophysiology, advanced computational analysis techniques, and whole-brain histological processing and imaging under the guidance of experts in a supportive training environment. These skills will prepare me for an independent career as a neuroscientist working to advance the understanding of brain function and behavior.