Johns Hopkins University

NSF Awards · FY 2025 · 2025-07

The research will provide a more detailed understanding of the ways that interplanetary (IP) shocks, a common space weather event, can impact Earth’s magnetic environment (magnetosphere). Past studies have focused on a limited range of shock properties that do not reflect the possible breadth of parameters. This research study will expand the range of shock properties investigated by comparing observations from multiple space missions with detailed computer simulations. These detailed, multi-platform studies will be the first to fully exploit existing data sets to address fundamental problems that are vital for achieving NSF’s strategic goals. Such events may affect technological systems, astronauts and spacecraft, electrical power grids, and other important technologies that modern society has come to depend on. The long-term impact of the study will be to significantly benefit society by allowing us to eventually predict the geoeffectiveness of potential IP shock impacts and take steps to mitigate their damage. The results of our study may also be relevant to understanding the behavior of other planetary magnetospheres to IP shock impacts. Numerous satellites orbit the Earth within its magnetosphere, often taking measurements simultaneously after the occurrence of space weather events such as interplanetary shocks. The research will investigate a large database of such simultaneous observations, showing how different regions of near-Earth space react to shocks with different properties. This analysis will be complemented by computer simulations that investigate variations in one shock property at a time, which will reveal the most important properties or combinations and their possible consequences. Specifically, we will determine how the response, typically an electromagnetic wave pulse, propagates through the magnetosphere (radially, azimuthally, or a combination thereof); what wave mode and Poynting flux are associated with this response; and how the wave mode evolves. We will also characterize particle energization, scattering, and loss associated with the passage of the pulse through the dayside magnetosphere. 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 2025 · 2025-07

Extreme space weather events can disrupt satellite communications, GPS systems, and power grids and even pose risks to astronauts. Understanding and predicting these events is essential for protecting critical infrastructure and ensuring national security. This project aims to develop an advanced cyberinfrastructure that integrates artificial intelligence (AI) with diverse space weather data to improve the forecasting of extreme space weather events. By incorporating generative AI models for data creation, the project enables predictive analyses that are both data-rich and scalable. This significantly enhances the ability to forecast extreme events, including solar flares, coronal mass ejections, and solar energetic particle events, thus helping mitigate their effects on technological systems. Additionally, the project fosters collaboration between computer scientists and heliophysicists while providing open-access tools and datasets to the research community. The project also involves student groups in hands-on research and training, offering mentorship opportunities, and partnering with high schools. This contributes to building a skilled STEM workforce, advancing scientific knowledge through data-driven analysis, advancing core scientific knowledge and contributing to national security. This project develops a cyberinfrastructure for AI-enabled multimodal extreme space weather events forecasting. The cyberinfrastructure enables predictive modeling of solar transient events by integrating solar photospheric magnetogram data spanning three solar cycles or more than 30 calendar years. A key technical advancement is the application of generative AI, with a physics-infused conditional diffusion model, to enhance historical datasets by filling spatial and temporal resolution gaps. Another significant contribution is using multimodal machine learning and explainability techniques to improve the current state-of-the-art space weather prediction methods. The project builds a homogenized dataset of vector magnetograms, open-access computational tools, and machine learning models to process vector magnetograms, time series, and derived metadata parameters. The cyberinfrastructure integrates scalable generative AI techniques and multimodal learning frameworks to optimize forecasts of solar flares, coronal mass ejections, and solar energetic particle events while providing an interoperable learning framework for heliophysics research, benefiting both the scientific community and sectors reliant on accurate space weather predictions. 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 · 2025-07

SUMMARY This study aims to demonstrate accurate quantification of changes in brain morphology at 0.05T. We plan to accomplish this tracking by exploiting the portability of our 0.05T scanner to acquire dense temporal sampling of neuroimaging data coupled with autonomous control and deep-learning-based super-resolution reconstruction. Magnetic Resonance Imaging (MRI) has been the primary tool to investigate these disorders, highlighting structural, functional, and metabolic changes. For example, 3T structural MRI data have significantly improved our understanding of the youths’ developing brain in health and disease. Recent studies have highlighted the need for densely sampled temporal neuroimaging data to maximize clinical insight in patients with mental health challenges. High-field systems' cost, power, and siting requirements impede dense longitudinal imaging in large populations, especially in low-resource settings. In contrast, we hypothesize that a portable 0.05T can deliver the required densely sampled neuroimaging data. We expect equivalent statistical power in detecting brain changes associated with young adults at 0.05T with a five-time-point than a two-time-point 3T study. However, 0.05T MRI suffers from lower spatial resolution and signal-to-noise ratio (SNR), impacting the volumetric accuracy required to monitor brain changes using structural imaging. These limitations render these scanners supplementary devices to high-field systems. For meaningful use, there is a critical need to develop novel methods to produce low-field, structural MRI data statistically equivalent to or better than 3T data. To address this gap, we hypothesize that three orthogonal acquisitions and using DL-based super-resolution reconstruction of five-timepoint data from children (10 – 17 years) at 0.05T provide similar accuracy to two-timepoint 3T data. We have demonstrated the image quality of 0.05T data in phantoms over thirty sessions and the pipeline for in vivo data acquisition, reconstruction, and segmentation on one healthy volunteer. These data show the potential of 0.05T data for brain volumetry and the benefits of consistent scanner operation and image quality. In Aim 1, we will demonstrate the feasibility of our 0.05T scanning pipeline to track brain changes and address the need for the high-density temporal sampling of neuroimaging data. Second, the deployment of 0.05T is affected by artifacts caused by external magnetic interference, magnetic field inhomogeneity, subject motion, degrading image quality, and scanner operation. To address these challenges, we will adopt our automated MRI methods to 0.05T in Aim 2. The densely sampled temporal neuroimaging data will yield early, accurate, and personalized developmental trajectories of the youth brain, with the potential to scale this project in an equitable and accessible manner. These methods will enable the broader scientific community to perform previously prohibitive structural MRI studies without compromising accuracy, especially in underserved settings.

NIH Research Projects · FY 2025 · 2025-07

Metastatic recurrence in melanoma patients often occurs when dormant tumor cells at distant sites reawaken, even after seemingly successful initial treatment. This process of tumor dormancy, where disseminated tumor cells remain inactive before eventual reactivation, remains poorly understood despite its clinical significance. Notably, aging emerges as a critical factor in poor melanoma prognosis, suggesting that age-related changes in the tissue environment may influence both tumor dormancy and therapeutic resistance. Our research has revealed that aged lung fibroblasts significantly impact how melanoma cells emerge from dormancy through complex Wnt signaling pathways. Recent findings demonstrate a crucial switch between non-canonical and canonical Wnt signaling that appears to control entry into and exit from tumor dormancy. Additionally, we have discovered that host factors, including sex, influence age-related metastatic spread and treatment response. Particularly intriguing is our observation that aged fibroblasts, unlike their younger counterparts, show unique responses to the presence of cancer cells, even at distant sites. These aged fibroblasts increase their proliferation and secrete factors that create an immunosuppressive environment by recruiting myeloid-derived suppressor cells. This immune-suppressed environment may then permit the growth of rapidly proliferating cells that would typically be eliminated by immune surveillance. The relationship between dormancy and therapy resistance presents another critical aspect of this research. While Wnt5A drives resistance to targeted therapy through a senescence-like state, canonical Wnt signaling typically increases sensitivity to BRAF/MEK inhibitors. Understanding how these opposing pathways interact, particularly in the context of aging, may reveal new therapeutic opportunities. This research aims to uncover how the aging immune microenvironment influences tumor cell dormancy and subsequent recurrence. By investigating the complex interplay between stromal cells, immune components, and Wnt signaling pathways, we hope to identify new therapeutic strategies to prevent metastatic recurrence in aging melanoma patients. These findings could lead to more effective treatments that consider both the age of the patient and the dynamic nature of tumor dormancy.

NIH Research Projects · FY 2025 · 2025-07

Project Summary Reinforcement learning is a highly successful framework that guides learning through reward and punishment. Standard Hebbian plasticity cannot account for how animals learn through delayed reinforcement as reward/punishment received after a behavior must specifically modify relevant synapses which were active seconds to minutes before. A theoretical solution to this discrepancy suggests the generation of transient synaptic tags, referred to as eligibility traces (eTraces), which decay after neural activity. The theory further posits that such transient and “silent” eTraces are then converted to express synaptic plasticity upon release of chemical neuromodulators conveying reward information. The first experimental demonstration of cortical eTraces by the Kirkwood lab was in the visual cortex, at the feedforward layer 4 → layer 2/3 connection, where neuromodulators acting through G-protein coupled receptors (GPCRs) anchored at the postsynaptic density (PSD) convert eTraces into synaptic plasticity. Recently, the Kirkwood lab found that neuromodulator effects are restricted to L4 → L2/3 synapses and are not effective at L2/3 → L2/3 inputs. In this application, I aim to test the hypothesis that eTraces are pathway specific even within a single postsynaptic neuron. Furthermore, I hypothesize that GPCRs involved in converting eTraces are differentially expressed at postsynaptic compartments to define which pathways are competent for eTrace-mediated synaptic plasticity. I aim to test the hypothesis, using electrophysiology, that within a single layer 2/3 pyramidal cell eTraces are restricted to the feedforward pathway (Aim I). Additionally, I will investigate the presence of eTrace-specific GPCRs at each of these pathways to confirm my prediction for a molecular definition of eTrace competence (Aim II). Lastly, I will test the predictions of input-specific eTraces using several models of in vivo plasticity, which produce bidirectional plasticity specific to the layer 4 → layer 2/3 and/or the layer 2/3 → layer 2/3 pathways. Results from this work will molecularly define reinforcement competent synapses and show that these are a subset of all plastic synapses, demonstrating previously undescribed synaptic diversity that is relevant for fully understanding how neural circuits learn. Finally, this knowledge may allow the development of methods to transplant reinforcement learning with the goal of facilitating functional recovery and learning in defined regions of the brain.

NIH Research Projects · FY 2025 · 2025-07

Project Summary Emerging clinical evidence shows that activated immune cells, especially B and T lymphocytes, enhance the response to cancer immunotherapies but are often excluded from tumors. High endothelial venules (HEVs) may facilitate immune cell entry and tertiary lymphoid structure (TLS) formation within tumors, as observed in histological samples. Dr. Komatsu’s lab has developed an immunostimulatory treatment to induce HEV and TLS formation in previously HEV/TLS-free tumors. The combination of lymphotoxin beta receptor (LTβR) and STING agonists reduces tumor size and promotes robust anti-tumor immunity. This study uses transgenic mice with a dorsal skin window chamber (DSWC) tumor model undergoing intravital microscopy (IVM) to visualize B cell infiltration through HEVs and immunity development via TLS formation. Bulk sequencing and immunofluorescence analysis suggest that HEVs are the main route for B cell recruitment into tumors; intravital imaging shows B cells roll more slowly on the endothelium of HEVs, indicating HEVs facilitate B cell entry into tumors. Transgenic mice with fluorescent red B cells and fluorescent green blood vessels in DSWCs will visualize and analyze B cell recruitment, rolling speeds, transmigration through tumor-associated HEVs, and real-time TLS formation in agonist-treated KPC tumors using repeated IVM. These results will demonstrate for the first time that HEVs are critical gateways for B cell entry and TLS formation within tumors, providing foundational insights for targeted immunotherapies to enhance anti-tumor immunity. TLS formation in tumors may require continuous B cell recruitment via chemokine signaling. This study investigates whether TLS are sustained by ongoing B cell recruitment from circulation or clonal expansion within the tumor. Adoptive transfer experiments suggest that TLS recruit B cells from the circulation, evident by the upregulation of chemokine genes known for B cell recruitment following LTβR/STING agonist combination therapy that induces TLS formation. Maintenance may involve both initial B cell infiltration and subsequent clonal expansion, marked by germinal center gene upregulation. The anticipated findings will reveal that continuous recruitment of naïve B cells is essential for TLS maintenance, offering new insights into tumor immunity mechanisms and paving the way for novel therapeutic strategies that exploit B cell recruitment and clonal expansion to improve cancer treatment outcomes. The role of chemotaxis in B cell recruitment to TLS will be tested by inhibiting this process with pertussis toxin-treated naïve B cells, determining whether LTβR/STING agonist combination therapy promotes clonal expansion of B cell-comprised TLS and anti-tumor immunity development. Results are expected to show that continuous recruitment of naïve B cells and clonal expansion are essential for TLS formation and maintenance, providing insights for novel targeted cancer immunotherapies. This research will produce novel insights into immune cell infiltration and aggregation into intratumoral TLS, demonstrating experimental models needed for continued onco-immunology research.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT A large body of animal model evidence supports the conclusion that lengthy early life exposure to anesthetic and sedative drugs (ASDs) can impair the development of brain circuitry such that the organism exhibits lasting impairments in a range of neurologic functions. If ASD exposure has similar consequences for the developing human brain this poses a major challenge for public health, as tens of thousands of children receive medical care each year in the U.S. that is dependent on these medications. The clinical literature on this topic is comprised of a few clinical trials focused on determining whether short exposures in healthy children are safe and many diverse epidemiological investigations, and it does not allow for any clear conclusions about the concerns raised by animal studies, particularly given the confounds of surgery and co- morbid disease. There are important knowledge gaps in our understanding of the putative neurotoxicity of ASDs, which the research program described in this proposal is designed to address. First, given the substantial differences between animal and human neurobiology, it is unknown whether ASDs act on human brain development to impair processes that are critical for the formation of neural circuitry and ongoing during the window of vulnerability in humans. Second, the extensive investigations in animal models have not yet generated a coherent understanding of a fundamental underlying molecular mechanism by which a limited exposure to ASDs could have lasting, harmful effects on brain development that are translatable between animal models and humans. The broad, long-term objective of this R35 MIRA proposal is to use cutting-edge translational laboratory approaches in neuroscience to address the fundamental knowledge gap surrounding whether ASD developmental neurotoxicity that is observed in animals poses a risk to human brain health. To accomplish this goal we will conduct studies of the effects of ASDs on the formation of synapses and myelin, both of which are putatively vulnerable processes that are critical for the development of neural circuitry, in a three-dimensional model of developing human brain tissue. We will also conduct studies in both rodent and human brain development model systems to determine whether the lasting effects of ASDs on the mechanistic/mammalian target of rapamycin signaling system represent an overarching mechanism to explain ASD neurotoxicity. The work described in this proposal is designed to have an immediate and lasting effect on our understanding of the impact of ASD exposure on brain health, to provide needed insights to move this field forward, and additionally to contribute broadly to the field of neurotoxicity during development.

NSF Awards · FY 2025 · 2025-07

This award supports research on the fire behavior of timber structures to develop novel engineering methods to design mass timber buildings for fire resilience. Recent innovations in engineered wood products unlock benefits for the built environment, however, knowledge gaps in fire performance can limit adoption or lead to inadequate fire safety in buildings. To date, design has relied on empirical methods based on charring rates that do not capture the complex fire-structure interaction and the potential for collapse during the fire decay phase, highlighted by recent experiments. This project aims to derive novel modeling capabilities to enable the fire-resilient design of mass timber buildings. The research efforts will be integrated with dissemination activities involving professional committees, aimed at informing building codes. Through enabling resource-efficient designs with novel timber structures that address fire safety challenges, this award will contribute to NSF’s mission to advance the national prosperity, safety, and welfare. The goal of the research is to develop a computational framework for understanding and modeling the response of timber structures in fire and use this framework to derive design methods for fire-resilient timber buildings. The research methodology will combine computational modeling, machine learning, and topology optimization. By analyzing recent timber fire test data with Bayesian inference techniques and surrogate modeling, the project looks to derive accurate material models and properties for timber in realistic fire scenarios. The project will also seek to enhance current fire models to incorporate the contribution from bio-sourced structural materials in the fire intensities used for design. A finite element computational framework that captures the fire-thermal-structural response, validated against full-scale experiments, will then be used to construct fragility functions for timber frame structures. Additionally, the project will explore innovative design approaches to enhance fire resilience through topology optimization applied at different scales, including optimization of the cross-section and optimization of the column layout through a stiffness projection method. This effort looks to advance understanding of the effect of key design parameters on the vulnerability to fire-induced collapse and result in methodologies to uncover resilient designs optimized at both the member and system levels. The research has the potential to advance modeling capabilities and transform fire design for timber structures from an empirical to a performance-based design approach, addressing the complexity of the structural fire response and enhancing safety and resilience. 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 · 2025-07

PROJECT SUMMARY Advances in cancer immunotherapy have great potential for treating tumors that are refractory to conventional treatments, and T cells primed ex vivo by natural or artificial antigen-presenting cells (APCs) to target and kill cancer cells have been shown clinically to improve survival in patients with highly aggressive cancers. APCs normally prime T cells by presenting a tumor antigen-specific signal 1, consisting of a major histocompatibility complex (MHC) I molecule with a tumor antigen peptide; a co-stimulatory signal 2 that directs the action of the T cells upon recognition of the tumor; and a secreted signal 3 for recruitment and activation of immune cells. Instead of engineering the patient's APCs to direct a T-cell response against a tumor or fabricating artificial, synthetic APCs, both of which are costly, complex, and/or patient-specific processes, we propose to reprogram cancer cells themselves to become tumor-associated APCs (tAPCs). Because tumor cells already intrinsically express signal 1 (tumor antigen in the context of MHC I), they can be engineered in situ to express the other necessary signals and therefore act as APCs, directing cytotoxic T-cell responses against themselves. Tumor cells with low MHC I expression will stimulate natural killer (NK) cells to aid this purpose. We have designed synthetic, non-viral nanoparticles that can deliver DNA to cancer cells with high efficacy and specificity over healthy tissue, and we will inject these into a tumor mass to induce expression of signal 2 and signal 3, using two different in vivo orthotopic tumor models (melanoma and triple-negative breast cancer) and four in vitro tumor models as examples. Having optimized a nanoparticle formulation with anti-cancer efficacy after intratumoral injection in local and metastatic cancer models, we will further this strategy during the R37 extension period by co-delivering a gene cassette to locally express checkpoint inhibitor antibodies, following our discovery in the first phase of the R37 that our nanoparticles (1) synergize with systemic checkpoint inhibition and (2) prevent immunotoxicity of systemic immunotherapies by sequestering gene expression primarily to the local tumor. We will further discover new genetic pathways leading to susceptibility and resistance to this immunotherapy strategy via comparative transcriptomics across different tumor types, allowing us to apply the new knowledge to the development of even more successful immunomodulatory gene therapies. This extension remains within the initial scope of the project, which focused on local therapy and immunological analysis thereof, but broadens its goals by further innovating on the platform technology developed in the first phase. If successful, this could result in an affordable, fully synthetic, local, antigen-agnostic therapy that nevertheless leads to antigen-specific systemic immune rejection of a wide range of different tumor types.

NSF Awards · FY 2025 · 2025-07

This I-Corps project focuses on the development of a non-invasive neuromodulation oral appliance designed to relieve the symptoms of chronic rhinosinusitis. Chronic rhinosinusitis affects 40 million U.S. adults and causes persistent nasal congestion, facial pain, mucus overproduction, headaches, and poor sleep. Existing pharmaceutical treatments rely on nasal sprays and other anti-inflammatory drugs but fail to provide relief in around 50% of patients. When medications fail, some patients may qualify for invasive and costly surgery. However, symptom recurrence after surgery is common, leaving millions of patients without an effective solution to get symptom relief. This project addresses this gap in care by exploring an alternative method that targets the nasal nerve pathways shown to contribute to excessive mucus production and inflammation. The goal is to offer a drug-free, effective, and accessible approach to improve daily functioning, sleep, and quality of life. By reducing dependence on costly medications and surgical procedures, this technology has the potential to save up to $1 billion annually on healthcare costs, improve productivity, and reduce the burden of chronic sinus disease on patients, families, and the healthcare system. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of the technology. This solution is based on the development of an oral device that delivers gentle electrical stimulation to nerve pathways in the nasal cavity. The technology introduces an innovative neuromodulation approach for treating the symptoms of chronic rhinosinusitis, addressing a critical gap in current therapies that overlook the role of neural overstimulation in sinonasal inflammatory disease. Unlike existing therapies that rely on immune suppression or invasive procedures, this approach is the first to address the neurological component of chronic sinus disease using a non-invasive, drug-free method. The device is a custom-fitted mouthguard that delivers gentle electrical pulses to the nasal cavity. This neuromodulation technology was validated in a successful animal model, showing significant decongestion and improved nasal airflow. Following successful preclinical validation, the device is undergoing human testing. This early success points to the device's potential to improve chronic rhinosinusitis management, giving patients greater autonomy over symptom control and relief. 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 2025 · 2025-07

In today’s rapidly evolving information technology landscape, network security is a critical pillar of cybersecurity. Preparing the next generation of IT research professionals to secure digital infrastructure requires theoretical knowledge, but also demands hands-on experience with real-world threats and data. This project bridges this gap through integration of advanced data science techniques and practical skills in cyberinfrastructure (CI) within the classroom. This project establishes the Cybersecurity Community Hub (C2Hub)—a platform for developing, delivering, and disseminating CI-enabled cybersecurity education and training resources. The project incorporates modular, open-source course materials for both undergraduate and graduate levels, including software tools, real-world datasets, and auto-graded assignments in the C2Hub platform. These modules are designed for seamless execution on NSF-funded CI platforms such as the National Research Platform and Expanse, making it easier for educators to incorporate hands-on CI use into their curricula. To support adoption and community building, the project offers educator workshops to provide training, gather feedback, and cultivate a network of educators sharing resources and best practices. The course materials and community practices developed through this project can serve as a national model for integrating CI into cybersecurity and STEM education. C2Hub promotes a data-driven approach to teaching and learning and expands the nation’s cybersecurity research workforce by empowering students from different institutional backgrounds to engage in cutting-edge data science and cybersecurity training. 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 2025 · 2025-07

Proteins known as “receptor tyrosine kinases” (RTKs) mediate the transmission of information across the cellular membrane, and thus allow the cell to respond to extracellular signals. Intercellular communication is a fundamental process in multicellular organisms and its precision is crucial for the control of growth and development. Multiple extracellular ligands can interact with an RTK to promote different intracellular events. The research project seeks to obtain quantitative information about the signaling properties of a member of the RTK family in response to its different ligands. Highly quantitative biophysical methods will be used in an effort to understand how diverse extracellular signals are processed by this receptor to promote distinct events. In this project, graduate students will be trained in state-of-the-art fluorescence microscopy techniques and the educational experience of undergraduate students will be enhanced. In addition, broad outreach activities will be conducted benefiting young scientists. The first objective is to acquire the first comprehensive data set of ligand-specific efficacies, potencies, and signaling preferences for multiple responses of the epidermal growth factor receptor (EGFR) to its ligands. This will entail acquisition of dose response curves for a variety of biological responses, yielding information about the potencies, efficacies and preferences of the ligands when inducing these responses. The second objective is to perform the first comprehensive physical-chemical characterization of the self-association of EGFR in the plasma membrane in response to its ligands. EGFR ligand-specific oligomer sizes (orders) and stabilities, and ligand binding coefficients, will be measured. The third objective is to uncover currently unknown correlations between measurable physical parameters and measurable signaling outcomes. 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 · 2025-07

PROJECT SUMMARY/ABSTRACT Chronic obstructive pulmonary disease (COPD) is a slowly progressive disease that affects more than 13 million Americans and results in a long period of disability and reduced health related quality of life (HRQoL). Individuals with COPD are at high risk of financial burden from illness due to costly inhaled bronchodilators, unplanned ED visits and hospitalizations for acute exacerbations, as well as income loss due to disability. Financial toxicity, a term that describes the objective financial burden and subjective financial distress resulting from treatment for illness, has not been studied in COPD but is prevalent in other chronic medical conditions and has been associated with worse health outcomes. In contrast to absolute cost, financial toxicity takes into account the proportion of cost to an individual’s or family’s income and its psychological and behavioral impact. While cost has not been directly associated with worse outcomes in COPD, limited observational studies relying on self-reported adherence suggest that cost of treatment may contribute to suboptimal medication adherence. Poor adherence, in turn, is associated with worse outcomes including increased risk of exacerbations and mortality. Due to the high risk for financial burden in COPD, understanding the association between financial toxicity, a potentially modifiable determinant, and health outcomes is key to informing future interventions. The main objective of this proposal is to describe the impact of financial toxicity on health outcomes in individuals with COPD. We hypothesize that financial toxicity from treatment of COPD is associated with increased disability, decreased health related quality of life (HRQoL), and decreased medication adherence over time. We will use both quantitative and qualitative methods to comprehensively evaluate the role of financial toxicity in individuals with COPD. Using the Medical Expenditure Panel Survey (MEPS), a large nationally-representative longitudinal panel, we will assess the association between material financial toxicity resulting from treatment of COPD with disability and health related quality of life (Specific Aim 1) and medication adherence (Specific Aim 2). To better understand the impact of financial toxicity on patient outcomes, we will conduct qualitative semi-structured interviews with individuals who report financial burden related to treatment for COPD (Specific Aim 3). Taken together, the work from these complementary aims has the potential to identify areas for a future intervention to mitigate the adverse effects of financial toxicity in this population, which would serve as the basis for the applicant’s future career development award. This proposal will also provide the applicant with the skills needed to pursue an independent career as a health services researcher studying COPD.

NIH Research Projects · FY 2025 · 2025-06

The long-term goal of this K23 Career Development Award is to prepare the PI (Mayra Sánchez González, PhD) for an independent research career to implement interventions to improve the quality of life of older adults with multimorbidity. Multimorbidity, having two or more concurrent chronic conditions, is becoming increasingly prevalent in older Hispanics and is associated with poor quality of life. Although multimorbidity disproportionally impacts individuals in low socioeconomic groups, evidence suggests that these groups (vs. high socioeconomic groups) benefit less from multimorbidity interventions. Individuals tend to manage their health better when they are socially connected, but living with multimorbidity often contributes to isolation and loneliness. Hispanics are vulnerable to social disconnection due to social stressors, which can put them at risk of lacking critical support to live well with multimorbidity. The risk for social disconnection may be complicated by aging in communities with limited support infrastructure and workforce to meet their needs. Therefore, this K23 proposal seeks to identify social connection factors associated with the optimal management of multimorbidity among older Hispanics (Aim 1), modify Positive Minds-Strong Bodies for older Hispanics (50+) with multimorbidity (Aim 2), and evaluate the modified intervention's implementation determinants and implementation outcomes (primary outcomes) and preliminary efficacy in improving quality of life (exploratory efficacy outcome) via a Pilot RCT of Healthier Together vs control in 50 older Hispanics (50+) with multimorbidity (2+ chronic conditions) (Aim 3). We will use a community-engaged approach to inform this project via a community advisory board (CAB) integrated by individuals with lived experience, caregivers, health navigators, and clinicians. We will conduct in-depth interviews with 30 Hispanics (50+) with multimorbidity. We will collaborate with the CAB to modify PMSB and create Healthier Together, focusing on strengthening social connections. Lastly, we will evaluate Healthier Together in a pilot RCT. The PI has brought together an exemplary team of content experts in aging, social connection, implementation science, community-engaged research, and qualitative methodology. The PI will achieve the following career goals through mentorship, didactic experiences, and professional development opportunities: (1) develop expertise in implementation science with an emphasis on aging research; (2) develop proficiency in community-engaged research with older adults; (3) develop expertise in qualitative research methodology to inform intervention modifications; (4) gain expertise in designing, implementing, and analyzing randomized clinical trials. Completing this K23 proposal will provide the necessary training and preliminary data for the PI to obtain independent grant funding and systematically pursue a line of research to improve outcomes for older adults with multimorbidity.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY Mycobacterium abscessus is a rapidly growing non-tuberculous mycobacterium that can cause chronic lung disease that is associated with rapid lung function decline and is often incurable. There are no FDA-approved treatments for this indication. Existing treatments are based on repurposing of antibiotics approved for other diseases. Challenges of the currently recommended standard treatment of M. abscessus lung disease include a) poor efficacy, b) need for treatment durations lasting several months, c) frequent drug toxicities, d) need for parenteral (IV) antibiotics, and e) complicated logistics of long-term outpatient IV antibiotic treatment. The cure rate using current treatment recommendations is estimated at 30-50%. A simple and easy-to-implement animal model of M. abscessus lung disease is vital to translate findings from in vitro studies to develop new therapeutics and understand diseases’ pathological basis. By closely mimicking the interaction between the etiological agent and the host, an animal model is more informative than in vitro systems for assessing the potential utility of experimental treatments to humans. The overall aim of this proposal is to develop a simple and inexpensive yet robust mouse model of chronic M. abscessus lung disease that is easy to implement in diverse laboratory settings. We present a proof-of- concept of a new mouse model of M. abscessus lung disease using the BALB/c mouse that requires only once weekly administration of cyclophosphamide and permits the proliferation of M. abscessus in the lungs. In Specific Aim 1, we propose studies to verify the reproducibility of this model using additional M. abscessus isolates, as only a single M. abscessus isolate was used for the proof-of-concept studies. In Specific Aim 2, we will test if this mouse model can faithfully reproduce the efficacy of standard-of-care drugs used to treat M. abscessus disease. We will develop a validated mouse model of M. abscessus lung disease based on the evidence from these studies. We expect the deliverables of this proposal to fulfill the current need for a simple and inexpensive mouse model of chronic Mab lung disease.

NIH Research Projects · FY 2026 · 2025-06

The proposed work is for the continuation and expansion of the Hopkins Hub (formerly MACC+ Hub) to support the EHE initiative. The goal of this proposed Regional Consultation Hub is to enhance the technical rigor, capacity, collaborations, and generalizable knowledge among EHE investigators, community and implementing partners and the federal government. This will be achieved through three aims 1) Enhance the technical rigor of implementation science research, build capacity among investigators, and facilitate networking among HIV-related implementation science researchers; 2) Optimize the quality and quantity of generalizable knowledge from HIV-related implementation science research to support the Ending the HIV Epidemic initiative; 3) Advance community-academic partnerships to improve the impact of Ending the HIV Epidemic targeted research. Activities to be conducted through this award include coaching of and resource sharing with EHE awardees; engagement and support to the national coordinating center data and management center, including support for data harmonization; leading our flagship HIV and IS fellowship for training early stage investigators in HIV and implementation science (IS); public launch and updating of the EHE dashboard to highlight findings from the EHE HIV and IS investments; execution of HIV and IS-related meta- science reviews related to EHE, including reviews of implementation outcome measurements and focal areas of EHE funding announcements; and the development of tools and application of said tools to optimize measurement of implementation outcomes across EHE awardees and other NIH-funded researchers. In particular, there is a focus on community-academic partnerships, including curation of tools available to support and assess community engaged research (CEnR) and identification between community and academic partners of shared goals and priorities, and gaps in measures available; we will work in a co-design process with community and academic partners to fill gaps in tools through iterative feedback sessions, dissemination of available tools, and development of new tools when prioritized by the community-academic partners. Our team includes a dynamic and committed core of IS experts and mentors with a track record of leading IS research and providing high quality technical assistance and mentorship in IS.

NIH Research Projects · FY 2026 · 2025-06

This Mentored Patient-Oriented Research Career Development Award (K01) application aims to equip the candidate with the skills to establish an independent research program identifying modifiable lifestyle factors to enhance cognitive resilience in aging and Alzheimer's disease-related dementias (ADRDs) and develop neuroimaging measures to quantify these relationships. The proposed research will examine (1) actigraphy- based measures of physical activity and sleep, and (2) network neuroimaging-based measures of functional connectivity and microstructural integrity, as potential synergistic correlates of cognitive trajectories in older adults and those with AD pathology accumulation. Recent published work by the candidate suggests physical activity and sleep are synergistically related to better cognition and neuroimaging measures of functional connectivity and microstructural integrity, and that these neuroimaging measures may reflect mechanisms of cognitive resilience in aging and AD cross sectionally. This application proposes a longitudinal study to assess i) whether physical activity and sleep are factors associated with cognitive resilience to AD pathology accumulation over time, ii) if brain network connectivity and microstructure are neuroimaging correlates of cognitive resilience to AD pathology over time, and iii) the association between physical activity and sleep with functional connectivity and microstructure over time. With an excellent multidisciplinary mentorship team, the applicants career development plan builds on his research training to gain experience in 1) AD pathology biomarkers (specifically Positron Emission Tomography and Cerebrospinal Fluid), 2) actigraphy based measures of physical activity and sleep, 3) longitudinal statistical analysis, 4) theoretical training in cognitive resilience research and clinical knowledge of AD and related disorders, 5) professional development, and 6) responsible conduct of research. The research objectives and training goals will foster an exceptional learning environment, advancing the candidate's knowledge in cognitive aging and ADRD, ultimately facilitating their transition to an independent investigator exploring the impact of modifiable lifestyle activities and brain mechanisms underlying cognitive resilience in older individuals.

NIH Research Projects · FY 2026 · 2025-06

Project summary: Heart Failure with Preserved Ejection Fraction (HFpEF) affects over half of all heart failure patients, yet underlying mechanisms remain poorly understood. Using proteomic and transcriptomic analysis of human HFpEF myocardium, we found significant downregulation in ribosomal structure and protein translation pathways. In particular, activation of a critical translation factor, elongation factor-5A (eIF5A) by a process called hypusination (to form eIF5AHyp) is significantly reduced in HFpEF hearts. Mice with cardiac specific reduction of DHPS, the enzyme that generates eIF5AHyp (ciDHPS-KD), exhibit a HFpEF phenotype that supports a mechanistic role. Ribosome profiling using cardiomyocytes with pharmacologically inhibited eIF5AHyp identified a group of genes involved with ubiquitination as being most inefficiently translated. In particular, the ubiquitin precursor (UBC) and deubiquitinases (USP9X and USP7) responsible for generating free ubiquitin were major inefficient translation targets. USP9X and USP7 protein are downregulated in human HFpEF and ciDHPS-KD myocardium, and in myocytes with eIF5AHyp reduction. Total protein ubiquitination is also reduced in these conditions, and this does not appear due to increased clearance of ubiquitinated proteins by the proteasome or lysosome. This project hypothesizes that reduced hypusination of eIF5A impairs the translation of ubiquitin precursors and deubiquitinases that are all required to provide the substrate for free ubiquitin, and that this is mechanistically related to cardiac HFpEF pathobiology. This is studied in 3 specific aims. First, I test the hypothesis that depressed eIF5AHyp caused by lowering DHPS or as found in human HFpEF heart impedes translation of UBC, USP9X, and USP7 resulting in free ubiquitin deficiency, hypo-ubiquitination, and thereby impaired PQC. This is tested using paired polysome profiling and proteomics in human myocardium and the ciDHPS-KD myocardium. Proteasome flux, free ubiquitin, and protein aggregation will be assessed in ciDHPS- KD mice. Other translation-stalled protein groups/pathways will also be determined and can be pursued subsequently. Secondly, I determine mechanisms by which reduced eIF5AHyp is linked to lower UBC, USP9X, and USP7 translation. This is thought to involve specific amino acid motifs that are hard-to-translate without eIF5aHyp but may also be related to activation of a broader integrated ribosomal stress response. Both of these are tested. Lastly, I will examine this pathobiology in vivo, testing whether reducing the free ubiquitin pool by genetic knock-down of UBC is sufficient to induce a HFpEF phenotype, or that replenishing this pool by cardiac over-expression of a single ubiquitin or enhancing DHPS activity with spermidine supplementation can rescue the HFpEF phenotype in ciDHPS-KD mice. Together these studies will advance our understanding of a new previously unknown feature of myocardial etiology in HFpEF, and the role that depressed protein translation from reduced eIF5a activity plays in ubiquitin-related protein quality control.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY/ABSTRACT Candidate: Catherine Ettman, PhD, is an early career mental health services researcher. Her long-term career objective is to become an independent investigator and national expert on the role of different assets in shaping mental health and mental health services utilization towards the end of reducing inequities. Research Context: Depression is common, costly, and its burden is felt unequally. Treatment for depression can be effective but is hampered by interruptions in care, such as appointment non-adherence, or no-show. Reducing appointment no-show is a feasible and cost-efficient way to improve patient care and outcomes. Specific Aims: 1) To test whether higher out-of-pocket healthcare costs increase psychiatric appointment no- show; 2) To estimate the causal effect of clinical operations features (such as telehealth and appointment reminders) on no-show and whether the effect varies across patients with access to different financial assets; 3) To identify the financial and other factors that most strongly predict psychiatric appointment no-show. Research Plan: Using electronic health records (EHR) in a cohort of 23,420 patients with depression from the Johns Hopkins Medicine Precision Medicine Center of Excellence on Mood Disorders, Dr. Ettman will comprehensively examine the effect of financial and clinical operations features on psychiatric no-show in patients with depression to inform intervention. In Aim 1, Dr. Ettman will use an instrumental variables approach to estimate the effect of higher out-of-pocket costs on subsequent appointment no-show, leveraging variation in facility fees, external to the patient and induced by Maryland state policy, as an instrument. In Aim 2, Dr. Ettman will use contemporary matching approaches such as full propensity score matching and doubly robust methods to estimate the causal effect of clinical operations features (such as telehealth and appointment reminders) on psychiatric appointment no-show and she will assess if the effect varies across patients with access to different financial assets. In Aim 3, Dr. Ettman will use modern prediction models including random forest and Lasso to determine which financial and other factors predict psychiatric no-show. Career Development Plan: Dr. Ettman will develop expertise in 1) causal design, including instrumental variable analysis and contemporary matching approaches; 2) health informatics, specifically advanced prediction models; and 3) ethical and practical health system clinical operations. Dr. Ettman’s training will be supported by close mentorship, advanced didactic coursework, and career development activities. Research Goals: This proposal builds on Dr. Ettman’s track record of successful publication and project management, a highly involved primary mentor and expert mentorship team, and strong institutional support, while providing protected time for training. Together, this body of work will identify implementable policy recommendations that improve population mental health.

NSF Awards · FY 2025 · 2025-06

With support from the Environmental Chemical Sciences program in the Division of Chemistry, Professors Howard Fairbrother and Carsten Prasse at Johns Hopkins University, Professor James Ranville at the Colorado School of Mines, and their students will investigate the effects of free chlorine, a common disinfectant used in drinking water distribution systems, on plastic pipes. Plastic pipes are replacing traditional metal pipes in distribution systems due to the well-documented health and safety issues caused by leached toxic metals during aging. However, the safety of these replacement plastic pipes is unclear. One unintended consequence of using plastic pipes is their susceptibility to degradation, a process that has been shown to result in the formation of microplastics (MPs). Additionally, organic chemicals, frequently incorporated as additives into pipes to enhance their properties, can leach from plastic pipes during the degradation caused by free chlorine. Moreover, these organic chemicals can react with free chlorine once they have been leached to produce new chemicals that can be more toxic than the additives themselves. The potential health risks associated with MPs and chemical additives in drinking water have raised increasing concerns. Through this study, we intend to holistically evaluate the safety of plastic pipes in the presence of chlorinated drinking water. Students involved in this research will acquire skills in materials chemistry, environmental chemistry, and environmental engineering. Students at the K-12 and university level will participate in educational activities, such as hands-on experiences with model drinking water and pipe materials to demonstrate the breakdown over time. This project aims to develop a safety profile of polyvinyl chloride (PVC) and polyethylene (PE) under the oxidizing conditions presented by free chlorine in drinking water. This will be accomplished by synthesizing model pipe materials containing a metal tag and exposing them to model drinking water; any microplastics formed will be quantified by measuring the embedded metal tag via single particle inductively coupled mass spectrometry (spICP-MS). Additives leached from PVC and PE synthesized with known concentrations of additives will be probed via liquid chromatography- and gas chromatography-high resolution mass spectrometry, including the identification of transformation products formed from the reaction of leached chemical additives with free chlorine. These results will help to inform the health and safety impacts of plastic pipes in drinking water distribution systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-06

Project Summary/Abstract Respiratory viral infections (RVI) including SARS-CoV-2, RSV, and influenza, are major threats to the health of solid organ transplant recipients (SOTRs), who live at the intersection of chronic comorbidity, frailty, and heavy immunosuppression. These factors contribute to high rates of clinically observed severe RVI and pose risks for poorly understood post-acute syndromes including organ dysfunction and protracted infections associated with immune evasive mutations of public/health/relevance. Furthermore, as starkly outlined during the COVID-19 pandemic, RVI vaccine immunogenicity and effectiveness are suboptimal in SOTRs, connoting ongoing risk for adverse outcomes despite vaccination. Due to a lack of clinical trials of novel platforms in SOTRs, such as variant-updated SARS-CoV-2 and RSV vaccines, robust prospective observational data are urgently needed. In this proposal, we will leverage and expand the first national-scale prospective cohort of US SOTRs designed to measure acute and post-acute RVI outcomes in the COVID-19-endemic era and assess real-world immunoprotective effects of vaccination. Goals of this proposal include ascertainment of acute RVI events in a large national cohort of SOTRs through asymptomatic and symptom-driven screening protocols to calculate effectiveness of clinically-available vaccinations (Aim 1). Clinical and immunological associations with breakthrough RVI in SOTRs post vaccination will then be assessed, including the role of longitudinal pathogenspecific plasma and mucosal immune responses (Aim 2). Additionally, the prevalence and phenotypes of postacute RVI sequela including “Long COVID” in SOTRs will be determined, including evaluation of potential associations with persistent RVI shedding and evolution as well as vaccine-associated immune responses (Aim 3). Taken together, this proposal will generate critical data on the contemporary burden of RVI among US SOTRs, with particular focus on vaccine-preventable infections, to inform personalized risk calculations incorporating clinical and mechanistic data. These findings will provide evidence base for further optimization of immunoprophylactic interventions against acute and post-acute RVI complications among vulnerable SOTRs in the COVID-19-endemic era.

NIH Research Projects · FY 2026 · 2025-06

Project Summary Cognitive deficits are a core feature of schizophrenia and are particularly prominent in patients of advanced age. In fact, schizophrenia patients are likely to experience worsening cognitive symptoms in mid- to late-life. There is an abundance of evidence suggesting that targeting glutamate-mediated neurotransmission could modulate neural connections that are responsible for the abnormal signaling and improve memory symptoms of schizophrenia. GRM3, the gene that encodes the metabotropic glutamate receptor 3 (mGlur3), is a GWA- associated risk gene for schizophrenia, and alterations in mGluR3 signaling change memory performance in both animal models and humans. N-acetyl-aspartyl-glutamate (NAAG) is a peptide neurotransmitter that acts as the only selective endogenous agonist of mGluR3. The amount of NAAG in the synapse is primarily regulated by glutamate carboxypeptidase II (GCPII), which inactivates NAAG by cleaving the glutamate from NAA. Increasing NAAG levels, through the inhibition of GCPII, may be effective for the treatment of memory dysfunction in schizophrenia, as suggested by several animal models. This could be particularly relevant in patients with schizophrenia in mid- to late-life, as GCPII levels are known to rise in the brain with aging. However, there is a paucity of human data regarding the functional role of NAAG in cognition, and the behavioral and neural consequences of human NAAG modulation is currently unknown. Before investing in the development of a GCPII inhibitor, it is critical to determine the relationship between NAAG levels, memory performance, and neural activity during memory in mid- to late-life. We propose to measure NAAG levels using magnetic resonance spectroscopy in schizophrenia patients and healthy adults in mid- to late-life and to correlate these NAAG levels with declarative and working memory performance (Aim 1) and neural activity during memory tasks measured by functional MRI (Aim 2) in the same individuals. We expect to 1) identify memory domains that are associated with differential NAAG levels, 2) identify memory task-related brain activity patterns that are regulated by NAAG, 3) determine if the relationship between NAAG and memory if changes from 35y to 65y, and 4) determine if the influence of NAAG on memory and brain function is greater in patients with schizophrenia in mid- to late-life compared to healthy adults. This proposal will therefore link variation in human NAAG levels with memory performance and brain function that would shed light onto the pathophysiology of memory dysfunction in schizophrenia in mid- to late-life and guide future development of treatments aimed at modulation of NAAG levels to improve memory symptoms. Furthermore, these findings will inform the future use of neuroimaging biomarkers in relevant clinical trials involving modulation of NAAG and mGluR3 for the treatment of memory dysfunction in mid- to late-life.

NIH Research Projects · FY 2025 · 2025-06

Project Summary Staphylococcus aureus (S. aureus) is a common pathogen causing healthcare associated infections (HAI) in neonates. An estimated 2-3% of very low birth weight infants develop S. aureus bloodstream or central nervous system infections with an overall mortality of 10-25%. During delivery or after birth, S. aureus can transfer from people or the environment and asymptomatically colonize neonates, primarily in the anterior nares. S. aureus colonization is a well-established predisposing factor to invasive, life-threatening infection, with up to one third of S. aureus colonized neonates in the neonatal intensive care unit (NICU) developing a S. aureus infection. Recently, we characterized the nasal microbiome of neonates in the NICU and found that neonates with S. aureus bloodstream infections had an increased relative abundance of S. aureus sequences in nasal swab samples and lower alpha and beta diversity measures compared to neonates with and without S. aureus colonization. These data suggest that a more diverse bacterial community may promote colonization resistance to S. aureus and protect against infection. Our long-term goal is to develop paradigm-changing interventions to prevent life-threatening S. aureus infections in neonates. Recently under an FDA IND, we launched two pilot placebo-controlled trials to test the safety and feasibility of the first-ever parent-to-child nasal microbiota transplant (NMT). Using stored samples collected during these pilot trials, we propose to determine whether bacteria from the parent anterior nares can be transferred to and seed the neonate's nares, engraft in the neonatal microbiome, and increase neonatal nasal microbiome diversity. Our specific aim is to characterize the neonatal nasal microbiome following a parent-to-child NMT. Using samples collected from parents, neonates (prior to and periodically after NMT), and environmental controls, we will perform shotgun metagenomic sequencing to characterize and compare the nasal microbiome of neonates who received NMT or placebo. This study will characterize a novel strategy to assess the biologic plausibility of an NMT. Findings from this work will inform future studies in children and adults to manipulate the nasal microbiome as a strategy to prevent S. aureus colonization and disease.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY Mycobacterium abscessus (Mab) is a rapidly growing non-tuberculous mycobacterium that can cause chronic lung disease that is associated with rapid lung function decline and is often incurable. There are no FDA- approved treatments for this indication. Patients report to the clinic with chronic disease and reduced lung function, and for the majority of them, the optimistic objective is to effectively manage the condition to prevent its deterioration, given that current treatments are largely ineffective in achieving a stable cure. In the course of chronic disease, Mab develops biofilms in the lungs, creating a protective shield against antibiotics. Existing treatments are based on repurposing of antibiotics approved for other diseases. Challenges of the currently recommended standard treatment of Mab lung disease include a) poor efficacy, b) need for treatment durations lasting several months, c) frequent drug toxicities, d) need for parenteral (IV) antibiotics, and e) complicated logistics of long-term outpatient IV antibiotic treatment. The cure rate using current treatment recommendations is estimated at 30-50%. One reason commonly cited for the limited effectiveness of antibiotics against Mab disease, as well as the need for prolonged treatment durations, is their challenge in efficiently penetrating and eliminating the Mab subpopulation present in biofilms. The overall aim of this proposal is to generate proof-of-concept data on a non-traditional strategy that acknowledges the necessity of disrupting Mab biofilms. For antibiotics to demonstrate the anti-Mab activity observed in in vitro settings, where antibiotics effectively kill planktonically growing Mab, it might be essential to first destroy Mab biofilms in the lungs. CMTX-101 is a monoclonal antibody that works to disrupt Mab biofilms by removing DNABII proteins, which are crucial for the lattice organization and stability of DNA providing structural integrity to Mab biofilms. Given its effective disruption of Mab biofilms in vitro, we aim to investigate in a mouse model of chronic Mab infection whether CMTX-101 can similarly disrupt Mab biofilms in the lungs. If CMTX-101 can effectively modify Mab biofilms in the lungs, the results from the proposed studies can serve as proof-of-concept for an unconventional approach to treating not only Mab disease but also other conditions where bacterial biofilms pose a challenge to effective treatment.

NIH Research Projects · FY 2026 · 2025-06

Project Summary/Abstract In visceral inflammatory disorders the excitability and activation of visceral nociceptive sensory nerves are abnormally enhanced, contributing to the difficult-to-treat clinical symptoms such as visceral pain and discomfort, bladder irritability, diarrhea/constipation, cardiac arrhythmias, bronchospasm, heartburn, dyspnea, and unproductive coughing. The pathogenesis of visceral nociceptor sensitization is complex and poorly understood. Our long-term objectives are to elucidate the ionic/molecular mechanisms underlying the regulation and dysregulation of visceral nociceptor excitability, and to identify novel therapeutic strategies aimed at reducing the suffering of the millions afflicted with chronic visceral diseases. The excitability of neurons, including visceral nociceptors, is dynamically regulated by concerted action of excitatory and inhibitory ion channels. The last few decades of intensive research in visceral nociceptive nerves has mainly focused on various excitatory ion channels while much less is known about the K+ channels that exert inhibitory control on nociceptor excitability. Our recently published work and new preliminary data are revealing that among the plethora of functionally diverse voltage-gated potassium (KV) channels two subtypes, the KV7/M-type (IM) and KV1/D-type (ID) K+ channels, mediate the majority of sustained inhibitory K+ currents at the subthreshold voltages, thereby playing the critical role of "braking" the activation in vagal visceral nociceptors. We therefore hypothesize that inhibition in activity and/or expression of KV7/IM or KV1/ID channels in vagal nociceptors leads to vagal visceral nociceptor sensitization and thus contributes to exaggerated visceral nociceptive reflex responses, and that selective pharmacological activation of "braking" K+ channels may provide novel therapeutic strategies for the management of debilitating neurological symptoms associated with various visceral disorders. Our four specific aims are designed to address these hypotheses by investigating the consequences of genetic inactivation and pharmacological activation of KV7/IM and KV1/ID channels on the excitability of the vagal visceral nociceptive nerves at the levels of cell bodies, nerve terminals as well as defensive reflex behaviors, and by investigating the effects of visceral inflammation on the expression and function of these channels in vagal nociceptors. To achieve these aims, we will use the most up-to-date innovative technologies, including single-cell RNA sequencing, state-of-the-art patch clamp techniques, two- photon microscopic calcium imaging and extracellular electrophysiological recording of single fiber activities, and respiratory reflex measurement in awake mice, combined with sensory neuron- and nodose neuron- specific gene knock-out and knock-down strategies. By pursuing the proposed study, we will advance our knowledge about the ion channel mechanisms underlying the vagal nociceptor sensitization associated with inflammatory diseases, and identify the braking K+ channels as promising novel therapeutic targets to quell the abnormal visceral nociceptive responses in diseases.