Johns Hopkins University

NSF Awards · FY 2026 · 2026-04

This award will support a workshop to bring together principal investigators supported by NSF Trailblazer Engineering Impact Award program, also known as NSF Trailblazer. The principal investigators are thought leaders on topics ranging from biotech and robotics – areas of national need that are important for U.S. leadership in high technology. Over the two-day event, the principal investigators will brainstorm future research directions in high technology areas important for the U.S. The workshop will also include students of principal investigators and involve them in the visioning process. These discussions will promote a culture of creativity and risk-taking that align with the NSF mission to advance U.S. leadership in science and engineering. The Trailblazer Engineering Impact Award (NSF Trailblazer) Workshop will bring together current awardees of the NSF Trailblazer program for two days of structured dialogue and collaboration. The workshop will provide a dedicated forum for sharing transformative research directions, exchanging lessons learned, and exploring convergence opportunities across diverse engineering domains that address national research needs in emerging technologies, particularly in diverse areas of bioengineering, hazards & resilience, quantum science & computing, semiconductors, and robotics. Through presentations, interactive sessions, and collaborative activities, participants will collectively articulate emerging themes and future research visions aligned with the goals of the NSF Trailblazer program. By amplifying communication and collaboration within this unique community, the event will accelerate the translation of bold ideas into impactful directions and inform future priorities for transformative engineering. Outputs such as a collaboratively authored perspective document and recorded sessions will extend the reach of these discussions, promoting a culture of creativity and risk-taking that aligns with the NSF mission to advance U.S. leadership in science and engineering. 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 · 2026-03

Dating violence (DV) is common among U.S. high school age adolescents and has significant and lifelong negative health consequences, including suicide behaviors. Native American (NA) adolescents are at increased risk for violence victimization and/or perpetration in their dating violence, given their high rates of violence exposure in their homes and communities. Key challenges for dating violence prevention are the lack of services, fear of stigma and discrimination, and limited trust in and access to skilled professionals. The Fort Peck Reservation is home to the Assiniboine and Sioux Tribes in rural Montana. The reservation community reports high rates of violence and suicide behavior with underfunded and limited health and social service, especially for adolescents. The wide range of negative health and social outcomes associated with violence experienced by reservation-based NA adolescents underscores the call for innovative and targeted behavioral health interventions using appropriate technology. myPlan Teen, is an evidence-based healthy relationship and dating violence prevention intervention for adolescents and is delivered through a secure and confidential web based and mobile app. myPlan Teen provides adolescents with immediate access to information about healthy and unhealthy behaviors, safety strategies tailored to their situation with links to youth friendly resources, to reduce confusion, feelings of isolation and stigma associated with unhealthy relationships. In our CDC funded randomized control trial (RCT) with a national sample of 609 adolescents aged 15-17, we found adolescents randomized to myPlan Teen had a significant increase in use and helpfulness of safety behaviors compared to control group (adolescent health website). Further adolescents who used myPlan Teen reported a significant reduction in physical/sexual violence perpetration and suicide behaviors compared to control group. To advance the relevance and use of myPlan Teen with NA adolescents, our interdisciplinary team in partnership with Tribal Health leaders and Youth Advisory Board (YAB) will adapt myPlan Teen by integrating culturally relevant content, including tribal identity and communal mastery for NA adolescents to build healthy relationships, develop safety skills and access culturally relevant resources. Following the adaptation process, the team will evaluate the effectiveness of the culturally adapted myPlan Teen app on health and safety outcomes with 550 NA adolescents. In addition, we will examine the mechanisms by which myPlan Teen improves health and safety outcomes. The study will advance violence prevention interventions with NA adolescents and inform future processes to adapt and disseminate a digital intervention with adolescents nationally.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY: Cognitive flexibility is disrupted in many neuropsychiatric diseases, but how the brain generates flexible behavior is not fully understood. Learning from recent actions requires neural mechanisms that maintain information about relevant decision variables to influence future decisions. Persistent activity in cortical areas required for cognitive flexibility, such as prefrontal cortex (PFC), connect an animal’s choices and recent outcomes. Neural mechanisms for generating and maintaining this persistent activity involve excitatory loops between the neocortex and subcortical structures. Recent studies suggest that the claustrum, a poorly understood subcortical nucleus that forms reciprocal connections with the neocortex, is particularly highly interconnected with cortical areas strongly implicated in behavioral flexibility. We propose to test whether the claustrum contributes to generating flexible behaviors using two tasks, dynamic foraging and reversal learning. These tasks require medial prefrontal cortex (mPFC) and lateral orbitofrontal cortex (lOFC) function respectively, two areas likely influenced by claustrum activity based on recent studies of claustro-cortical- claustral loops. First, we will test the hypothesis that the activity of claustrum neurons encodes decision variables in these two tasks. Second, we will test whether claustrocortical projections contribute to generating persistent cortical activity and influence the encoding of decision variables by cortical neurons. We will further test whether claustrocortical neurons with projections biased to two different cortical areas, Cla→mPFC and Cla→lOFC neurons, form distinct functional modules within the claustrum and whether the claustrocortical projections to mPFC and lOFC influence cortical activity using similar cellular mechanisms. In addition, we will determine whether claustrocortical neuron activity is required for dynamic decision making and reversal learning, respectively. Third, we will test whether claustrocortical projections are required for learning at different timescales, both during and after the acquisition of a reversal learning task. We predict that claustrocortical loops contribute to generating and maintaining persistent cortical activity required for task performance and learning at multiple timescales. Together, these data will represent the first studies of claustrum neurons in well established, carefully controlled, decision-making tasks combined with quantitative models using normative theory. Furthermore, these experiments will directly test effects of claustrocortical inputs on cortical activity during flexible behavior and on an animal’s behavioral responses, enabling the integration of the claustrocortical system into models of flexible decision making and cognitive control in health and disease.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Collective cell moment is a complex phenomenon in which cells integrate global and local cues to determine their collective positional changes. This process is fundamental to various tissue morphogenesis during embryonic development, and also plays roles in immune responses and diseases such as cancer. While significant progress has been made in identifying molecular and chemical regulators, the importance of mechanical cues has only been emerging in the last decades, primarily through in vitro and/or in single-cell studies. Our understanding of mechanical regulations in vivo, particularly in collective cell movement, is still limited. This knowledge gap aligns with the challenges in tissue engineering, where synthetic tissues for disease modeling and drug screening struggle to replicate the structural complexity of their native counterparts. As Richard Feynman famously stated, “What I cannot create, I do not understand.” The Weng lab aims to bridge in vivo and in vitro studies by integrating biology and engineering. The overall vision is to decode and harness the fundamental mechanical principles from collective cell behaviors during tissue morphogenesis, and to advance technical innovation in creating functional 3D tissues and organs. Two synergistic strategies will be employed to achieve this goal: (1) Understanding mechanical regulations of collective cell movement in vivo, and (2) engineering synthetic cues to control these regulations and recreate collective cell movement by design in vitro. Research in the Weng lab currently focuses on convergent extension (CE), a conserved collective cell movement critical for the elongation of body axis and multiple tissues during development. Using Xenopus laevis embryos and Xenopus and mammalian cells as the in vivo and in vitro models, complemented by in silico computational models, the lab studies multiscale mechanical regulation of CE. Over the next five years, this research program aims to address two key questions: (1) How do mechano-sensing and -responses between individual cells instruct CE in vivo? (2) Is it possible to engineer mechanical conditions that replicate in vivo environments to leverage cells’ mechano-sensing and -responses, eliciting CE-like collective cell movement in vitro? These studies will advance our understanding of mechanical regulations in CE, and identify key principles that warrant further exploration into other forms of collective cell movement. Additionally, this research will uncover new targets as the Weng lab continues to decode and engineer the mechanical feedback mechanisms regulating collective cell behaviors. In the long term, this program will also contribute to the fundamentals of mechanobiology and tissue engineering, as well as the prevention and treatment of aberrant collective ell movement in congenital diseases and cancer metastasis.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Symbiotic relationships between animals (including humans) and bacteria are ubiquitous in the natural world, and cultivating a healthy microbial community, or microbiota, is critical for the health of hosts. Our lab explores the fundamental principles of host-microbe symbiosis to learn how these relationships are formed and maintained. We focus on flagella, tail-like structures that are commonly used by bacteria to navigate their environments. Many symbiotic bacteria use flagellar motility to colonize their hosts, and the proteins that govern flagellar development and activity are critical for beneficial and pathogenic host-microbe associations. Many species from the Vibrio genus of bacteria form symbiotic relationships with animal hosts, ranging from invertebrate mutualists like Vibrio fischeri to human pathogens like Vibrio cholerae. In symbiotic Vibrios, flagellar motility is critical for the establishment of the host-microbe relationship, and mutations in the flagellar apparatus reduce both their general motility and their ability to colonize their hosts. Although flagellar motility is well-described in some bacteria in vitro, the genetic requirements for flagellar function and specific types of motility are often restricted to artificial conditions that do not reflect real world conditions. Further, we and others have found that in vitro characterizations of flagellar motility in simple environments do not generalize to the motility behaviors that bacteria use inside the bodies of their host organisms. Over the next five years, we will use the model symbiosis between the Hawaiian bobtail squid and Vibrio fischeri to characterize the role of flagellin proteins, which make up the flagellar filament, in symbiotic motility. We will determine the role of individual flagellins and flagellin diversity in motility, then will measure how flagellins shape motility in complex, host-like environments. Finally, we will assay the role flagellins play in symbiotic colonization. This work will uncover new information about the structure and function of bacterial flagella, and will further characterize how bacteria use motility to colonize and impact their hosts.

NIH Research Projects · FY 2026 · 2026-03

The rates of neurodevelopmental disorders and Alzheimer’s disease are rising, yet success in drug development and public health interventions remains limited. Developmental neurotoxicity testing is hindered by reliance on animal models, creating a backlog of untested chemicals. The proposal outlines a Drug Research Organoid-Integrated Development platform (DROIDp) – an in vitro neural system that combines human iPSCderived 3D brain organoids with advanced sensors in form of 2D and 3D microelectrode arrays, and AI-driven analytics – to develop a combinatorial New Approach Methodologies (NAMs) of learning and memory. This approach is a novel combinatorial NAMs, serving as a human-based alternative to traditional animal behavior studies in neuropharmacology and (developmental) neurotoxicology. In DROIDp, organoids will be stimulated using open- and closed-loop paradigms, measuring neural activity, synaptic plasticity, and network dynamics in response to stimuli to develop a set of neural learning metrics, which can assess neural function in disease settings or in response to neuroactive compounds. The study will evaluate organoids derived from both healthy individuals and patients with SYNGAP1-related disorders and Alzheimer’s disease, testing their neural responses and sensitivity to pharmacological interventions. Data from electrophysiology, transcriptomics, and extracellular vesicle (EV) profiling will be analyzed using self-supervised learning and explainable AI (xAI) to correlate the in vitro data to clinical data to develop robust biomarkers for function. By enabling measurement of learning and memory processes in human neural tissue, the platform addresses a critical gap: current in vitro assays cannot capture higher-order neural responses, and evaluations of neurotoxicity or drug efficacy still rely on animal behavioral tests. This interdisciplinary project led by a team with a well-established history of collaboration, fostering a cohesive and productive working environment. The team’s expertise spans neuroscience, toxicology, engineering, data science and neuroethics to drive a paradigm shift in drug development and chemical safety testing. DROIDp will advance neuroscience by enabling human-based models of neurodevelopmental and neurodegenerative disorders for studying disease mechanisms and evaluating candidate therapeutics. It will offer a more predictive tool for developmental neurotoxicity testing, capturing complex neural functions to improve risk assessment. Expected outcomes include a fully developed, standardized organoid platform demonstrating reliable readouts of learning and memory on the cellular level, reproducibility across batches and cell lines across many individuals, and responsiveness to known neuroactive compounds, yielding performance benchmarks ready for formal validation by the NIH Complement-ARIE network or regulatory agencies. Successful completion will deliver a combinatorial NAMs in neuroscience – a critical need identified by the Complement-ARIE program’s consortium. This outcome is expected to significantly improve the predictive accuracy, efficiency, and ethical standards of preclinical drug discovery and toxicity screening.

NIH Research Projects · FY 2026 · 2026-03

Project Summary I am an Assistant Professor of Neurosurgery at Johns Hopkins, and my clinical practice focuses on brain tumors. I am applying for a mentored surgeon-scientist research career development award to gain advanced training in molecular biology, cancer metabolism, and novel drug delivery strategies to the brain. Glioblastoma (GBM) is a devastating brain cancer with a median survival of just 13 months. Challenges in treatment are largely due to tumor heterogeneity and the impermeability of the blood-brain barrier (BBB). Current treatments offer limited efficacy, necessitating innovative approaches to improve drug delivery and targeting. My project addresses this critical need by leveraging MRI-guided focused ultrasound (MRIgFUS) to transiently disrupt the BBB, enhancing the delivery of ME3BP7, a novel, stable pyruvate analog that targets MCT1, a metabolic transporter overexpressed in over 80% of GBMs. The Specific Aims of the proposal are to: (1) Elucidate the mechanism of action of ME3BP7 in GBM, focusing on its impact on MCT1-dependent metabolism and resistance pathways, and (2) to optimize ME3BP7 delivery across the BBB using MRIgFUS in patient-derived xenograft models. These experiments will validate the potential of MCT1 targeting with ME3BP7 while pioneering a clinically translatable approach for BBB disruption. As a neurosurgeon interested in translational research, I have extensive experience in cancer cell biology, orthotopic murine GBM models, and biomarker-driven drug development, including the successful design and preclinical validation of ME3BP7 in pancreatic cancer models. This K08 proposes building upon my cancer research and drug development postdoctoral training towards a new direction at the interface of metabolic targeting and translational therapeutics. Under the mentorship of Dr. Chetan Bettegowda, an internationally recognized leader in brain tumor research, I will refine my expertise in GBM metabolism, molecular biology, and drug delivery. Specific training goals include: (1) Hands-on training in molecular biology techniques, including CRISPR-Cas9 gene editing and metabolic enzyme quantification; (2) Didactic and experimental training in cancer metabolism, with a focus on metabolic flux analysis; (3) Advanced training in pharmacokinetics and drug delivery, particularly in MRIgFUS for BBB disruption; (4) Formal coursework in biostatistics, grant writing, and research ethics to strengthen scientific rigor and independence. We have created a high-quality educational and mentorship plan to complete this research with a multidisciplinary team of collaborators to help develop my career as an independent clinician-investigator. My scientific advisory committee will also support my overarching career goals and evaluate my progress. This proposal represents a novel research line for which I will be responsible and is specifically designed to help me establish an independent investigation, ultimately advancing the field of GBM therapy by supporting my long-term goal of integrating metabolic targeting with precision drug delivery to the brain.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract Cells host non-membrane-bound organelles, many of which form through a phase-separation mechanism. These dense assemblies of proteins and nucleic acids, termed biomolecular condensates, enable key cellular functions from ribosomal assembly to stress response and metabolism, and are implicated in neurodegenerative diseases and cancers. In contrast to membrane-bound organelles, which are impermeable to most cellular molecules, biomolecular condensates are open to their surrounding environment. They constantly exchange components with the dilute phase and can form and dissolve as needed in response to cellular signals. Such dynamical exchanges are crucial to the biochemical processes taking place inside condensates and to the response of condensates to a changing environment, as well as to the regulation of the number, size, and placement of condensates in the cell. A quantitative understanding of condensate dynamics is therefore key to discovering the physical principles and biological mechanisms underlying condensate functions. Advances in imaging techniques have led to great improvements in the measurement of dynamical properties of condensates, and increasingly allow for the probing of condensates with multiple components and complex structures in an intact cellular environment. However, there is a very limited set of mathematical models aimed at quantitatively interpreting these experimental results. The growing wealth of quantitative data calls for a new generation of dynamical models capable of capturing the complexities encoded in the data. We propose to develop biophysical models to unravel both the physical principles and biological mechanisms underlying condensate dynamics via interpreting highly quantitative data, such as from single-molecule tracking. We will investigate condensate dynamics by integrating biophysical modeling, coarse-grained simulations, machine learning, and targeted experiments with expert collaborators – a research style characteristic of our lab. Specifically, we expect this research program to (1) provide a quantitative picture of the key factors controlling how long a molecule dwells within a condensate, (2) predict the timescales of material exchange for multi-component, multi-state condensates, and (3) bring new insights into the molecular interaction network and its relationship to spatial and dynamic heterogeneity within condensates. Beyond these immediate research goals, we will address broader questions in the long term, including: How are the internal structure and dynamics of multi-species condensates related? How does the complex intracellular environment impact condensate dynamics? And how do the dynamics of condensate components influence their biological functions? Ultimately, the results and tools developed in this research will advance our understanding of the dynamic behaviors of biomolecular condensates, shedding light on their functions in health and disease, and paving the way for condensate bioengineering.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Translation converts genetic information encoded in nucleic acids into functional proteins, a process fundamental to cellular function and regulation. However, the mechanics of translation at the single- mRNA level within the native cellular environment remain poorly understood. Recent evidence highlights that mRNAs are not passive conveyors of information but are dynamically regulated, transitioning between translationally active and inactive states in a phenomenon termed "bursting translation." Dysregulation of these processes is linked to diseases such as cancer and neurodegenerative disorders. Despite its importance, the molecular basis of bursting translation, particularly the roles of RNA-binding proteins and mRNA conformation, remains elusive. This project builds upon our pioneering Single-molecule Imaging of Nascent Peptides (SINAPS) technology to elucidate the mechanisms governing translation dynamics of normal and erroneous messages in live cells. Specifically, we will: (1) establish a system to visualize single protein-RNA interactions in live cells, refining single-molecule translation assays and developing tools to correlate protein binding with translation dynamics; (2) investigate how protein factors in ribosome-associated quality control (RQC), such as ZNF598 and ASCC3, interact with substrates to resolve ribosomal collisions; and (3) uncover the role of mRNA looping and initiation factor binding in activating translation. This research will provide a comprehensive understanding of in vivo mRNA translation dynamics and regulation. The novel methodologies and insights generated will pave the way for future studies into translation-related disorders and therapeutic strategies.

NIH Research Projects · FY 2025 · 2026-03

TITLE: Identifying and Measuring the Palliative Needs of Children in Foster Care A major challenge in tailoring palliative care for children in foster care is a lack of appropriate measures and data identifying their needs. Among children with medical complexity, 27% utilize concurrent (hospice and end of life) care. This high percentage suggests that many CMC with more than 6 months of life expectancy could benefit from palliative care. The known health challenges among children in foster care and CMC suggests a strong likelihood of unmet palliative care needs for CMC in foster care, however, the scope and severity are unclear due to an absence of literature and limitations of data. Participatory action research methodologies with critically ill patients have led to positive outcomes between patient need and medical intervention. Research suggests collaborative co-design could help provide the context, insight and understanding to address unmet palliative needs for children in foster care. Therefore, this exploratory mixed methods study using a participatory co-design approach will determine what palliative care needs should be measured among CMC in foster care from the perspective of two partner groups: 1) Foster partners, including foster and biological parents, and adults formerly in foster care, and 2) health care team partners (including nurses, nurse practitioners, physicians, and social workers). Aim 1a: Qualitatively identify the lived experiences of foster partners caring for children in foster care with palliative needs, and quantitatively assess the clarity and relevance of an existing palliative screening tool in this population. Narrative interviews will be followed by a quantitative content validity index for a current parent-reported pediatric palliative care screening tool. Aim 1b: Qualitatively understand the lived experiences of health care partners caring for children in foster care with palliative needs, and quantitatively assess the clarity and relevance of an existing palliative screening tool for this population. Focus groups will be followed by a quantitative content validity index for a current health care team-reported pediatric palliative care screening tool. Aim 1c: Integrate qualitative and quantitative data into preliminary synthesized findings. Aim 2a: Conduct reflexive discussion and validation of the preliminary Aim 1c findings using a participatory co-design approach with representatives from the foster and health care team partner groups and Aim 2b: Collaboratively co-design screening priorities for palliative needs among foster children. This work will inform future research and clinical practice by anchoring inquiry within human-centered design research approaches to address palliative care needs in foster care.

NIH Research Projects · FY 2025 · 2026-03

PROJECT SUMMARY/ABSTRACT: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of systemic autoimmune dis- eases characterized by organ- and life-threatening inflammation of small and medium blood vessels. Half of AAV cases are driven by ANCAs targeting neutrophil cell-surface bound proteinase 3 (PR3), which leads to patho- genic neutrophil activation. However, total PR3-ANCA plasma levels correlate poorly with disease severity and relapse risk, and limited knowledge of the variable immunopathogenic potential of distinct PR3-ANCA subsets has challenged the advancement of more accurate diagnostic and prognostic tests. Moreover, severe infection caused by current, broadly immunosuppressive treatment strategies is the leading cause of mortality in AAV. To this end, we have developed PR3-chimeric autoantigen-T cell receptor (CATCR)-T cells, a precision cellular immunotherapy which uses engineered receptors (PR3 fused to T cell receptor subunits) to specifically engage and eliminate pathogenic ANCA+ B cells through their B cell receptor (BCR). Initial CATCR-T cell designs demonstrated potent killing of ANCA+ B cells, though moderate killing of normal B cells indicated off-target bind- ing of CATCRs to other surface antigens. The overall goal of this proposal is to characterize the pathogenic features of PR3-ANCA on the monoclonal antibody level, and to increase PR3-CATCR selectivity by identifying and disrupting off-target binding partners through targeted mutagenesis of the CATCR PR3 binding moiety. In preliminary work, we have synthesized and expressed 18 novel patient-derived monoclonal PR3-ANCAs to identify shared features of pathogenic autoantibodies in AAV (Aim 1). Standard kinetic and competitive surface plasmon resonance (SPR) and ELISA assay formats will be used to measure PR3-ANCA binding affinity, epitope specificity, and their ability to disrupt PR3 binding with its neutrophil surface receptor NB1. Individual PR3-ANCA monoclonal autoantibodies will then be assayed for their ability to trigger pathogenic neutrophil activation in vitro to identify common determinants of pathogenicity. To mitigate off-target PR3-CATCR-T cells cytotoxicity (Aim 2), we will use BioID-mass spectrometry to identify non-BCR binding partners of PR3-CATCRs. Rounds of tar- geted mutagenesis informed by in silico modeling of protein-protein interactions will be validated using in vitro binding assays. Optimized PR3-CATCR-T cells using mutagenized PR3 as a binding domain will be tested for their selective killing in model human ANCA+ B cell lines and primary human B cells from patients with AAV. Overall, this proposal aims to i) advance our understanding of PR3-AAV immunopathogenesis with the goal of improving diagnostic and prognostic clinical tests, and ii) enable the development of PR3-CATCR-T cells, a novel cellular immunotherapy modality for the treatment of AAV. This research plan provides valuable training in im- munological wet lab techniques, cell culture modeling of rheumatic disease, protein engineering, and the pro- cessing and assaying of clinical samples. Findings from this proposal will be of broad interest to the immuno- therapy field and will serve as preliminary data for a future NIH K99 Career Development Award.

NIH Research Projects · FY 2026 · 2026-03

In the process of asymmetric cell division (ACD), two daughter cells with identical genetic information, but distinct fates, result from one cell division. Adult stem cells can undergo ACD to produce one self-renewed stem cell and one differentiating daughter cell. This process allows for important physiological processes including tissue development, homeostasis, and healing. Regulation of proper stem cell division can be lost in aging as well as cancer and other chronic diseases. How stem cells regulate ACD is not fully understood, but has broad implications for the study of cell fate determination and cellular reprogramming. To study ACD in an in vivo adult stem cell lineage, the Chen lab uses the Drosophila male germline. Germline stem cells (GSCs) in the Drosophila testis divide to generate both a self-renewed GSC and a differentiating daughter cell, called a gonialblast, which divides symmetrically to produce spermatogonial cells (SGs) that eventually undergo meiosis and terminal differentiation into sperm. Our group previously showed that histones that existed in the cell before DNA replication are retained in the self-renewed GSC, while newly synthesized histones are enriched in the differentiating daughter cell. The lab then discovered that during S- phase in GSCs, old histones are biased to the leading strand while new histones are biased to the lagging strand. Interesting, the catalytic subunits of both lagging strand enriched polymerase complexes, Polα and Polδ, are present at a lower level in GSCs as compared to SGs, while the leading strand enriched polymerase, Polε, shows comparable levels. Compromising Polα either pharmacologically (by an inhibitor) or genetically (polα+- flies), induces asymmetry in histone incorporation in SGs. However, how this differential expression of Polα and Polδ, but not Polε, is regulated is unknown. According to my preliminary data, polα and polε RNA levels reflect the protein level trend, and a stepwise increase in polα RNA across SG divisions was noted. I hypothesize that GSC transcriptionally repress polα, and this repression is lost as SGs divide. I will determine what cis-regulatory elements are responsible for this differential expression using a reporter assay. I will integrate transcription factor motif analysis, genomic data, and transcriptomic data to identify candidate trans-acting factors, which I can test further using molecular and genetic assays. In my second aim, I will investigate the functional outcome of reduced Polδ levels. The lab found that both polδ+/- and polα+/- flies display sustained fertility during aging. polα+/- flies also demonstrate enhanced regeneration in the germline. I will characterize the cell biology and morphology of polδ+/- testes during aging and test their regenerative potential using a genetic ablation experiment. The Chen lab has the expertise and resources necessary for me to carry out this proposed work. Between Dr. Chen’s mentorship and both academic and career support from the Johns Hopkins Department of Biology, I am confident I will have a successful doctoral research career and my findings will contribute to the NIH’s public health goals as well as benefit the broader scientific community.

NIH Research Projects · FY 2026 · 2026-03

Summary More than 1.8 million people worldwide are diagnosed with non-small cell lung cancer (NSCLC) every year. Of these patients, 20% present with stage I or II disease. For these patients, neoadjuvant immune checkpoint blockade is now standard of care. However, even in apparently curative surgery, >40% of patients treated with this regimen will experience disease recurrence and will eventually die of the disease. Under the parent R37 award, we used whole exome sequencing, neoantigen predictions, functional assays, and single cell transcriptomics to identify transcriptional signatures of tumor-reactive TIL that were associated with response and resistance to neoadjuvant ICB. These signatures allowed us to develop a 3-gene score, called ‘MANAscore’, that can identify tumor-reactive TIL with high specificity and sensitivity from single cell transcriptomics alone, without the need for cumbersome functional assays. We also identified two dichotomous Treg subsets: a CCR5+ Th1-like subset that was associated with response, and a highly immunosuppressive subset, characterized by high OX40 expression, that was associated with resistance5. Intriguingly, tumor-reactive TIL expressed high levels of OX40L, thus hinting at the possibility of direct interaction between tumor-reactive TIL and this highly immunosuppressive Treg subset. However, this is not something that can be deciphered using single cell transcriptomics of live cell suspensions; it must be resolved spatially. Moreover, it is unclear if the underpinnings of pathological response that we identified in the parent award are the same mechanisms that promote long-term disease remission after surgical resection. In this R37 extension, using the same patient cohort, we will build on our discoveries from the parent award to optimize and apply MANAscore to spatial transcriptomics (sMANAscore) of resected lung tumors. This will allow us to discover and validate spatial interactions between pTRC and our Treg subsets of interest that are associated with disease recurrence after neoadjuvant ICB. Identification of targetable markers of disease relapse, development of novel bioinformatic approaches to analyze spatial transcriptomics data, and enumeration of immunogenomic determinants of disease relapse or remission are only some of the key outcomes of this study.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY The long-term goal of my laboratory is to elucidate the mechanisms that control mechanotranduction in hair cells, and the defects in this process that cause deafness. We propose here to study the mechanisms by which mechanical force regulates the activity of the mechanotransduction complex of hair cells. We hypothesize that several proteins that are linked to deafness, including TMIE, LHFPL5, TMC1/2, and CIB2 assemble into a mechanotransduction complex in hair cell stereocilia. We predict that the multimeric nature of the MET-channel complex is critical to establish the sensitivity of this ion channel to mechanical stimulation. We hypothesize that some proteins of the MET-channel complex couple the pore-forming channel subunits to the tip link, while others act by different mechanisms such as to regulate protein:lipid interactions. To test our hypothesis, we will use genetically modified combined with biochemical, cell biological and electrophysiological methods to study protein function in mechanotransduction. Our preliminary data show the feasibility of our approach. We have new evidence regarding the structural determinants and mechanisms by which components of the mechanotransduction machinery function to regulate the transduction process.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) is a debilitating condition characterized by intense type 2 inflammation of the paranasal sinus mucosa. A subset of eCRSwNP, including many patients with comorbid asthma and aspirin-exacerbation, can be particularly recalcitrant to medical and surgical treatment. Type 2 cytokines derived from innate and adaptive immune cells are responsible for most of the epithelial pathologic features in eCRSwNP. Dupilumab, a human monoclonal antibody to the IL-4 receptor alpha subunit, has been approved for use in eCRSwNP since 2019. The effectiveness of dupilumab for nasal polyps strongly implicates IL-4/IL-13 signaling as critical to CRSwNP pathogenesis, but the mechanism of disease recidivism when the antibody therapy is discontinued remains unknown. In this proposal, our central hypothesis is that a chronic type 2 inflammatory environment in eCRSwNP results from ongoing expression of IL-4 and IL-13 by CD4+ resident memory T cells (Trm), arising locally from memory-like Th2 progenitors. This premise is supported by evidence from flow cytometry and single cell RNA sequencing studies. At this time, the spatial location of these cells in polyp tissue has not been demonstrated. We hypothesize that while the clinical features of the eCRSwNP derive from the effects of IL-4/IL-13 receptor signaling on the epithelium, the ultimate basis of eCRSwNP resides in the ongoing dysregulated expression of type 2 cytokines by T cell populations residing in tertiary lymphoid structures. In aim 1, we will use spatial proteomic and transcriptomic methods to identify the IL-13-producing cells in their cellular neighborhoods, characterizing the cell types contributing to tertiary lymphoid structures and the cell-cell interactions that may provide upstream signals driving the disease. In aim 2, we propose to leverage the opportunity provided by patients receiving dupilumab therapy to gain further insight into upstream pathways though a transcriptomic approach. We will investigate differential gene expression within TLSs in the microenvironment of IL-13-producing Trms, identifying networks of stromal and innate immune cell populations driving IL-13 production under dupilumab treatment. In total, these studies will significantly advance current knowledge about type 2 inflammation in the nasal mucosa and will create an opportunity to develop innovative and potentially more durable therapies for eCRSwNP.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY This new R21 application focuses on extending our work on the neuronal membrane proteasome derived peptides (NMP-peptides)1-7 and their link to peripheral neuron crosstalk and regulation. In this proposal, we present new data describing NMP-peptides presence and function on DRG neuron signaling in the PNS. In our previous studies using central nervous system (CNS) neurons, we developed new tools and protocols to purify, identify, and test specific NMP-derived peptides.2,4,5 In the peripheral nervous system (PNS), we made the important discovery that NMPs are expressed only on a subset (Mgpra3+ and Cystlr2+) of somatosensory DRG neurons.7 Using approaches developed for our CNS studies, we have found a preliminary set of NMP-peptide sequences that can lead to modulation of neuronal signaling in diverse populations of naïve DRG neuronal subtypes, including those that do not express NMPs. Taken together, we now hypothesize that specific NMP- peptides mediate ‘crosstalk’ between sensory DRG neuron subtypes (NMP(+) and NMP(-)) to induce downstream changes in neuronal signaling. Consistent with our hypothesis, we demonstrated that inhibition of NMPs modulate cell autonomous and cell non-autonomous responses to stimulation between DRG subtypes.7 In this proposal we aim to test our hypothesis in the PNS, using proteomics, calcium imaging, and single cell RNA sequencing studies with the following expected outcomes: 1) Identify sequences of PNS NMP-peptides following distinct stimuli; 2) Determine which NMP-peptides actively stimulate specific DRG subtypes; And 3) Show the NMP-peptide induced sensory neuron-specific transcriptional changes. Our goal with this application will be to reveal the actions of NMP-peptides in the PNS and provide a foundation for further studying this novel mechanism of crosstalk between sensory neurons that we have shown is critical for sensory behaviors such as touch and pain.7 NMP peptides offer a new opportunity in this area of DRG crosstalk and this R21 is foundational as a first of its kind investigation in NMP peptides and PNS function. To attain our goal, we will focus on the mouse DRG sensory neurons which has a variety of tools for evaluating the details of cell type specific biochemical, cellular, and calcium signaling changes. Specifically: Aim 1. To define and classify the stimulus induced NMP-derived peptides from DRG neurons, to test our working hypothesis that NMP expressing DRG neurons produce NMP-peptides following specific stimuli (depolarization or pruritogen stimulation). Aim 2. To study and identify the NMP-peptides that activate DRG neurons, to test our working hypothesis that active NMP-peptides have unique signature sequence and stimulate distinct subsets of DRG neurons. Aim 3. To determine the DRG-specific transcriptional programs stimulated by active NMP- peptides, to test our working hypothesis that NMP-peptides work to drive new downstream transcriptional changes in diverse populations of DRGs. This will begin to define a mechanistic link between specific NMP- peptides and the downstream autonomous and non-autonomous regulation of DRG subtypes.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Cardiac valve and arterial wall calcification are associated with a 3- to 4-fold increased risk of all-cause mortality and catastrophic cardiovascular events such as myocardial infarction and stroke. A number of factors and disease processes predispose to ectopic and vascular calcification, including aging, hypertension, diabetes, and chronic kidney disease. Given the overall aging population and the increasing incidence of these common and chronic conditions, it is imperative to delineate the underlying mechanisms of pathological calcification to better understand inciting events and develop new treatment strategies. Ectopic calcification, once considered passive precipitation of calcium and phosphate, is now recognized as a consequence of dysregulated extracellular ATP metabolism with a reduction of the pyrophosphate/inorganic phosphate ratio. Prior work investigating Mendelian calcification disorders has helped elucidate these mechanisms. By exploring genetic modifiers of these rare conditions, we have the opportunity to discover and leverage potent therapeutic strategies for monogenic, common, and complex presentations of ectopic calcification. Biallelic variants in ABCC6 typically cause pseudoxanthoma elasticum (PXE) which is characterized by elastic fiber calcification in the skin, eyes, and vessels, causing skin laxity, central vision loss, and peripheral arterial disease in the third to fourth decade of life. Interestingly, in approximately 10% of cases, these ABCC6 variants result in generalized arterial calcification of infancy (GACI), a much more aggressive disorder characterized by occlusive arterial calcification causing myocardial infarction, stroke, and death in 50% of patients by 6 months of life. There is no evidence for a genotype-phenotype correlation nor known environmental determinants of disease severity. This striking clinical dichotomy strongly supports the existence of unknown genetic modifiers. To test the central hypothesis that genetic modifiers contribute to this phenotypic variability, an established Abcc6 mouse colony, biobank of patient DNA and cell lines, purine metabolomics, CRISPR gene editing, and computational genomics, will be employed to explore the following specific aims: 1) Determine how genetic background modifies the calcification phenotype in Abcc6-/- mice; 2) Distinguish ABCC6-related phenotypes in vitro to discover and validate potential modifiers; and 3) Identify candidate modifiers in patients with biallelic ABCC6 variants. These studies will define and validate one or more genetic modifiers of the ABCC6-associated calcification disorders PXE and GACI in mice and humans and expose new therapeutic targets to be further investigated in both rare and common calcification disorders.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Sexual agency among adolescent girls and young women (AGYW), or an individual’s ability to make decisions about engaging in sexual activity independently, fully informed, and free from coercion, has become a topic of interest in sexual and reproductive health and rights. However, readiness to initiate sexual activity, itself a reflection of sexual agency, has been less studied. To advance the understanding of sexual readiness, its causes, and associated sexual and reproductive health (SRH) outcomes in low- and middle-income countries (LMICs), this study will explore the cross-cultural applicability of a measure of sexual readiness, examine its social determinants, assess its predictive value on SRH outcomes across LMICs, and evaluate the adaptation of the measure in humanitarian settings. Specifically, Aim 1 analyses will examine the construct of readiness at sexual debut Sub-Saharan Africa (SSA), identify profiles of adolescents’ readiness at sexual debut, and compare the measures of age at sexual debut and readiness in predicting SRH outcomes. Using Performance Monitoring for Action (PMA) surveys with national longitudinal data about fertility and contraceptive behaviors among women ages 15-49 in five SSA countries, this analysis involves using latent class analysis to identify readiness profiles and assess their predictive effect on subsequent SRH outcomes. Secondly, using multilevel structural equation models, Aim 2 analyses will examine the association between social norms, individual attitudes, and sexual readiness as well as the association between sexual readiness and SRH outcomes and the moderating role of social norms. Finally, Aim 3 analyses will adapt this research and model to humanitarian settings with data on marriage and SRH outcomes among AGYW from the “Early Marriage and Fertility Decision Making Among Conflict-affected and Displaced Adolescents in Bangladesh and Yemen” (EMEC) study. Using multilevel multivariate logistic regression, the analysis will evaluate the influence of social norms on adolescents’ readiness in marriage in humanitarian settings in South and Western Asia and examine the effect of readiness in marriage on subsequent SRH outcomes and the moderating role of social norms. To support this dissertation research, the applicant has brought together a group of faculty with extensive subject-matter and methodological expertise related to the research proposal to serve as her mentorship team, led by Dr. Caroline Moreau. The training plan includes coursework, research, conferences, and other opportunities that will deepen the applicant’s conceptual understanding and subject matter expertise in adolescent SRH and social norms, strengthen her advanced methodological skills in statistics, including structural equation modeling, and expand her research experience addressing SRHR issues in humanitarian contexts. This research aligns with the NICHD 2020 Strategic Plan to “characterize typical and atypical physical, social, and emotional development in adolescence”. This training plan and research project will enable the applicant to build the skillset critical to becoming an independent researcher with expertise in applying a life course framework to issues of adolescent development and SRH.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY / ABSTRACT Specific Aims: This proposal aims to identify opportunities to improve the prevention and mitigation of risks associated with cognitive impairment among people aging with HIV. Aim 1 will estimate the proportion of cognitive impairment cases potentially attributable to psychosocial and behavioral risk factors to prioritize those, which if intervened upon, could hypothetically result in the greatest prevention of cognitive impairment. Aim 2 will determine whether cognitive impairment increases the risk of losing one’s durable (sustained) viral suppression so we may mitigate this adverse outcome. Significance: As people with HIV (PWH) live longer due to treatment advances, they face a growing burden of age-related conditions, including cognitive impairment. PWH experience higher rates of cognitive impairment than people without HIV despite widespread viral suppression, which implicates non-HIV-related factors in their cognitive risk. Focusing on psychosocial and behavioral risk factors, which are prevalent in PWH and causally linked to cognitive impairment, can help to prioritize fruitful prevention strategies. In addition, cognitive impairment may threaten the durability of viral suppression, which could hinder cognitive maintenance and prevention of HIV transmission. Considering these issues in tandem can inform preparations for the long-term healthcare needs of people aging with HIV. Approach: These aims will leverage the Multicenter AIDS Cohort Study (MACS) (Aim 1), which includes 10 years of longitudinal cognitive screening data, and the Johns Hopkins HIV Clinical Cohort (JHHCC) (Aim 2), an urban cohort of PWH with rich clinical data. In Aim 1, we will estimate population attributable fractions for incident cognitive impairment, using longitudinal data and methods to account for time-varying risk factors, censoring, and competing risks. In Aim 2, we will employ a longitudinal closed cohort design to estimate the risk ratio for loss of durable viral suppression in PWH by cognitive impairment status. Training Information: The proposed research encompasses the dissertation of Madeline Brooks, a PhD student in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health. The training plan consists of coursework, mentorship, and professional development to support the successful completion of these aims and prepare Ms. Brooks to become an independent research epidemiologist. These aims address priorities of the NIH Office of AIDS Research to address the role of non-infectious comorbidities in central nervous system complications and subsequent implications for HIV transmission.

NSF Awards · FY 2026 · 2026-02

The equivalence principle (EP) states that all massive objects fall at the same rate in a given gravitational field. This idea can be tested by measuring the difference in acceleration of two freely falling objects. Since the EP is the foundation of general relativity, our most precise theory of gravity, EP tests probe the relationship between gravity and the other fundamental forces. In addition, EP tests are sensitive to the existence of new particles that could comprise “dark matter,” the matter of unknown composition that has been observed in astronomical data but has not yet been detected in the laboratory. In this project, the PI and team will perform an EP test by measuring the difference in acceleration between two atomic isotopes in an ultracold atom cloud. The positions of the atoms as they fall will be read out with high precision. The experiment will use recent advances in quantum science to reach a higher accuracy than previous EP tests, providing the most stringent searches for new gravitational physics, new long-range forces, and leading dark-matter candidates. In addition, this program will provide opportunities for students to learn the experimental techniques of modern quantum science and will support a summer school on quantum sensing and precision measurement. To carry out this measurement, the research team will produce an ultracold atom cloud containing two isotopes of ytterbium, an alkaline-earth-like atom. The ytterbium atoms will be optically launched into an atomic fountain, where they will interact with a sequence of laser pulses to measure their accelerations as they freely fall. The laser system will be designed to enable hundreds of atom-light interactions, greatly increasing acceleration sensitivity, while avoiding atom loss and unwanted forces from the light pulses themselves. The team will characterize and control systematic effects from many sources, including gravity gradients, magnetic fields, black-body radiation, and the rotation of the Earth. After characterizing systematic effects, the results of the differential acceleration measurement will be analyzed to discover or set constraints on new gravitational physics and dark matter candidates. 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 · 2026-02

Project Summary/Abstract: Small-vessel-disease related vascular cognitive impairment and dementia (VCID) represent the second leading cause of cognitive dysfunction in older individuals. Small artery abnormalities have been assessed using surrogate markers such as cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and arterial transit time (ATT). However, post-mortemly it has been shown that VCID hallmarks such as white matter hyperintensities (WMH) are more associated with small vein pathologies such as stenotic or tortuous veins. However, few studies have examined in vivo venous hemodynamics in small vessel disease, due to a scarcity of available tools. Importantly, venous transit time (VTT) provides unique information about venous vessel function and represents an important candidate biomarker in small vessel disease. VTT denotes the time it takes for the water molecules to travel from the exchange site, typically the capillary bed, to draining cerebral veins, e.g., superior sagittal sinus (SSS). The central goal of this application is to develop and validate a novel non-contrast MRI technique, dubbed Venous transit time Imaging by Changes in T1 Relaxation (VICTR), to measure VTT in the brain and to conduct the first clinical application of VTT in VCID. This technique is based on the notion that, when water molecules are exchanged from the tissue into the veins, they will experience a transition in T1 relaxation time. Therefore, by measuring the T1 recovery curve of MR signals in the vein, one can estimate the time at which the transition took place. Our preliminary studies revealed excellent feasibility and sensitivity of the proposed technique. Our new preliminary data collected during the resubmission period also demonstrated the associations of VTT with vascular risk factors and white matter hyperintensities (WMH). This project has three Aims. Aim 1 will develop a non-contrast technique, VICTR MRI, to quantitatively evaluate VTT. We will conduct VTT measurements in several clinically important veins, including superior sagittal sinus (SSS), straight sinus (SS), internal cerebral veins (ICV), the vein of Galen (GV), basal veins of Rosenthal (BV), and internal jugular veins (IJV). VTT measurements in these veins will provide a comprehensive assessment of venous hemodynamics in different brain regions, based on their respective draining territories. Aim 2 will conduct validation, verification, and multi-vendor harmonization of VICTR MRI for VTT assessment. We will test the sensitivity of VICTR MRI to VTT increase (using caffeine ingestion) and VTT decrease (using CO2-inhalation). We will validate VICTR MRI with contrast-agent-based bolus-tracking MRI. We will also harmonize VICTR MRI across major vendors of MRI (General Electric, Philips, and Siemens), making VICTR MRI a scalable technique. Aim 3 will conduct clinical application of VICTR MRI in small-vessel- disease related VCID. We will compare VTT between cognitively normal controls and impaired patients, and examine the associations among VTT, cognitive function, WMH, and Alzheimer’s biomarkers.

NSF Awards · FY 2026 · 2026-02

Color is essential to communication, identification, and technology, yet most manufactured colors rely on chemical pigments and dyes that fade over time, generate waste, and require environmentally harmful processing. In contrast, many natural systems produce color through precisely organized microstructures that interact with light, creating vibrant and durable effects without chemical colorants. However, manufacturing such microstructure-based color in scalable, customizable ways remains a major challenge, particularly for additive manufacturing technologies that are widely used for rapid prototyping and distributed production. This project seeks to establish new scientific principles for producing durable, tunable color directly during additive manufacturing by controlling how microscopic material structures form on printed surfaces. Rather than depositing multiple colored materials or using chemical dyes, the approach enables color to emerge from physical structure alone. This capability would reduce material waste, simplify manufacturing systems, and expand the functionality of additively manufactured parts. The project supports national priorities by advancing manufacturing efficiency, strengthening domestic innovation in advanced materials, and enabling new capabilities for applications such as secure identification, sensing, energy-efficient displays, and adaptive surfaces. Educational and workforce development activities will train students and researchers at the intersection of manufacturing, materials science, and data-driven design, while outreach efforts will broaden participation in emerging areas of functional materials and advanced manufacturing. The overall goal of this project is to enable programmable structural color in additively manufactured materials by directing microstructure formation during material extrusion and curing. The research is guided by the hypothesis that printable inks can be engineered so that macroscopic shape formation and microscopic particle organization occur simultaneously, allowing optical functionality to emerge during fabrication rather than as a post-processing step. Achieving this requires understanding and controlling non-equilibrium assembly processes at material interfaces under flow, external fields, and evolving material properties. The research plan integrates experiments, theory, and data-driven modeling to resolve how rheology, particle interactions, and external stimuli govern surface microstructure evolution. Specific aims are to: (1) characterize the coupled effects of material flow and curing on surface microstructure formation during extrusion; (2) determine how electrically and thermally mediated interactions can be used to direct particle organization for tunable optical response; and (3) develop real-time feedback strategies that adapt processing conditions to achieve target optical properties on demand. Success will be demonstrated through controlled reflectance across the visible spectrum, improved angular color stability, and reproducible microstructural ordering across printed surfaces. The outcomes will establish generalizable design rules for coupling additive manufacturing with directed microstructure formation, advancing the broader fields of manufacturing science, soft matter physics, and functional materials. 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 · 2026-02

ABSTRACT IdenƟfying Alzheimer’s disease (AD) in its presymptomaƟc stage can allow early intervenƟon and improve paƟent care. Crucially, the AD-induced amyloid/tau pathology is not limited to hippocampal insult or memory loss, but also impairs /disrupts funcƟonal connecƟons that integrate sensory inputs in the cortex. As these sensory deficits often precede the decline of cogniƟve funcƟon in AD paƟents, understanding their characterisƟc altered funcƟonal connecƟvity and neural hyperacƟvity patterns early in the AD cascade has the potenƟal to yield new diagnosƟc biomarkers or therapies. Similarly, blood flow decline and endothelial dysfuncƟon posited by the vascular hypothesis of AD remains underexplored. While the availability of transgenic AD mouse models has created a unique platiorm for invesƟgaƟng how AD pathogenesis can disturb the neurovascular unit (NVU), design limitaƟons of imaging hardware, e.g. bulky PET, MR or SPECT, that are not developed/opƟmized to probe AD onset, make it unfeasible to image AD pathogenesis at the spaƟal scale of the NVU. Specifically, AD insults the NVU on mulƟple fronts including neural, vascular/blood flow change that span from neurons to cortex-wide brain acƟvity changes, which are modulated with uneven sleep cycle fragmentaƟon/disrupted circadian rhythms. In contrast, preclinical imaging methods are restricted to short duraƟons (< 2 h) due to anesthesia use when imaging a small animal AD model with a device >1000× in size (e.g. PET), and even the state-of-the-art AD studies assess AD-inflicted NVU change only once in every 1-2 months, which substanƟally under-samples the Ɵme course of AD onset. Moreover, since no two brains age the same, subject-specificity can also mask AD-related NVU changes when imaged intermittently. Therefore, new imaging technologies that can generate large neuroimaging datasets and covering mulƟple temporal (days-months), spaƟal (neurons-whole cortex), and modal (neural-vascular) scales are needed to characterize the “funcƟonal fingerprints” of cortex-wide NVU disrupƟon during AD onset. Therefore, we are proposing the development of NeuroCube, which is a miniaturized microscope that will enable mulƟmodal, cortex-wide in vivo imaging >30 days during AD onset in mice. Unlike extant microscopes that lack capacity for long-term operaƟon (<3 h), we will use 3D-prinƟng and fabricate NeuroCube as a robust unit for longitudinal imaging amidst the harsh, jolty condiƟons in an animal enclosure (Aim 1A). To avoid photobleaching, we will use low-light levels, obtain images at low-signal-to-noise raƟos (SNR)/resoluƟon (50 µm), and recover high-SNR/resoluƟon (10 µm) images via a deep learning (DL) backed generaƟve adversarial network (GAN) (Aim 1B). To limit oversized data volumes, we will image in 1-min bursts (0.75 GB) per hour, and curate an imaging dataset that characterize cortex-wide changes of AD, together with gender/age-matched controls (Aim 2). We believe that The NeuroCube and publicly shared in vivo AD datasets will become a vital new tool for the broad AD research community. Moreover, NeuroCubes could be widely useful for interrogaƟng cortex-bound dysfuncƟon in aging and other brain disease.

NIH Research Projects · FY 2025 · 2026-02

Project Summary/Abstract The tongue mediates behaviors fundamental to survival, such as vocal communication and food manipulation. Cerebellar dysfunction disrupts normal tongue muscle activation patterns, leading to significant clinical pathologies in swallowing and speech that severely impact quality of life and can be fatal. Despite this clinical significance, the neural mechanisms of cerebellar tongue control in non-human primates remain largely unexplored, with no standardized behavioral tasks for measuring lingual motor learning in these models. Pathologically, cerebellar dysfunction is characterized by deficits in Purkinje cells (P-cells), the sole output neurons of the cerebellar cortex. P-cells produce two types of action potential: the simple spike, which is their primary output, and the complex spike, which is triggered by climbing fiber inputs to the P-cells. Complex spikes are often in response to error, and are always followed by complete suppression of the simple spikes. Though we know that P-cells sculpt the computational output of the cerebellar cortex, the way in which they enact population-level control of tongue movements remains mysterious. Here, I propose to establish the marmoset (Callithrix jacchus) as a model for cerebellar tongue control. Marmosets present several key advantages: 1) their long and protrusive tongue is easy to track with computer vision, 2) their cerebellum demonstrates developmental alignment with non-human primates while remaining accessible with recording instruments designed for mice, and 3) their survival depends on harvesting tree sap via skilled licks, suggesting robust cerebellar involvement in control of targeted tongue movements. Our recent work in marmosets has yielded a breakthrough: when a P-cell is briefly but completely suppressed by a complex spike, the result is a small displacement which serves as a proxy for that cell's causal contribution to behavioral output. I hypothesize that grouping P-cells by their downstream effects on licking will reveal population-level computations that the cerebellum performs to aid in control of the tongue. However, testing this hypothesis requires mapping downstream effects of P-cell suppression across cerebellar lingual regions, as it is a prerequisite for functional classification of P-cells and subsequent analysis of population-level dynamics during targeted licking. Here, my aim is to first develop an experimental setup that will allow for a wide range of errors during licking, thus driving complex spikes. Next, I will record from various cerebellar lingual regions and use spike-triggered averaging to measure the change in tongue kinematics caused by the complex spike-induced suppression of each P-cell. To test specificity of the effects due to suppression, and not error, I will consider movements in which there was no error, but a suppression occurred. This will test whether downstream effects of P-cells are regionally organized in the cerebellum. Overall, my proposed work will bridge the gap in our understanding of cerebellar control over tongue movements and will aid lingual neuroscience by developing a new non-human primate model in marmosets.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Despite vast economic investments to mitigate the harms of opioid use disorder (OUD), the prevalence of the disorder remains high in addition to an estimated 80,000 Americans dying from opioid-related overdoses yearly. Given the significant heterogeneity across multiple dimensions of OUD, prioritizing investigations of multidimensional phenotypes such as resilience may improve our etiological understanding of the disorder. The goal of the proposed study is to develop a laboratory model of resilience, allowing the objective examination of this construct in a controlled laboratory setting. The outpatient study will employ a within-subjects, randomized design and investigate associations of resilience with opioid-seeking and decision-making behaviors. In addition, this study aims to better characterize resilience in individuals with OUD through a deep multidimensional psychological, cognitive, and affective phenotyping approach. To accomplish these goals, individuals who meet DSM-5 criteria for OUD will be recruited to achieve N=125 completers. The primary aim will be to assess whether Resilience Laboratory Tasks (control, cognitive and emotional flexibility) demonstrate convergent validity with self-reported resilience under stress (Maastricht Acute Stress Test, MAST) and non-stress (non-stress test; NST) experimental conditions. Participants will undergo these two experimental sessions (MAST and NST) in random order. During the sessions, heart rate (HR) and HR variability, blood pressure, and galvanic skin response will be assessed as physiological measures of stress reactivity. Immediately following the MAST and NST sessions, participants will complete self-report assessments of stress (perceived stress, craving, and desire to use opioid), a Hypothetical Drug Purchase Task (proxy for opioid self-administration) and Resilience Laboratory Tasks. This proposal will allow the validation of a novel laboratory procedure to empirically examine resilience and provide preliminary data for the psychological, cognitive, emotional, and behavioral substrates of this construct. Additionally, this K08 proposal will provide critical training needed to achieve my career goal of becoming an independently funded scientist-clinician. Specifically, this mentored award will advance my research career by (1) providing essential training in study design and methodology to evaluate the convergent validity of measures of resilience using human stress paradigms, (2) supporting the development of a valid multidimensional phenotypic assessment battery to characterize heterogeneity across multiple dimensions of OUD, (3) improving my skills in advanced statistical methods and allowing me to develop a fundamental understanding of computational modeling, (4) improving my manuscript and grant record. The training goals outlined in this K08 resubmission will equip me with a unique set of skills in human laboratory paradigms and computational modeling which, in combination with the pilot data collected as part of the proposed research, will make me a highly competitive candidate for future R01 submissions.