University Of Pennsylvania

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Proper neuronal function relies on highly localized calcium (Ca2+) signals. Dysregulation of Ca2+ homeostasis and dynamics lead to a myriad of neurological disorders, including migraines, epilepsy and neurodegeneration. While the role of plasma membrane voltage-gated calcium channels in neuron function is well understood, there is a significant gap in our understanding of how alternative Ca2+ sources influence neuronal physiology. The main intracellular source of Ca2+ is the endoplasmic reticulum (ER). The ER releases Ca2+ through specialized channels, including inositol 1,4,5-trisphosphate receptors (IP3Rs). Previous work has implicated IP3Rs in the establishment of synaptic plasticity, a process that modifies the efficacy of neuronal connections in response to experience. Moreover, mutations in IP3R type 1 (IP3R1), the most abundant IP3R isoform in neurons, are associated with spinocerebellar ataxia (SCA) and Gillespie syndrome, diseases characterized by poor muscle control and cerebellar atrophy. Thus, ER Ca2+ release through IP3R1 seems to be central for maintaining proper neuron function; however, the underlying mechanism remains poorly understood. This proposal aims to define the functional role of IP3R1 in synaptic transmission and plasticity, and elucidate how mutations in IP3R1 alter neuronal function. IP3Rs organize in clusters in the ER membrane. Studies in non-neuronal cells have demonstrated that IP3R clustering facilitates Ca2+ release, indicating that proper IP3R function requires both individual channel activity and proper subcellular organization. This premise may also be true in neurons, given my preliminary data shows that IP3R1 selectively form clusters in postsynaptic dendritic spines that scale with neuron excitability, and IP3R1 mutations that either increase or decrease channel conductance both cause SCA. Thus, in this proposal I will test the overarching hypothesis that postsynaptic clustering of IP3R1 determines the efficacy of synaptic transmission and is necessary for synapse maintenance and plasticity. I will test this hypothesis by first defining the dynamic changes of postsynaptic IP3R1 cluster organization during synaptic plasticity (Aim 1A) and determining if changes in IP3R1 organization are accompanied by changes in Ca2+ release (Aim 1B). I will then determine if proper IP3R1 localization and clustering is necessary for synaptic plasticity (Aim 1C). Furthermore, I will determine the effects of disease-associated IP3R1 mutations on synaptic function (Aim 2A) and attempt to rescue resulting synaptic dysfunction observed in IP3R1 mutants (Aim 2B). This proposal would address fundamental questions regarding the functional significance of IP3R1 organization in determining the signaling strength of postsynaptic spines, at rest and during synaptic plasticity. Moreover, this proposal would elucidate the underlying synaptic mechanisms of a debilitating neurological disease, spinocerebellar ataxia, and identify novel therapeutic approaches.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Adult tissue homeostasis depends on the tightly regulated activity of tissue-resident stem and progenitor cells. With age, this regenerative capacity declines due to impaired progenitor function, contributing to tissue dysfunction and degeneration. One of the most striking examples of this occurs in the hair follicle, a highly regenerative mini-organ that undergoes cyclical phases of growth (anagen) and rest (telogen). Aging disrupts the cycle by prolonging telogen and diminishing the proliferative output of progenitor cells, ultimately leading to follicle miniaturization and hair loss. Despite its clinical relevance, the molecular mechanisms governing progenitor cell activation and maintenance in the hair follicle remain incompletely understood. To address this gap, I performed single-cell RNA sequencing analysis, RNA velocity analysis, and immunofluorescence staining of cycling postnatal mouse skin, identifying SOX5 as a transcription factor specifically expressed in the earliest subset of activated progenitor cells at anagen onset, localized to a key structure known as the secondary hair germ (SHG). Expression then persists throughout the anagen phase within the proliferative lower matrix before becoming undetectable until the next cycle, suggesting a temporally restricted role in activating progenitor cells and guiding their commitment to a follicular lineage. Supporting this, in vitro overexpression of SOX5 in primary human keratinocytes significantly enhances proliferation, pointing to SOX5 as a central regulator of proliferative dynamics during follicular regeneration. Based on these findings, I hypothesize that SOX5 induces anagen and protects the hair follicle against aging by regulating proliferation of the hair matrix cells and directing SHG cells towards a hair follicle lineage fate. In Aim 1, I will determine whether SOX5 is required for SHG activation and sufficient to initiate early lineage specification. I will also evaluate whether SOX5 overexpression reprograms human keratinocytes toward a follicular identity. In Aim 2, I will assess the role of SOX5 in maintaining matrix proliferation and hair follicle structure during aging using a combination of ex vivo human hair follicle organ culture and a transgenic Sox5 overexpression mouse model. By elucidating how SOX5 governs progenitor cell activation and maintenance, this work may uncover therapeutic strategies to restore hair progenitor cell function in aging and hair loss disorders. More broadly, it will contribute to our understanding of how tissue-specific progenitor programs can be leveraged to counteract age-related regenerative decline.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT │ Chronic pain affects approximately 20% of the global population, significantly diminishing quality of life and posing a substantial socioeconomic burden. One of the most debilitating aspects of chronic pain is sleep disruption, which affects up to 90% of pain patients. Poor sleep worsens pain sensitivity and contributes to other health issues, creating a vicious cycle where pain disrupts sleep, and poor sleep exacerbates pain. Recent research has identified key brain regions involved in both pain processing and sleep regulation, particularly the centrolateral thalamus (CL) and anterior cingulate cortex (ACC), which are central to pain perception and sleep maintenance. Dysregulation of these regions in chronic pain may underlie the sleep disturbances experienced by patients. Projections from the CL to the ACC (CL→ACC) are implicated in both pain-related arousals and the affective-motivational aspects of pain. Our R21 study will be led by a collaborative team including Dr. Gregory Corder, an expert in pain biology and neural circuit mechanisms; Dr. Franz Weber, specializing in sleep electrophysiology and closed-loop optogenetics; and Dr. Raquel Adaia Sandoval Ortega, an expert in pain-sleep interactions leveraging electrophysiology, calcium imaging, and deep-learning behavior tracking. This project aims to provide the first direct evidence of how chronic pain disrupts the CL→ACC pathway, contributing to sleep fragmentation and heightened pain sensitivity. We will use advanced techniques, including in vivo calcium imaging, closed-loop optogenetics, and the LUPE deep-learning behavior tracking system, to investigate this neural circuit and assess how its modulation can alleviate both pain and sleep disturbances. Aim 1 will focus on the electrophysiological characterization of CL and ACC activity during sleep and wake states as chronic pain develops. Mice will be implanted with electroencephalography (EEG), electromyography (EMG), and intracranial electrodes targeting the CL and ACC to monitor neural oscillatory activity. Using LUPE, we will analyze pain- and sleep-related behaviors and correlate them with neural dynamics over 24-hour recording periods, mapping how nerve injury alters neural circuits over time. Aim 2 will explore bidirectional modulation of CL→ACC projection neurons using closed-loop optogenetics to either enhance or reduce pain and sleep disturbances in a peripheral nerve injury model. Excitatory and inhibitory opsins will be used to manipulate pain- active CL→ACC neurons, and we will assess the effects of optogenetic modulation on neural activity and behavior through in vivo miniscope calcium imaging of the ACC, alongside behavioral tracking with LUPE. By identifying the neural mechanisms driving pain-induced sleep disturbances, this project aims to uncover the role of thalamocortical nociceptive processes in both pain and sleep. This work will provide the foundation for future grants focused on improving sleep as a strategy to reduce chronic pain, ultimately offering new therapeutic targets and an integrated approach to pain management.

NIH Research Projects · FY 2026 · 2026-03

A universal feature of early development is the transition from maternal to zygotic control. Following fertilization, the embryo is transcriptionally inactive for a defined period in which development is governed by maternal factors. For the embryo to develop further, zygotic nuclei must awaken in the process of zygotic genome activation (ZGA) which culminates in spatiotemporally restricted gene expression patterns that drive cell fate determination. The precise timing of ZGA onset is stereotyped and critical for early developmental transitions. The goal of this research is to elucidate the molecular mechanisms governing ZGA, including how a ‘licensing’ system controls the precise timing of onset. Reduced female reproductive success is a rising global issue; understanding the maternal to zygotic handoff and essential mechanisms that safeguard these early developmental transitions are critical to deciphering its etiology. Pioneer transcription factors, such as those in Pouf and Sox families are required for ZGA. They bind closed chromatin and recruit factors to open it for transcription, and their nuclear accumulation is temporally regulated, rising sharply prior to ZGA. Whether they are sufficient to control ZGA licensing and how their nuclear partitioning drives transcriptional onset are not known. To fill these gaps, we will use Xenopus embryos that undergo a stereotyped spatial sequence of ZGA onset: first in animal pole (AP) cells and later in vegetal pole (VP) cells. These cells are the same developmental age but have different timing of ZGA, providing a powerful system to identify the key factors that govern genome activation. We will test the hypothesis that pluripotency factor nuclear accumulation underlies the spatiotemporally ordered pattern of ZGA. We will measure and manipulate Pou5f3 and Sox3 levels in Xenopus AP and VP cells, and quantify chromatin accessibility and zygotic transcription. These experiments will reveal the extent to which pluripotency factors pattern the major wave of ZGA onset. Multiple distinct repressive mechanisms have been proposed to suppress premature ZGA in early embryogenesis, including histones and immature nuclear pore complexes. We hypothesize a nuclear import competition mechanism suppresses early partitioning of factors that activate ZGA, that histones function as the repressor and that de-repression is mediated by increasing nucleocytoplasm (NC) ratio which repartitions histones to the genome. To test this model, we will use slbp2 mutant zebrafish embryos that contain reduced levels of core histones and vary NLS motif strengths of pluripotency factors. We will measure nuclear enrichment of pluripotency factors and timing for chromatin remodeling and ZGA onset. The major wave of zygotic transcription comprises multiple ZGA control systems, including genes with NC-dependent and timed onset. We will test the hypothesis that Pou5f3 and Sox3 binding predicts NC-dependent but not time- dependent gene expression. This will reveal how zygotic gene expression integrates distinct ZGA regulatory mechanisms for spatiotemporally patterned lineage commitment. Revealing the molecular mechanisms that license ZGA will provide critical new insights on systems that safeguard the fidelity of embryo development.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Data science approaches to classify aggressive tissue phenotypes that impact survival in HPV- negative head and neck squamous cell carcinoma (HNSCC) Head and neck squamous cell carcinoma (HNSCC) is a potentially fatal disease with a reported 5-year overall survival of 64.5 percent. Despite decades of research into the molecular pathogenesis of HNSCC, researchers have yet to identify reliable prognostic factors to implement into clinical practice to guide treatment decisions beyond conventional TNM (tumor, node metastasis) staging. Efforts to correlate gene expression with aggressive histopathologic phenotypes, such as nodal disease and perineural invasion, have intensified with the increasing availability of sequencing data. However, singular tumor markers such as TP53 mutational status have not proven statistically significant in predicting recurrence or survival. Rather, clinical studies suggest that differences in histopathologic factors may explain differences in survival among patients within the same TNM stage. Consequently, there is a pressing need to elucidate genetic differences between indolent and more aggressive tissue phenotypes in HNSCC. Furthermore, the molecular pathways driving these aggressive tissue phenotypes HNSCC remain inadequately understood, and their presence is analyzed through visual examination alone, a method prone to imprecision and potential diagnostic oversights. To this end, a more precise evaluation method based on molecular data could enhance the detection of adverse histopathologic features that may lead to recurrence and decreased survival. This project aims to delineate molecular variations within tumors based on distinct histopathologic features and employ machine learning techniques to construct a predictive model using molecular data. This model would offer clinicians a more objective means of identifying adverse prognostic tissue phenotypes, potentially leading to improved stratification of patients into low-risk and high-risk groups for disease progression. Secondly, our findings will shed light on the underlying molecular pathways driving different histologic phenotypes that can open new avenues for targeted therapeutic interventions. Using existing data repositories from TCGA and DBGap as well as a multi-institutional cohort of cases (Rutgers, Indiana, Columbia), a key feature of this project is to apply machine learning methods on large-scale molecular data to develop an algorithm that can accurately predict the presence of aggressive disease. Dr. Yingci Liu will lead this research initiative under the K08 award proposal, with the goal of developing expertise in computational genomics and machine learning to establish an independent translational research program in computational genomics and head and neck cancer. Dr. Liu will receive support from a robust, multidisciplinary mentoring team consisting of experts in oncology, machine learning, and head and neck cancer, which includes Dr. Shridar Ganesan, Dr. Antonina Mitrofanova, and Dr. Flora Momen-Heravi.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract Most human diseases are complex, manifesting from an interplay between genes and environment over the lifespan that involve myriad biological processes. Genome-wide association studies have primarily implicated non-coding variation that is thought to lead to disease via disruption of complex, multi-level biological systems. Thus, improvements in our understanding of these fundamental processes underlying disease necessitates studying the relationship between multiple omics (multi-omic) modalities, both longitudinally and in conjunction with non-omic data. While recent years have seen an explosion of studies collecting multi-omic data in human populations, analysis of these data remains challenging both statistically and computationally. Here, I propose several new methods based on correlated latent factor models that will extend the capabilities of multi-omic inference methods to more complex study designs. I will develop model-based imputation methods that allow robust handling of missing data, enabling larger-scale studies of multi-omic biological contexts, and allowing researchers to design targeted multi-omic panels to extract the maximum amount of clinically-relevant information. I will develop multi-omic analysis methods that integrate across tissues and time points, enabling the study of dynamic molecular process and detection of systems-level impacts of intervention or disease onset. Finally, I will develop integration methods based on non-linear representation learning. This will enable detection of complex relationships between omics methods and integration with structured non-omics data such as doctor’s notes and radiographic images. To demonstrate the broad utility of the proposed methods, I will conduct collaborative analyses of varied cohorts. These include a population of individuals with subclinical atherosclerosis (MESA), a study anlyzing the relationship between microbiome features and immune health in the context of the COVID-19 pandemic (ImmunoMicrobiome), and a study of the impact of Alzheimer’s disease on neuroimaging and spinal uid biomarkers (ADNI). Completion of this research program will provide new insights into the fundamental biological processes underlying a host of common conditions, while bootstrapping the larger multi-omics research community by providing new tools that can handle complex study designs and integration tasks.

NIH Research Projects · FY 2026 · 2026-03

Project Summary: Type 1 diabetes (T1D) is a chronic autoimmune disease that affects millions globally, and the incidence of T1D is increasing. Early-life disruptions of the gut microbiome have long-lasting impacts on the risk for developing type 1 diabetes (T1D), yet how the composition of the early-life microbiota contributes to T1D and whether manipulating it can prove therapeutically beneficial remains largely unexplored. To address this gap, we created a gnotobiotic model of the early-life microbiome, composed of a simple consortium of 9 culturable bacteria (PedsCom) that dominate the early-life microbiome of diabetes-protected animals. We found that PedsCom microbes confer protection from developing type 1 diabetes (T1D) in NOD mice. Importantly, PedsCom-mediated T1D protection is dependent on PD-1 signaling, as PD-1 blockade in PedsCom mice abrogates T1D protection. Remarkably, this PD-1-based protection from developing T1D is completely dependent on early-life colonization of NOD mice by PedsCom, thereby demonstrating a critical time window in which specific commensal microbes induce tolerance. The goal of this proposal is to identify mechanisms by which the early-life microbiome can modulate the immune response to inform microbiome-based therapeutics to prevent T1D in high-risk patients. To investigate immunomodulatory mechanisms of early-life microbes, we are integrating the innovative PedsCom gnotobiotic model of the early-life microbiome with key immunologic techniques, including high- dimensional spectral flow cytometry and single-cell RNA sequencing. In Aim 1, I will determine the degree to which PedsCom-induced PD-1+ T cells are anergic, hypofunctional, and islet-autoreactive. In Aim 2, I will establish whether PedsCom enhances PD-1 expression on T cells during specific early-life developmental windows. In Aim 3, I will determine whether specific PedsCom microbes are sufficient to induce PD-1 and restrain T1D in the context of a complex microbiome. During this fellowship, these investigations will diversity and strengthen my technical laboratory skills, expand my ability for experimental design and computational analysis, and enhance my scientific writing and communication skills. I will complete this fellowship at the University of Pennsylvania, in association with the Children’s Hospital of Philadelphia, both of which offer programs, courses, meetings, and structured mentorships that will aid my career development. In addition, I will take advantage of opportunities offered by the Immunology Graduate Group at Penn to improve my abilities as an educator through teaching programs and mentoring younger students. With these resources available, I will investigate the fundamental and clinically relevant questions in this proposal to gain the skills necessary to become an impactful scientist in an academic institution.

NSF Awards · FY 2026 · 2026-03

Bacteria have the remarkable ability to swim upstream. This motion against fluid flows, called rheotaxis, enables bacteria to invade anatomical tracts and biomedical devices. Upstream swimming can lead to conditions including urinary tract infections and the contamination of catheters. This CAREER project will use experiments and modeling to reveal how bacteria can swim upstream against flows, how bacteria can navigate in complex flow networks, and how microbial communities can gain control over their hydrodynamic environments. Importantly, this project will also show how these processes can be controlled and prevented. This work is timely because it is estimated that by the year 2050, microbes will kill more people than cancer. Moreover, this research will elucidate how microbial consortia can help improve soil quality and suppress crop diseases. As such, this project unites the disciplines of microbiology, engineering, medicine, and agriculture. To connect this research with a broader community, the project includes the development of a course about “Culinary Fluid Mechanics and Science Communication,” where undergraduates will teach basic science concepts at high school using live demonstrations that can be performed with affordable kitchen equipment and cooking ingredients. To develop a fundamental and quantitative understanding to predict and control bacterial upstream swimming, this project will combine techniques from biophysics, microbiology, holographic 3D microscopy, nanofabrication, and network theory. The project will: (1) Determine the ability of bacteria to invade upstream in nanofabricated flow networks; (2) Tune multi-species bacterial interactions in mazes with dynamical microgradients; and (3) Uncover the rules governing self-regulation of microbial communities in adaptive flow networks. Hence, this award will unravel how the microstructure of flow networks can promote or inhibit rheotaxis, how cells navigate in biochemical landscapes subject to currents, how bacteria can reshape their hydrodynamic surroundings, and how this knowledge can be used to control bacterial transport. Results from this work can contribute to inhibiting infections caused by bacteria and other pathogens and provide new strategies to stop the contamination of biomedical devices. More generally, the coupling between microbes and flows is essential in numerous applications in the food industry, pharmaceuticals, and biotechnology. 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

PROJECT SUMMARY In this K23 career development award, Dr. Christopher Brown, a cognitive neurologist and Instructor of Neurology at the University of Pennsylvania, will obtain training in integrating advanced imaging and fluid- based biomarkers in clinical research studies of Alzheimer’s disease (AD) and related dementias (ADRD). This project will support his long-term career goal of an independent career using multimodal biomarkers to understand neuropathology propagation and clearance and its clinical manifestations in ADRD. Dr. Brown will benefit from the strong institutional environment of the University of Pennsylvania, and the expertise of his mentorship team, including his primary mentor, Dr. David Wolk, and co-mentor, Dr. Corey McMillan. The advisory team brings additional specialized expertise that will help Dr. Brown meet his training goals to learn: 1) additional skills in clinical research methods and project management in observational longitudinal studies in ADRD, 2) longitudinal analysis of advanced MRI, and 3) biomarkers of neuroinflammation. To obtain these goals, Dr. Brown will receive a combination of didactic and one-on-one training while carrying out a research project examining neurodegeneration and neuroinflammation in the setting of anti-amyloid therapy. Anti- amyloid therapy is associated with robust clearance of amyloid and slowing of cognitive decline, but a lack of clarity of its benefits on downstream aspects of the AD pathologic cascade as well as neuroinflammatory side effects have limited enthusiasm for its use. This study will evaluate two barriers: 1) accelerated brain volume loss associated with treatment, and 2) frequent occurrence of amyloid related imaging abnormalities (ARIA). Participants will be followed over their first year of treatment with FDA-approved anti-amyloid therapy and have additional advanced MRI sequences added to clinical safety MRIs and plasma draws at infusion visits. This minimal additional burden will allow for increased participation in research while receiving treatment. In Aim 1, advanced MRI will be used to evaluate the microstructural alterations driving brain volume loss in the first year of treatment. Based on prior work, this aim will test the hypothesis that reductions in brain volume are primarily driven by decreases in non-tissue components, including perivascular spaces, that are known to increase with higher levels of AD pathology. Aim 2 will evaluate microstructural and perivascular space changes in the setting of ARIA, as well as evaluate alterations in plasma biomarkers of neuroinflammation during ARIA. Finally, Aim 3 will explore how neuroinflammatory response in early stages of treatment influence changes in downstream measures of AD neuropathology at 1 year. The results of these studies will help identify important markers of treatment response, neuroinflammatory and structural alterations associated with ARIA, and further our understanding of the interplay between neuroinflammation and neurodegeneration. Moreover, this project provides the critical training and resources to support Dr. Brown’s successful transition to independence.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract This proposal encompasses a research and training plan that will transition Dr. Jackson from a mentored role to an independent investigator. She is an Assistant Professor of Neurosurgery at the University of Pennsylvania with a background in brain tumor immunobiology. Her long-term goal is to become an independently funded neurosurgeon-scientist with a translational laboratory focused on understanding the immunobiology and immunometabolism of brain tumors to develop novel immune-based therapies against these tumors. Her short- term goals, that will be facilitated through the K08, include gaining technical proficiency in measuring metabolites and metabolic flux in immune cell using mass spectrometry and stable isotope tracing. Furthermore, she aims to develop expertise in advanced gene knockout methods and sophisticated conditional knockout mouse models for preclinical therapeutic testing, with the ultimate aim of translating her findings into clinically relevant trials. Dr. Jackson has chosen Dr. Celeste Simon as her primary mentor and Dr. John Wherry as her co-mentor. Dr. Simon is a renowned expert in cancer and immune cell metabolism and Dr. Wherry is a world leader in T cell biology including the mechanism of T cell exhaustion and immunotherapy resistance. In addition, she has assembled a strong and complementary scientific advisory committee composed of basic scientists and physician-scientists from diverse and complementary fields to support her in her research direction and career development. Dr. Jackson's recent manuscript in Science identified myeloid-derived suppressor cell (MDSC) populations that are unique to glioblastoma (GBM) that drive tumor aggression through immune suppression and direct promotion of tumor growth. Gene and protein expression analyses demonstrated that the most induced cellular programs in MDSCs are dominated by metabolic pathways. Yet it remains unclear the mechanisms of how metabolic processes regulate MDSC functionality. The proposed research focuses on identifying how metabolic reprogramming in these cells drive their function, specifically the role of branched-chain amino acid (BCAA) metabolism. Dr. Jackson hypothesizes that BCAT1, the first enzyme in BCAA metabolism drives metabolic reprogramming of MDSCs to contribute to their function. Thus, she will test whether 1) BCAT1 regulates MDSC differentiation or immunosuppressive function (Aim 1), and 2) BCAT1 in MDSC facilitates their ability to promote GBM tumor growth (Aim 2). Dr. Jackson will leverage her unique role as a neurosurgeon-scientist and the robust research support at University of Pennsylvania to provide valuable insights into these questions. These studies will advance the field of GBM immunotherapy by elucidating the role of BCAA metabolism and BCAT1 in regulating the function of MDSCs. These results will lead to innovative therapeutics targeting the myeloid compartment of GBM microenvironments that can be complimentary and synergistic with immune checkpoint inhibitors. The mentorship and training provided will effectively transition Dr. Jackson to an independent research career leveraging immunometabolism to develop novel immune-based therapies against these tumors.

NIH Research Projects · FY 2026 · 2026-03

SUMMARY The intestinal epithelium displays remarkable spatial organization, with enterocytes adopting specialized functions along the villus axis in a process known as zonation. While conventional wisdom suggests zonation is determined by luminal contents, our preliminary data challenge this paradigm, indicating it emerges as a self-organizing property through local cell-cell interactions. We will investigate this hypothesis using innovative computational approaches and spatial transcriptomics in novel experimental models. Aim 1 will establish computational models of self-organizing zonation by developing and applying our niche- driven coordinated progression model (CoPro) to characterize how local cell-cell interactions drive enterocyte zonation patterns. By integrating spatial transcriptomics with our novel SpaceBar lineage tracing technology, we will decompose intrinsic versus extrinsic influences on cell state, quantifying the spatial length scale of these interactions and establishing causal relationships. Our interpretable linear model will identify the gene programs underlying spatial coordination and reveal principles of self-organization in both 2D enteroids and mouse intestinal tissue. Aim 2 will directly demonstrate zonation as a self-organizing property through spatial perturbation experiments. By inserting enterocytes into non-natural positions in 2D enteroids and tracking their adaptation via spatial transcriptomics, we will determine whether cells adopt zonation patterns consistent with their new spatial location, supporting the self-organization model. CoPro analysis of time-course data will reveal the key genes driving zonation "resolution" and characterize their spatiotemporal dynamics, illuminating the principles governing epithelial self-organization.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Human subjects research with novel neural devices raises unique ethical issues, such as post-trial responsibilities, privacy of brain data, and atypical risks such as changes to personality. To manage the discrepancy between research practices and ethics oversight, in 2018 the NIH added a mandatory neuroethics section to a subset of neuroscience grants in addition to the standard protection of human subjects component. However, despite the unique nature of this requirement, to date there have been no systematic efforts to assess stakeholders’ experiences with and attitudes toward these mandates. This represents both a critical gap and opportunity. Without empirical research evaluating the impact of neuroethics mandates, we risk implementing ineffective requirements, lack the information needed to make useful modifications, and remain unaware of their strengths and weaknesses. Furthermore, given that there is no established pathway nor guidance for investigators to address neuroethics requirements, examining researchers’ experiences offers a valuable opportunity to understand how they devise neuroethics plans as well as barriers they might encounter when implementing them. The overall objective of this short-term R21 exploratory proposal is to assess the impact of mandatory NIH neuroethics guidelines on the ethical design and conduct of brain-related research and to identify effective strategies that investigators have utilized to address neuroethics in their research. This will be achieved through two complementary aims that involve interviewing researchers who have been funded through NIH grants requiring neuroethics sections (Aim 1) and surveying those who review neuroethics components of grant applications (Aim 2). This project directly addresses the broad area of RFA-MH-25-171 (“enhance integration of neuroethics and neuroscience”). The expected outcomes of this two-year exploratory R21 project are a set of multistakeholder perspectives on the impact of neuroethics mandates and recommendations for improving them, an identification of strategies that researchers have utilized to address neuroethics mandates, and a determination of areas of unmet needs regarding resources for addressing neuroethics requirements. Our findings will benefit funders, by providing insights into the impact of neuroethics requirements and recommendations for improving them; researchers, by providing a set of effective strategies that have been used to address neuroethics sections; neuroethicists, by determining areas of unmet need regarding neuroethics resources; and the public, by identifying pathways for enhancing the ethical conduct of neurotechnology research. This project is significant because it has the potential to impact the way that the ethics is integrated and assessed across BRAIN Initiative research and in other scientific endeavors.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Antibiotic resistance is a major global health challenge, leading to 1.14 million deaths worldwide and 2.8 million infections annually in the United States. Infection by multidrug-resistant strains such as methicillin- resistant Staphylococcus aureus have grown by 100% since 1990 and are primarily responsible for these statistics. These pathogens employ myriad strategies to resist antibiotics, including modifying macromolecules that antibiotics target within bacterial cells. One such strategy is the methylation of adenosine 2503 (A2503) of 23S ribosomal RNA by the enzyme Cfr which confers resistance to several classes of antibiotics. A2503 is also methylated by RlmN in Escherichia coli which enhances translational fidelity. These enzymes belong to the radical S-adenosylmethionine (SAM) superfamily of enzymes which contain at least one iron-sulfur (Fe-S) cluster. Both enzymes utilize a methyl-cysteine radical to active the substrate, generating a protein-RNA cross- linked (PRCL) species which undergoes deprotonation and radical fragmentation to yield the methylated product. RlmN methylates C2 of A2503 in the 23S rRNA and A37 various tRNA molecules, making it one of only two known RNA-modifying enzymes with dual specificity. Cfr preferentially modifies rRNA at C8 but can also methylate C2 to generate dimethyladenosine. The project goal is to understand the basis of dual specificity methylation by RlmN and site-selectivity of Cfr. Previous work has demonstrated that mutation of an active-site cysteine results in a stable PRCL species suitable for structural and spectroscopic characterization. The structure of Cfr modifying C8 of an 87-mer rRNA substrate has recently been solved by cryo-EM. We will determine the structure of Cfr modifying C2 by enzymatic synthesis of 8-methyl-adenosine 87-mer (m8A) followed by cryo-EM of the PRCL. This will reveal the basis for site-selectivity and dimethylation activity in this enzyme. The structure of RlmN bound to tRNA has been solved by X-ray crystallography. We propose to solve the structure of RlmN bound to the 87-mer rRNA using cryo-EM. Comparison to the tRNA-bound structure will uncover the basis of the dual specificity will be followed by mutagenesis of Cfr to test these hypotheses. The C8-bound PRCL radical species has been observed in Cfr by EPR spectroscopy but never in RlmN. We will characterize the C2-bound Cfr species by EPR and ENDOR using the m8A substrate to determine if this kinetic behavior is due to the protein environment or the site of modification. These studies will yield fundamental insights into both catalysis and antibiotic resistance mechanisms. This work will be carried out in the laboratory of Prof. Squire J. Booker at the University of Pennsylvania (Penn) and involve collaborations at Penn State University and Northwestern University. Prof. Booker is the preeminent figure in the field of radical SAM enzymology and his laboratory is highly experienced in the proposed methods, making this an ideal training environment. The project will incorporate training in cryo-EM, anaerobic biochemistry, RNA biology, spectroscopy, and kinetics.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT The International Vasculitis Workshop is the premier academic meeting in the field of vasculitis, attracting the world’s leading clinical, translational, and basic science investigators studying this group of rare diseases. The overall objective of the 22nd International Vasculitis Workshop is to bring together biomedical scientists and clinicians, including new investigators, junior faculty, and trainees, who are interested in clinical, translational, and basic science discoveries and the relationship of these results with pathophysiology, genetics/genomics, and biomarkers of vasculitis and development of novel therapies for this fascinating group of organ- and life- threatening diseases. Since the first Workshop in 1988, this biannual meeting has attracted an increasing number of scientists from multiple disciplines and clinicians from many specialties. The Workshop is a unique venue for addressing the clinical and scientific complexities and broad scope of organ involvement that are the hallmarks of the vasculitides, ranging from small to large vessel diseases. Researchers who may otherwise have little opportunity to cross paths, given their varied specialties and geographic locations, are provided with an environment to interact and share ideas. The combination of an aging scientific workforce, increased competition for funding for biomedical research, financial pressures on academic institutions, and shifts in interests among biomedical trainees has led to a steady decline in the number of young MD, PhD, and dual-degree investigators dedicated to careers in hypothesis-based scientific research. These pressures are especially severe for people attempting to build careers studying aspects of rare diseases. It is critical that young investigators have opportunities to present their work at international conferences where they can receive meaningful recognition and feedback, gain awareness of the broader advances in their areas of inquiry, and develop relationships with both junior and senior colleagues that lead to meaningful scientific partnerships. In this R13 grant application, we outline plans to use requested funds to support the active participation of trainees and junior faculty in the 2026 International Vasculitis Workshop to directly advance their career development in the field of vasculitis research with the goals of expanding their interest in the field and providing opportunities for collaboration. The Workshop will also feature an enrichment program to assist trainees and junior faculty in getting the most out the Workshop through i) selection and recognition of outstanding abstracts by young investigators; ii) guided poster tours by experienced investigators highlighting both outstanding science and the interrelatedness of the work; and iii) social networking events to encourage ongoing collaborations and a sense of community in the field of vasculitis. The support of early-career investigators for this activity is an excellent investment in the future of biomedical research in this set of complex diseases.

NSF Awards · FY 2026 · 2026-02

Liquids composed of polymers exhibit unusual flow properties. These liquids contain long, flexible molecular chains that induce surprising behaviors in flow. Even when flowing slowly, they can generate a chaotic motion called elastic turbulence. When flowing rapidly, they can generate another chaotic state called elasto-inertial turbulence. These unusual flow behaviors are seen in common materials such as saliva, mucus and tree sap. They also are observed in advanced manufacturing processes, inkjet printing, energy production, and food manufacturing. Most mathematical models of these flows do not reproduce what experiments show, which limits their use in predicting and controlling polymer liquid flows. This joint project between NSF and UK's EPSRC will combine laboratory experiments, computer simulations, and machine-learning tools to construct models that capture the flow behaviors of polymeric fluids. Results will improve understanding of complex flows, support the development of more energy- and cost-efficient processing technologies, and improve the design of new materials. Undergraduate and graduate students will be trained in fluid mechanics and data science. Computational and data-analysis tools developed in the project will be shared with the scientific community. The proposal aligns with NSF priorities by supporting artificial intelligence/machine learning tools for advanced manufacturing. This project will close long-standing gaps between theoretical predictions and experimental observations of viscoelastic flows. The project will focus on three interconnected goals. First, the team will integrate two-dimensional experiments and simulations to achieve quantitative agreement in statistics, flow structures, and dynamical features. Machine-learning methods will be developed to infer optimal model parameters and to reconstruct polymer stress fields directly from experiments – an essential but historically inaccessible quantity that limits the accuracy of constitutive models. Second, the project will investigate the differences and universality of elastic-turbulent states in flows with streamline curvature and in parallel shear configurations, spanning both 2D and 3D geometries. Third, the project will explore how increasing inertia leads to the transition from elastic turbulence to elasto-inertial turbulence to examine whether these states share underlying mechanisms. Together, these efforts will expand the fundamental understanding of viscoelastic flows, delineate the parameter space in which chaotic flow arises, and generate high-fidelity datasets and modeling approaches that can be applied broadly. The project’s outcomes, including computational tools, improved models, and interdisciplinary training, will strengthen U.S. research capacity in fluid mechanics and support technological advancement in polymer processing and material design. 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 2026 · 2026-02

With support from the Macromolecular, Supramolecular and Nanochemistry program in the Division of Chemistry, Professor Tianquan Lian and a team of Emory graduate and undergraduate students are developing two novel ways to control photoinduced electron transfer (ET) from quantum confined semiconductor nanocrystals (NCs), one of the most important processes in photocatalysis and quantum information science. Quantum confined semiconductor NCs are promising novel materials with potential applications in energy conversion and quantum information science. In this project, the first aim is focused on using polaritons formed by coupling NCs with optical cavity modes as a new way to control photoinduced ET. The second aim is focused on NC Donor-chiral Bridge-Acceptor (D-B-A) complexes for selective transfer of light generated spins using chiral-induced spin selectivity (CISS) effects. The goals of the research are: 1) to advance the understanding of the formation and decay dynamics of polariton states; 2) to directly measure polariton mediated ET in NC-molecular acceptor complexes in cavity and test theoretical models; 3) to develop design principles for NCs with both slow electron spin relaxation and fast ET rates; and 4) to advance the understanding CISS effect in photoinduced ET in NC-chiral bridge-acceptor complexes. Molecular polaritons, formed by coupling the molecular electronic or vibrational transition to a photonic cavity mode have received intense interest in chemistry since the reports that they can provide a novel approach for controlling chemical reactions. The proposed effort is focused on polariton mediated electron transfer because of its potential roles in polariton enabled chemical reactions. The proposed study will provide much needed experimental data to test current models of polariton state dynamics and polariton mediated ET, as well as important insights on how to use cavities to control ET rates for many potential applications. Controlling electron spin states is essential for spintronics and quantum information. Although electron spins can be selectively transferred during transport through chiral materials, this process is not understood at the quantitative level. The proposed NC donor-chiral bridge-acceptor platform represents a new approach to combine photonics with spintronics for potential applications in quantum information processing. The proposed study will lead to the development of design principles for NCs with both slow electron spin relaxation and fast ET rates and advance the understanding of the CISS effect in photoinduced ET in NC-chiral bridge-acceptor complexes. The proposed research program also offers unique opportunities for training graduate and undergraduate students and for integrating research with teaching and outreach activities. 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 2026 · 2026-02

Non-technical Abstract: The current memory technology in the commonly used hard drives is based on ferromagnetic materials that contain Cobalt or Iron. The operating speed limit for these materials is often in the gigahertz (1,000,000,000 Hz) regime. Another class of magnetic material known as antiferromagnets can support memory operation in the much higher terahertz (1,000,000,000,000 Hz) frequency. This project is to designed to realize the switching between the bit 1 and bit 0 memory states in antiferromagnets, and to measure how light converts into electric current in these two-bit states, to enable novel materials for future fast hard drives. Studying these systems will answer fundamental questions about the nature of the memory switching and the photocurrent, and enable their practical use in future faster memory and more efficient light-harvesting applications. Educational work in this project includes outreach activities on a broad introduction of quantum technology to the STEM students and to the general public. Technical Abstract: Since the discovery of giant magnetoresistance, the community has been pursuing more energy-efficient spintronic devices. Antiferromagnets are promising new pathways for developing next-generation low-dissipation technologies. Antiferromagnets, with the advantages of absence of a stray field and terahertz spin waves, are emerging as a new route to control magnetism and engineer memory devices. Antiferromagnets can have smaller independent devices to increase the storage density and faster dynamics in terahertz regime than the traditional ferromagnetic materials. Despite these promising advantages, how to directly detect and control the full switching have been challenging in the bulk materials without a canted moment. Secondly, the photocurrents in antiferromagnets have not been studied extensively due to the domain averaging effect but also exhibit new and poorly understood mechanisms. In this project the research team uses scanning second harmonic generation microcopy to directly detect antiferromagnetic full domain switching. Secondly, the research team detects the photocurrents in antiferromagnets and investigates the light-to-current conversion mechanisms. This project helps to establish the comprehensive fundamental understandings of various aspects of antiferromagnets and the domain switching mechanism and new photocurrent to establish them as new platforms for the spintronic and light-harvesting devices. In the education part, this project raises the awareness of the STEM fields involved for K-12 students. These activities include mentoring graduate and undergraduate students and performing electromagnetism demos onsite for K-12 students and the general public. 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 Stroke education represents a unique opportunity to empower stroke survivors (and caregivers) to promote self- management, augment adherence, and reduce post-stroke healthcare utilization. Despite being a key quality metric for stroke centers, most patient and caregiver education is poorly retained and a common source of dissatisfaction. In fact, most survivors are unaware of the cause of their stroke, their modifiable risk factors, and how to properly respond to future stroke symptoms. Although there is no gold standard, most centers rely on a combination of bedside verbal communication and standardized printed materials. Prior work has clarified that effective and durable educational interventions benefit from engaging content, personalization, accessibility, and low cost/burden. Retention is very poor during the stroke hospitalization, but this can be overcome by promoting ongoing engagement after discharge. To that end, our group developed a web-based educational platform (MyStroke) that leverages the electronic health record to personalize video-based educational content for each stroke survivor. Simple but engaging videos are curated to address each patient's stroke etiology, individualized risk factors, prescribed stroke prevention medications, and post-stroke lifestyle issues. This approach transforms point-of-care stroke education, and integrated nudges reveal opportunities for re-education and re-engagement after hospital discharge to achieve a durable impact. In a recent single-center pilot trial, MyStroke improved patient and caregiver satisfaction and improved key elements of stroke knowledge. The objective of this proposal is to build upon our encouraging preliminary experience and conduct a multicenter randomized trial to evaluate the impact of MyStroke on both patient-centered (stroke knowledge, self-efficacy, satisfaction, quality of life) and health system-centered outcomes (medication adherence and health system utilization). Electronic nudges will leverage principles of behavioral economics (i.e. enhanced nudges) to promote ongoing engagement. Our preliminary data indicate that even bland nudges promote engagement, but here we propose to use both bland nudges and enhanced nudges, such that platform analytics will compare the influence of different nudge types. Use of technology in this context stands to bridge geographic distances, connect stakeholders, and increase access to information, but it important to recognize the potential to exacerbate inequities for elderly patients and those with limited access to technology. Issues of digital engagement will be evaluated to reveal opportunities for platform improvement. The MyStroke platform offers a scalable solution stroke education which imposes no burden on the clinical team due to its reliance on a limited number of input fields which can be harvested from the electronic health record to individualized content for each patient.

NIH Research Projects · FY 2026 · 2026-02

Abstract Duchenne muscular dystrophy (DMD) is a rare childhood onset neuromuscular disease caused by genetic deficiency of the protein dystrophin. DMD is an incurable disease with a devastating impact on patients as a result of progressive weakness, wheelchair confinement, loss of independence/activities of daily living, and ultimately premature death from combined cardiorespiratory insufficiency. The majority of dystrophin gene mutations worldwide are multi-exon, frameshifting deletions that eliminate expression of variable portions of the 79 exon gene into the 427 Kd full length protein isoform Dp427. Dp427 is a cytoskeletal protein primarily composed of three protein folding domains, the largest of which is the rodlike mid-section composed of 24 spectrin-like triple helical repeats. Dp427 is thought to transmit muscle contractile force between the outermost sacomeres and the membrane-spanning proteins of the dystrophin-glycoprotein complex (DGC). Recently, an ultra-rare subset of DMD patients has been found to develop T cell-mediated, treatment-emergent serious adverse events (TESAEs) following systemic gene therapy using AAV vectors encoding miniaturized, ~ 140 Kd recombinant proteins derived from Dp427 by internal deletion. Our preclinical studies, as published in 2019 by Song, et al, Nature Medicine, predicted these TESAEs by virtue of our use of an informative animal model, the German Shorthaired Pointer Muscular Dystrophy (GSHPMD) in which a naturally occurring deletions eliminates peptide epitopes corresponding to the miniaturized versions of Dp427. In this study we also showed that a non- immunogenic alternative AAV vector encoding a miniaturized version of the dystrophin-related protein utrophin was protected from T cell destruction of transduced myofibers by central immunological tolerance towards this “self” protein. In this U01 proposal, we provide a milestone-driven, comprehensive translational and clinical research program to set the stage for a safe and effective alternative for the ultra-rare subset of DMD patients excluded from dystrophin gene therapy trials. We propose innovative, non-invasive physiological and biochemical outcome measures precisely targeted to the underlying pathophysiology of the disease, segmental myonecrosis incited by forceful muscle contraction. The four Specific Aims are structured to yield the highest probability of a successful IND application as the final deliverable, while providing ample information generalizable to therapeutics development for other genetic diseases under the NINDS mission. The proposed IND application will set the stage for a phase 1/2a clinical trial of AAV-microutrophin gene therapy in the ultra- rare subset of DMD patients with N-terminal dystrophin deletions, with results of the trial anticipated to apply broadly to the entire DMD patient population.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT There are developing data that in the hypothalamus neurons that promote sleep are intermingled with neurons that promote wakefulness. Moreover, there is a considerable molecular heterogeneity even within neuronal groups that express the same major neurotransmitter. Thus, new techniques capable of simultaneously detecting both molecular and functional heterogeneity are needed to achieve a new understanding of the neurons involved in sleep and wake regulation. We have proven that single-nucleus RNA sequencing is suitable for this task by clustering cell-based gene expression patterns to determine the molecular identity of cell types, combined with examination of changes in activity regulated genes (ARGs) to determine functional involvement. When we applied this approach to the preoptic area of the hypothalamus, we successfully identified a subset of galanin neurons that were activated during sleep with high sleep drive (high delta power). We now plan to expand this approach to the whole hypothalamus. In our previous study we found that there was increased expression of a particular pyrimidine and of a serotonin receptor during recovery sleep following six hours of sleep deprivation only in the subset of galanin cells activated during high sleep drive. This finding could reveal novel signaling mechanisms for sleep homeostasis. We hypothesize that if these receptor genes are involved in sleep homeostasis, their expression should increase during the period of sleep deprivation, even prior to sleep onset. Thus, in addition to comparing gene expression during sleep with high sleep drive (recovery sleep following sleep deprivation) to low sleep drive, we will compare gene expression between animals kept awake and animals sleeping. All groups will be sacrificed at same diurnal time to remove circadian effects. In addition to detecting changes in gene expression, we propose to measure changes in chromatin accessibility in the same nuclei using the new Multiome assay from 10xGenomics. This will for the first time allow detection of cell-type specific regulatory elements in the hypothalamus involved in sleep, wake, and sleep homeostatic regulation. While this study will address specific and important questions, it will also allow us to provide a single-cell gene expression and ATAC-seq atlas related to sleep regulation that will facilitate the work of other investigators in the field of sleep research.

NIH Research Projects · FY 2026 · 2026-02

Although aphasia remains the most common focal cognitive deficit associated with stroke, affecting 1–2 million Americans, effective targeted treatments are still lacking. Transcranial magnetic stimulation (TMS) shows promise for aiding recovery by focally altering brain activity. However, the lack of a model that adequately explains how the brain’s language network reorganizes after stroke—and how TMS influences that reorganization—has hindered further optimization of this treatment approach. Current TMS strategies often focus on inhibiting the right pars triangularis (rPTr), based on the assumption that excessive right hemisphere activity impedes recovery. However, emerging evidence suggests a more nuanced role for the right hemisphere in aphasia recovery and highlights the complex ways in which TMS of the rPTr impacts language outcomes. This project aims to advance the understanding of post-stroke language reorganization by combining innovative computational and imaging techniques for structural network analysis with TMS to clarify the roles of the rPTr and other brain regions in recovery. Preliminary findings suggest that in individuals with left hemisphere strokes that result in aphasia, the rPTr undergoes changes in network controllability, a network property that facilitates guiding brain activity into specific states. We hypothesize that network controllability is a structural characteristic of brain regions involved in cognitive control of language, which is crucial for optimal language performance in many individuals with post-stroke aphasia. Thus, increased network controllability in the rPTr may reflect its capacity to support cognitive control of language in persons with aphasia. Conversely, when the rPTr exhibits inefficient network controllability, it may hinder recovery, which could explain why inhibiting its activity with TMS often improves language outcomes. This study will explore these concepts through three specific aims. First, we will simulate lesions in brain connectomes to predict how structural brain networks shift after stroke and how these changes correlate with language recovery in aphasia. Second, we will investigate the relationship between rPTr network controllability and response to TMS treatment in a cohort of individuals with aphasia who recently participated in a clinical trial involving TMS targeting the rPTr. Finally, we will conduct a prospective study to evaluate whether directing TMS to individually identified right hemisphere sites with high network controllability enhances language performance compared to rPTr stimulation. These findings aim to refine our understanding of how brain networks adapt after stroke and to develop personalized, network-guided approaches for optimizing TMS in aphasia therapy. Beyond aphasia, this work represents an innovative step toward leveraging individual brain connectivity to improve neuromodulation strategies across neurological conditions.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY A major roadblock to the development of rational HIV-1 prevention strategies is the lack of a suitable primate model in which broadly neutralizing antibodies (bNAbs) can be commonly induced and the molecular, biological and immunological mechanisms responsible for eliciting such responses studied in a reproducible and iterative fashion. Recently, we demonstrated that primary HIV-1 Envs, when expressed by simian-human immunodeficiency viruses (SHIVs) in rhesus macaques (RMs), elicited patterns of Env-antibody coevolution strikingly similar to humans infected by homologous virus strains, leading to neutralization breadth in approximately 20% of monkeys after 1-3 yrs of infection (Science 371:142, 2021). These similarities in bNAb induction between humans and rhesus included conserved immunogenetic, structural and chemical solutions to epitope recognition and precise Env amino acid substitutions, insertions and deletions selecting for antibody affinity maturation. However, to be useful for immunogen design, an outbred model is needed where a much higher proportion of animals develop bNAbs in a shorter period of time so that the model can serve as an iterative guide or “blueprint” for immunogen development. We show in the Progress Report that we have reached this milestone for V2 apex, V3 glycan, CD4bs and FP epitope targets using novel SHIV designs that immunofocus naïve germline B cell responses to canonical bNAb epitope supersites on HIV-1 Env. In this application, we propose to develop this model further by showing that bNAb elicitation by such germline-targeted (GT) SHIVs can be recapitulated by GT-immunogens and that these immunogens can elicit clinically protective antibodies against heterologous tier 2 SHIV challenge. Specific aims are: (i) To isolate rhesus bNAb mAbs targeting V2 apex, V3 glycan, CD4bs, FP and SF epitopes, characterize their breadth, potency, immunogenetics, target epitopes and structural solutions to epitope recognition, and decipher Env-Ab coevolution from germline B cell precursors to mature bNAbs. This will define the molecular roadmap for rhesus bNAb elicitation. (ii) To design new immunofocused, GT-Envs that exhibit enhanced binding to diverse rhesus bNAb UCAs from Aim 1. We will introduce these Envs into new SHIV designs, infect RMs, and assess them for increased frequency of bNAb precursor priming and accelerated rates of bNAb induction. Env-Ab coevolution analysis will then identify candidate prime and boost immunogens to recapitulate bNAb induction. (iii) To downselect lead Env candidates from Aim 2 and conduct an immunogenicity trial in RMs testing the hypothesis that immunofocused, GT-Env trimer immunogens can prime, boost and affinity-mature bNAb responses in RMs to an extent that is superior to conventional Env trimers. We will then challenge monkeys by repeated low-dose intrarectal inoculation with a heterologous tier 2 SHIV to determine neutralization titer thresholds required for sterilizing protection from heterologous virus acquisition.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Metabolic diseases including metabolic dysfunction-associated steatotic liver disease (MASLD) pose a major threat to economic and healthcare systems worldwide. Accordingly, there is a great need for new therapeutic targets and strategies. Abnormal lipid metabolism in the liver is a hallmark of metabolic disease, and the enzyme ATP-citrate lyase (ACLY), which generates acetyl-CoA for lipid and cholesterol synthesis, has emerged as a promising therapeutic target against liver steatosis. To this point, several ACLY inhibitors have been developed and tested in preclinical studies, and one that specifically targets hepatic ACLY, bempedoic acid, has been FDA approved to treat high cholesterol. Despite this progress, it is now appreciated that there are multiple enzymatic routes to generate lipogenic acetyl-CoA that can be leveraged in different contexts. Our published studies and preliminary data across cell lines and mouse models suggest these pathways have specialized functions, including the production of bioactive lipids important for PPARα signaling. Furthermore, emerging evidence indicates that ACLY also contributes to lipid metabolism in the liver via regulation of gene expression to impact fatty acid oxidation. The diverse mechanisms through which ACLY and BPA influence lipid homeostasis in the liver remain poorly understood; yet they are key to effectively deploying acetyl-CoA metabolism inhibitors to combat MASLD. In this proposal, we will investigate the role of ACLY in mediating diet-dependent lipid metabolism, applying spatio-temporal lipidomics, flux analysis, and gene expression analysis to explore how ACLY regulates PPARα- dependent gene expression (Aim 1). We will also examine ACLY-independent functions of bempedoic acid to elucidate how this drug reshapes metabolism and circadian PPARα signaling (Aim 2). We will leverage genetic mouse models, in vivo stable isotope tracing, lipidomics, mass spectrometry-imaging, and compartmentalized ACLY expression to dissect these pathways. The long-term impact of this work will be a substantially strengthened understanding of the mechanisms through which acetyl-CoA is produced and used in the liver to regulate lipid metabolism, toward the goal of developing improved strategies to treat MASLD.

NIH Research Projects · FY 2026 · 2026-02

Molecular Genetic Analysis of the Role of Senescence in Liver Disease Abstract Senescent cells play a critical role in liver injury and regeneration; however, human hepatocellular carcinoma can overcome replicative senescence through lengthening of telomere repeats in cancerous cells. While elimination of senescent cells has been shown to be beneficial in mouse models of hepatic fibrosis, the cell type responsible for this effect has not been identified. Likewise, in contrast to the situation in humans, tumor development in mice is not dependent on re- activation of telomerase function due to the extremely long telomere repeat arrays present in common laboratory mice. To address these limitations, we have developed two innovative mouse models. The first, termed the “SenKiller” mouse, enables cell-type specific elimination of senescent cells from the fibrotic, injured liver. The second, termed “Telomouse”, is the first laboratory mouse with generationally stable human length telomeres. Using these models, we will address critical knowledge gaps regarding the role of senescence in liver disease. In specific aim 1, we will employ the SenKiller mouse to specifically target senescent hepatocytes, cholangiocytes, stellate cells and Kupffer cells for elimination in two models of hepatic fibrosis, in order to determine which senescent cell type is most relevant for the beneficial effects of senolysis. We will also determine the molecular consequences eliminating senescent cells on the neighboring liver cells to gain a true mechanistic understanding of this process. In specific Aim 2, we will employ Telomice to determine the mechanism by which human-length telomeres limit liver repopulation, as well as examine the effects of telomere attrition on tumor initiation. Through the use of these two innovative mouse models, this project will contribute significantly to our knowlege of the impact of senescence on liver biology by: (1) revealing the senescent cell type(s) critical to liver injury, which will provide potential therapeutic targeting pathways, and (2) using the first human-telomere-length mouse model to fundamentally understand how replicative senescence affects the liver during regeneration and hepatic tumor initiation.

NIH Research Projects · FY 2026 · 2026-02

The R00 phase will establish an independent laboratory to complete the planned studies on how Selenomonas sputigena (Ss), a motile oral bacterium strongly associated with early childhood caries (ECC), colonizes tooth surfaces and organizes with Streptococcus mutans (Sm) to promote virulent, spatially structured biofilms. ECC remains a major public health problem driven by biofilm formation under sugar-rich conditions, leading to rampant tooth decay and systemic complications in children. The long-term objective is to identify motility-driven mechanisms of supragingival biofilm virulence that can be targeted to reduce ECC burden. The central hypothesis is that Ss motility modulates early surface colonization and mixedspecies structuring with Sm, generating localized acidogenic niches that exacerbate enamel demineralization. To test this hypothesis, the project will 1) characterize Ss motility in relation to surface colonization and biofilm initiation under conditions relevant to the oral environment; 2) determine the spatiotemporal assembly of S~Sm biofilms and site-specific gene expression using single-cell and in situ transcriptomics integrated with local pH mapping and enamel demineralization readouts; and 3) investigate Ss-mediated colonization, interspecies spatial structuring/omics and biofilm virulence in vivo while assessing strategies that disrupt motility-modulated assembly. High-speed live imaging with quantitative trajectory analysis will define motility and colonization behaviors, while single-cell and spatial transcriptomics will resolve localized transcriptional states and an established rodent caries model will connect spatial organization to disease severity. The expected outcome is a mechanistic framework linking motility to cariogenic function and actionable targets for prevention. In addition, it will provide a platform to study other motile oral bacteria in health and disease, which remain understudied, and position the laboratory for sustained, independent investigation and future R01-level studies.