University Of Minnesota

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited lethal neurodegenerative disease caused by 39- 82 CAG repeats in the ATAXIN-1 (ATXN1) gene. Patients with SCA1 suffer from progressive gait and balance deficits, and severe degeneration of Purkinje cells (PCs) in the cerebellum. There are no effective disease modifying therapies currently available for SCA1, indicating a critical need for better understanding of disease pathogenesis. Studies using limited postmortem brain tissue from patients are complicated by practical and ethical concerns of tissue availability, late disease stage with the loss of neurons, and manipulation. Mouse models of SCA1 have been extremely useful in increasing our understanding of SCA1, but have important limitations due to the inherent species differences as well as genetic modifications, such as overexpression and much longer CAG expansions than seen in patients, needed to model disease. Because of these limitations, we propose to complement studies using mouse models with the investigations of human cells, including models of the human cerebellum. Recent study developed a robust and reproducible protocol to generate human cerebellar organoids from iPSCs. We propose to use this protocol and our iPSCs lines from SCA1 patients and sibling controls to establish a human cerebellar organoid model of SCA1. This human cerebellar organoid SCA1 model will enable us to determine how ATXN1 with CAG expansions commonly seen in patients impacts human cerebellar cells and cerebellar activity, as well as provide a platform to help identify and test molecular targets for intervention.

NIH Research Projects · FY 2025 · 2025-07

Deciphering APOBEC Inhibition: Unraveling Structural Dynamics via Viral Protein and Nanobody Interactions ABSTRACT This research delves into the intricate structural dynamics of APOBEC3A (A3A) and APOBEC3B (A3B) enzymes, key players in the delicate balance between host defense mechanisms and genomic stability. While these enzymes play pivotal roles in defending against viruses and maintaining genomic integrity, their involvement in cancer mutagenesis makes them a double-edged sword, necessitating the development of inhibitors. This project's primary objective is to overcome the impediment of limited structural information, which has been hampering the rational design of inhibitors for A3A and A3B. Aim 1 of this project focuses on elucidating the structures of A3A and A3B when bound to viral inhibitors, specifically, Macacine γ-herpesvirus 11 (McHV-11) and Kaposi sarcoma-associated herpesvirus (KSHV) ribonucleotide reductases (RNRs). Utilizing cryo-electron microscopy (cryo-EM), this aim seeks to unravel the molecular intricacies of APOBEC inhibition evolved through host-virus arms races, potentially paving the way for targeted therapeutics by comprehensively understanding the host-virus interaction. Aim 2 expands the investigation to novel alpaca-derived nanobodies exhibiting inhibitory activity against A3A and A3B. Employing a tailored approach and introducing a large protein scaffold to enhance imaging resolution, this aim seeks to uncover unique mechanisms of APOBEC3 inhibition. By mapping the A3-nanobody binding interface, this study intends to engineer these nanobodies for improved binding, with the ultimate goal of creating potent and specific A3-targeting degraders. This proposal seeks to bridge existing knowledge gaps regarding the structures and inhibition mechanisms of A3A and A3B. By advancing our understanding of these crucial enzymes, this project aims to facilitate the rational design of A3A/B inhibitors, which will mitigate their mutagenic effects in cancer cells to slow tumor evolution and enhance the efficacy of cancer treatments.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY Gene therapy provides a universal therapeutic option for patients with genetic or acquired disorders that can potentially benefit a broad patient populations. However, up to date several gene therapy clinical trials for lung- specific diseases, while well addressing safety concerns, have failed to demonstrate clear therapeutic benefits among the participated patients. This dismal reality is most likely attributed to the inability to achieve clinically- relevant gene transfer efficacy in the airway epithelium, and particularly to airway basal stem cell or basal cell. Recently, we have demonstrated the ability of AAV serotype 6 (AAV6) vectors to achieve widespread and efficient transgene expression in the human airway epithelial cell (AEC) in in vitro and in the mouse models in vivo. Importantly, subsets of the lung cell, such as basal cells, were targeting that provides anticipation for possible long-term gene expression in highly renewable layer of airways. Additionally we showed in our most recent published collaborative studies higher transduction efficiency over commonly used AAVs by extracellular vesicles associated AAV (EV-AAV) to the mouse lungs and human AEC cultured in air-liquid interface conditions. The large cargo of average EVs (100-200 nm) allows accumulation of multiple AAV particles (20-25 nm), and, unlike AAV, EVs enter cells multiple by ways that do not depend on receptor abundance. These important findings lead to the development of current proposal that combines non-invasive in vivo imaging with post-necropsy analysis of AAV-mediated gene expression in subpopulations of airway cells in non-human primates (NHP) model. NHP models play a critical role in feasibility and safety modeling for the development of therapeutics. The mechanistic underpinning is expected to provide critical information for the design of next-generation gene therapy vectors targeting lung, which can be used for wide range of pulmonary diseases required reliable expression of therapeutic modalities across airways.

NIH Research Projects · FY 2025 · 2025-06

There is strong evidence that changes in the primary aging hallmark of genomic instability, especially the accumulation of DNA damage and the resulting DNA damage response (DDR) signaling cascade, leads to changes in other hallmarks of aging, including cellular senescence, inflammation, epigenome, proteostasis, dysbiosis, and mitochondrial and stem cell dysfunction. Thus, there is a clear need to be able to quantitate and characterize the extent of DNA damage and DDR signaling comprising a key primary hallmark of aging and to quantitate DNA repair activity. The goal of this Minnesota (MN) Nathan Shock Center of Excellence on Genome Integrity and Aging (MN NSC) is to provide access to cores with the ability to accurately measure specific endogenous DNA adducts reflecting oxidative and metabolic stress in genomic DNA, the signaling associated with the DDR, including markers of senescence, and the extent of DNA repair activity as well as measure certain DNA methylation epigenetic changes associated with DNA damage and age. Also, the MN NSC will provide access to murine and human cells and tissues and mice with reduced DNA repair capacity and increased DNA damage, senescence and other hallmarks of aging. In addition, the MN NSC will provide access to mouse models with accelerated DNA damage for testing of agents for their ability to reduce DNA damage and/or the effects of DDR on other aging hallmarks. To accomplish this, the MN NSC will leverage existing resources and strong institutional support within the new UMN Institute on the Biology of Aging and Metabolism (iBAM) as well as the University of Minnesota (UMN). The MN NSC and the Administrative and Program Enrichment Core (A/PEC) A are co-directed by Drs. Paul Robbins and Laura Niedernhofer, Co-Directors of iBAM, both recognized experts in DNA damage, senescence, inflammation and aging and with a strong track record in mentoring young investigators. The Research Development Core B (RCD) is co-directed by Drs. Paul Robbins (UMN) and Doug Mashek, who directs a UMN graduate program and is working on the novel role of lipid droplets in regulating DNA repair and senescence. The DNA Damage and Epigenetic Changes Core C is co-directed by Drs. Natalia Tretyakova and Peter Villalta, providing quantitative and reproducible mass spectroscopy approaches for accurately measuring oxidative DNA lesions and methods for measuring DNA methylation changes that occur following DNA damage. The DNA Damage Signaling and Repair Core D is co- directed by Drs. Revelo and Elizabeth Schmidt, providing CyTOF single cell analysis of DNA damage, DDR signaling and senescence at the protein level in single cells and measuring DNA repair capacity in primary cells. Finally, the Models of Genome Instability and Aging Core E, directed by Drs. Laura Niedernhofer and Christina Camell, will provide mouse and human cells and tissues deficient in different key DNA repair proteins as well as access to mouse models of accelerated DNA damage, senescence and aging for drug testing.

NIH Research Projects · FY 2026 · 2025-06

Project Summary/Abstract: Ransomware attacks are devastating human-made disasters that increasingly afflict the health care sector. From 2016 to 2023, the number of ransomware attacks in health care increased nearly five-fold. During a ransomware attack, cybercriminals infiltrate an electronic system, install malicious software to encrypt data, and demand a ransom to restore functionality. Ransomware attacks are financially devastating for hospitals – particularly rural and safety-net hospitals that are more likely to be in dire financial straits prior to the attack. To recover financially, hospitals may economize in ways that harm access and quality of care. We propose the first study of long-term effects of cyberattacks in health care – focusing specifically on how ransomware attacks affect populations experiencing health care disparities. To do this, we will use data on hospital ransomware attacks from the Tracking Healthcare Ransomware Events and Traits (THREAT) Database. By linking the THREAT database to Medicare data, we will measure access to and quality of hospital care. We will then use a quasi-experimental stacked difference-in-differences research design to execute the analyses proposed in Aims 1 and 2. Aim 1 will quantify the long-term effects of ransomware attacks on access to care at rural and safety-net hospitals. We hypothesize that hospitals reduce access to unprofitable services (e.g., inpatient psychiatric care) and treat fewer publicly insured patients, following a ransomware attack. Aim 2 will quantify the long-term effects of ransomware attacks on safety and quality of care at rural and safety-net hospitals. We hypothesize that hospitals reduce their quality of care in ways that jeopardize patient safety, following a ransomware attack. Finally, in Aim 3 we will conduct a novel survey of physicians at ransomware-attacked hospitals. Results from this survey will help to minimize the harm of future cyberattacks by identifying best practices that promote hospital functioning and care delivery during an attack. This study responds directly to PAR-24-109, specifically addressing the National Institute on Aging’s interest in research focusing on the long-term impacts of disasters on health care systems serving older populations experiencing disparities. Results will inform ongoing federal policy debates on cybersecurity in health care – and will also inform organization-level planning, by identifying strategies of safe and effective health care delivery during cyberattacks.

NIH Research Projects · FY 2026 · 2025-06

Sepsis is defined as organ dysfunction resulting from dysregulated host response and is a both a leading cause of global mortality and the most expensive hospital treated condition. Gram-negative species underly about half of all bloodstream infections, thus bacteremia pathology is critical to understand. K. pneumoniae (Kp) is the second leading cause of Gram-negative bacteremia and a leading cause of health-care associated infections. The pathogenesis of Gram-negative bacteremia involves three phases: 1) initial site infection, 2) dissemination to the bloodstream, and 3) survival in blood filtering organs. Kp fitness in the lung, a common initial site of infection, has been studied but last phase of Kp-bacteremia is largely unexplored. There is a fundamental gap in our understanding of how Kp perpetuates infection in the blood and filtering organs. Macrophages have differing interactions with Kp across organs that correlates to overall Kp abundance within tissues during infection. However, the relationship between macrophages and Kp is poorly understood. The objective of this proposal is to define mechanisms of Kp restriction across distinct macrophage subsets relevant to bacteremia. The central hypothesis is that tissue-resident macrophages provide distinct niches that restrict or permit Kp in a manner dependent on bacterial initiation of cell death. I will test this hypothesis through three specific aims: 1) define splenic macrophage restriction of Kp during bacteremia, 2) define host pathways of Kp restriction by macrophages, and 3) discover Kp mechanisms of resistance to macrophage- mediated killing through initiation of cell death pathways. This work is innovative as it will harness CRISPR- genomic screening to study Kp pathogenesis and use existing transposon sequencing data to identify bacterial factors that are required for resistance to macrophage killing. Findings from these approaches will be applied to splenic macrophages, an immune cell subset rarely studied in Gram-negative disease. The research in this proposal will support sustained positive impact through identifying both host and pathogen factors required for unique tissue-specific responses across sites in bacteremia. This proposal is supported by a comprehensive training plan which will support the development of technical and conceptual skills to investigate host-pathogen interactions across tissue-resident immune cells during Gram-negative bacteremia. The skills gained with this training plan could be applied to multiple organ sites and Gram-negative pathogens. This training will occur at the University of Michigan with a team of mentors dedicated to the success of this proposal. The candidate's background in innate immunology and bacteriology will be unified by mentors with expertise in host-pathogen interactions, macrophage biology, CRISPR-genomics, bacterial genetics, and spleen biology. Together, the expertise of the mentors and the research in this proposal will facilitate independence of the candidate. This research will reveal tissue-specific interactions between macrophages and Kp during bacteremia.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY/ABSTRACT The primary, long-term goal of this project is to improve outcomes for people living with mental health conditions by enhancing technologies for semantic representation of mental, behavioral, and social phenomena thereby enabling researchers, clinicians, and consumers to leverage the growing landscape of computational methods and clinical decision support technologies to accelerate the rate of knowledge acquisition and translation. This research will address gaps in both the content and ontological representation of mental, behavioral, and social constructs. Ontologic representations are formal, explicit, computer-readable definitions of the meaning of entities and occurrences in some domain. This research seeks to develop, build, and evaluate high quality, machine-readable semantic models for mental, behavioral, and social processes, findings (signs, symptoms, exposures, disorders), assessment instruments, and interventions. Focusing on two highly important and diverse diagnostic constructs as test cases, borderline personality disorder (BPD) and psychosis, the proposed work will cover a broad and representative sample of clinical constructs, processes, findings, assessment instruments, and interventions that can be applied to many mental health conditions. Data sources include electronic health records, publication metadata, narrative text in published, peer reviewed research, existing terminologies and ontologies, and mental health subject matter experts, including patients and families. Qualitative methods, including focus groups, the Nominal Group Technique (NGT), and Delphi Method will be used to reach consensus about relevant concepts (clinical ideas), terms (clinical labels), definitions, and relationships. Methods and Materials include ontology development methods and software which will be used to physically build machine-readable ontologic models and terms. Models, terms, and definitions created will be evaluated by domain experts, and shared with publishers of widely adopted national and international clinical terminologies. The career development plan will focus on acquiring knowledge and skills in formal terminology development methods, qualitative methods, ontology definition languages, as well as conceptual models of both normative and pathological mental functioning and psychological assessment methods. By creating ontologic models capable of fully expressing the meaning of, and relationships among, mental, behavioral, and social constructs, this project will create a foundation upon which additional clinical findings, disorders, assessments, and interventions for mental, behavioral, and social constructs can be built. The substantial number of terms, concepts, definitions, and relationships created through this study will be published and made available to researchers, clinicians, and health systems for use in knowledge discovery and translation paradigms. This work directly addresses the strategic goal of the National Institute of Mental Health (NIMH) to develop new methods and tools to accelerate discovery and translation of new knowledge in behavioral science.

NIH Research Projects · FY 2025 · 2025-06

ABSTRACT As the major organ responsible for olfaction and air intake, and thanks to its rich connections to the autonomic nervous system, the nose plays many pivotal roles for survival. In fact, disruptions in olfaction and autonomic function are often observed before loss of brain function ensues during the progression of neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. As such, the nose is being increasingly recognized as a critical investigational target for understanding the complex functional interactions between peripheral and central nervous system, identifying mechanisms of action of disease, and even for delivery of therapeutic interventions. Yet, the characterization of system-wide functional connections between the nose and the central nervous system is challenged by the lack of neuroimaging methods which detect robust surrogates of functional activity in the nose. In fact, whereas standard functional MRI techniques are formidable tools for characterizing function in the brain, they are intrinsically inadequate for detecting functional signals in the nose, because the susceptibility artefacts originating from the air-tissue interfaces of the nasal cavity destroy magnetic field uniformity and lead to signal loss with standard fMRI techniques that rely on the use of an echo time (TE). To overcome the challenges of nose fMRI, in this project we will exploit the resilience to susceptibility artefacts offered by ultrashort/zero-TE acquisition schemes, which we previously demonstrated being capable of providing robust fMRI contrast primarily mediated by blood flow. Our pilot data demonstrate that unprecedented fMRI signals during both tasks and resting state can be detected with ultrashort TE (UTE) techniques in the human nasal cavity. Therefore, our plan here is to first optimize these innovative UTE protocols for fMRI of the human nose, and to apply them in cross-sectional and in test-retest studies designed to provide supporting evidence to our overarching hypothesis: UTE enables detection of robust nose fMRI signals primarily mediated by blood flow fluctuations that generally correlate with ANS activity and that during the presentation of odor stimuli specifically reflect olfactory processing in the nose. Protocol optimizations will be first performed to ensure maximum coverage, functional contrast, spatial and temporal resolutions on each of two clinical MRI platforms, 7T and 3T. Detection sensitivity and reproducibility of nose fMRI signals and system-wide connections between nose and the nervous system will be then evaluated on each MRI platform. To determine whether the fMRI nose signals reflect olfactory processing, we will deliver different sensory stimuli (odor, visual and odorless airflow stimuli); to characterize the dependence of nose fMRI signals on the function of the autonomic nervous system, we will correlate the nose fMRI signals with other surrogates of autonomic function such as hearth rate and breathing rate variabilities. Once completed, this study will have demonstrated the first proof-of-principle use of nose fMRI in humans by making use of widely available clinical scanners, thus greatly facilitating translational applications and dissemination to a broad community of researchers and clinicians.

NIH Research Projects · FY 2026 · 2025-06

PROJECT SUMMARY Like other drugs of abuse, psychostimulants enhance dopamine (DA) neurotransmission from the ventral tegmental area (VTA) to downstream targets including the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc). Direct stimulation of VTA DA neurons in rodents is reinforcing and sufficient to trigger an array of molecular, cellular, and behavioral adaptations linked to addiction. Psychostimulants can weaken inhibitory G protein-dependent signaling in VTA DA neurons and layer 5/6 pyramidal neurons of the prelimbic (PL) sub-region of the mPFC via suppression of G protein-gated inwardly rectifying K+ (GIRK) channel activity. In layer 5/6 PL pyramidal neurons, for example, repeated cocaine exposure in mice weakens GIRK channel regulation by the GABAB receptor (GABABR) in a DA- and phosphorylation-dependent manner. Genetic suppression of GIRK channel activity in PL pyramidal neurons of drug-naïve mice evokes some of the cellular and behavioral hallmarks of repeated cocaine exposure. The goals of this project are to elucidate the cellular and neurochemical mechanisms underlying the cocaine-induced suppression of GABABR-GIRK signaling in PL pyramidal neurons and to investigate the therapeutic potential associated with rescuing this signaling pathway in these neurons. Proposed experiments test key elements of the following conceptual framework: Cocaine provokes the D1 DA receptor-dependent excitation of PL GABA neurons, driving the feedforward inhibition of PL pyramidal neurons. Repeated GABAergic input to PL pyramidal neurons promotes the suppression of the GABABR-GIRK signaling pathway. Weakening of this inhibitory signaling pathway contributes to the hyperexcitability of PL pyramidal neurons, which promotes aberrant behaviors associated with repeated cocaine exposure. Mechanism-informed interventions that restore or strengthen the GABABR-GIRK signaling pathway in PL pyramidal neurons, therefore, will normalize behaviors linked to repeated cocaine exposure. There are two Specific Aims: 1) Elucidate mechanisms underlying the cocaine-induced hyperexcitability of PL pyramidal neurons. Using slice electrophysiological approaches, I will test the hypothesis that D1R activation of PL GABA neurons drives the feedforward inhibition of PL pyramidal neurons necessary for the cocaine-induced suppression of GABABR-GIRK signaling. 2) Test whether mechanism-informed interventions can rescue cocaine-induced behavioral deficits. Using complementary pharmacological and neuron-specific viral genetic interventions, I will test the hypothesis that mechanism-informed interventions that rescue and/or strengthen GABABR-GIRK signaling in PL pyramidal neurons can alleviate behavioral deficits provoked by repeated cocaine exposure in mice. Successful completion of this project will advance our understanding of the mechanisms and relevance of cocaine-induced suppression of GABABR-GIRK signaling in PL pyramidal neurons, and provide valuable training in ex vivo electrophysiology, intracranial genetic and pharmacological manipulations, and behavioral analysis in mice, building a strong foundation for my future career as an independent investigator.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY Adolescents who live in rural communities have significantly higher rates of depression, suicide, and mental health impairment than urban youth. They are also less likely to receive mental health care due to provider shortages and under-utilization of existing services. Our team is working to expand access to evidence-based practices (EBPs) in rural communities by “task-shifting” delivery from professional providers to youth mentors. Youth mentoring programs are low-cost and often viewed as more favorable in rural communities than professional mental health care. With input from rural youth, parents, and school partners who identified a need for mental health programming that supports interpersonal relationships, we adapted Interpersonal Psychotherapy–Adolescent Skills Training (IPT-AST), an evidence-based depression prevention program, for delivery by mentors of rural youth in an after-school setting. Our work is building on evidence from other task- shifting initiatives that demonstrates that paraprofessionals can be trained to deliver EBPs. The training process for paraprofessionals has typically involved multi-day expert-led workshops that are resource- and time-intensive. The high turnover rate among paraprofessionals can necessitate the need for additional workshops, further exacerbating resource strain. In addition, workshops are delivered weeks or months before the skills are needed, thereby limiting knowledge retention. The next step for realizing the potential of task- shifting EBP delivery for reducing mental health disparities is to develop implementation strategies that can be effective, sustainable, and scalable in low-resource settings with high provider turnover and non-expert supervisors. Just-in-Time Training (JITT) is one promising approach in which providers receive only the training necessary, at the time that it is necessary, to produce high program fidelity. We have developed a novel multi-level JITT implementation strategy (JITT-EBP) that aims to equip mentors and mentor supervisors to implement an EBP with fidelity using methods that are sustainable in rural communities. JITT-EBP integrates (a) self-directed, on-demand, online training modules for mentors and mentor supervisors, (b) synchronous evidence-based supervision strategies, and (c) an apprenticeship delivery model in which EBPs are co-led by an experienced mentor and a novice mentor, providing opportunity for in-the-moment training and support. Our hypothesis is that the use of JITT-EBP will result in IPT-AST fidelity and youth clinical outcomes that are as good as those observed with usual IPT-AST training, but with higher feasibility, acceptability, appropriateness, and perceived sustainability in low-resourced rural settings. To prepare for a subsequent fully-powered hybrid type 2 effectiveness-implementation trial, in this pilot trial, the aims are to optimize the usability, feasibility, and acceptability of JITT-EBP using a sequential mixed method design; and conduct a pilot randomized trial of JITT-EBP versus usual IPT-AST training to evaluate the implementation outcomes of JITT-EBP and the implementation and clinical outcomes of mentor-delivered IPT-AST.

NIH Research Projects · FY 2025 · 2025-06

Abstract/Summary Bacteria in the oral cavity contribute to human health and disease. Streptococcus mutans is commonly found in the oral microbiome and is recognized as a leading cause of caries (cavities). Some infections in the oral cavity can also occur after endodontic treatments such as root canals. Millions of patients undergo root canal procedures each year, and root canal failure rates can be as high as ~20%. A leading cause of infected root canals is the Gram-positive bacterium Enterococcus faecalis, which is found at low abundance in the gastrointestinal tracts (GIT) of humans, animals, and insects. E. faecalis can also be an opportunistic pathogen causing infections on implanted devices and in body sites such as the urinary tract, bloodstream, and wounds. Despite its prevalence in root canal infections, E. faecalis is not typically considered part of the core oral microbiome. Our preliminary data shows that natural products (such as non-ribosomal peptides/polyketides) synthesized by S. mutans can kill E. faecalis and other Gram-positive bacteria. Through this proposal, we will identify natural products with anti-bacterial and anti-biofilm activity produced by additional strains of S. mutans using a combination of targeted gene deletions, bacterial co-culture assays, and mass spectrometry. Additionally, we will test the hypothesis that S. mutans biofilms producing these natural products can exclude E. faecalis from invading pre-formed biofilms and can shape biofilm dynamics in conditions relevant to the oral cavity. This work will serve as the foundation for a future R01 to NIDCR to test models of colonization resistance and dysbiosis that may govern E. faecalis dynamics in the oral cavity, and to determine how streptococcal natural products shape the ecology of the oral microbiome.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY/ABSTRACT Addressing maternal and infant health disparities is an urgent public health concern with profound implications for health equity across the life course. Causes of disparities in maternal morbidity and birth outcomes are multifactorial and arise from an accumulation of short- and long-term environmental, economic, social, behavioral, and biological processes that unfold across the life course. To understand and ultimately address pregnancy disparities, research needs to move beyond cross-sectional designs at one point in life, to examine upstream, place-based, and macrostructural determinants of health that occur much earlier in life, using rigorous designs. Neighborhood context is a particularly important macrostructural, distal exposure, which is influenced by residential segregation, but can be altered through housing policy. The proposed project aims to understand the impact of housing policy on neighborhood context and infant and maternal outcomes in the U.S. To study this critical public health problem, we will leverage data from the Moving to Opportunity (MTO) Study. MTO started as a randomized trial of 16,000 individuals (adults and their children) in 4,600 low-income families, living in public housing at baseline, in five U.S. cities. Volunteer families were randomized beginning in 1994 to receive one of three treatments: (1) a housing voucher that subsidized rent in apartments located in low-poverty neighborhoods (<10% poverty) plus housing counseling; (2) a housing voucher subsidizing rent in any neighborhood; or (3) an in-place control group that received no voucher but remained eligible for public housing. The original MTO study ran from 1994-2010. We propose to link the MTO study participants to population-based administrative data to extend the study for an additional 15 years until 2024. Linkage with universal data will enable us to analyze the long-term effects of this experiment on household heads, their (now adult) children, and their infant grandchildren. We have four specific aims: (1) Test if MTO treatment improves neighborhood quality (neighborhood opportunity) in 2024; (2) Test if MTO treatment affects maternal morbidity (e.g., hypertensive disorders of pregnancy, gestational diabetes, obesity); adverse birth events (low birthweight, preterm birth); or fertility (short birth interval, number of births) by 2024; (3) Identify subgroups that are more or less likely to benefit from the MTO housing voucher experiment, i.e., test heterogeneity of MTO effects on fertility, maternal morbidity and adverse birth outcomes by baseline demographic factors and their combinations (effect modification); and (4) Calculate the number of adverse maternal and infant related events avoided, and how the racial/ethnic health gap would be narrower, at the population level, if voucher-based housing policy were broadly implemented to promote opportunity moves (simulation). This rigorous, long-term population health research project aims to achieve health equity across multiple generations of families, by improving housing and neighborhood contexts early in life.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY The prevalence of obesity and diabetes continue to rise unabated in the United States, creating a grave social and economic burden. Although development of these diseases is multi-faceted and complex, there is accumulating evidence for the impact of environmental chemical exposures on metabolic homeostasis. Currently, glyphosate is the most commonly used herbicide in the United States, however, to date, no studies have ever assessed whether glyphosate exposure impacts the development of obesity and diabetes. Thus, the long-term goal of this project is to better understand how recent and current pesticide usage can impact long-term metabolic homeostasis. Glyphosate targets the shikimate pathway found in plants, and not mammals, leading to the assumption of its general safety. However, glyphosate can also target bacteria, and glyphosate exposure results in an altered gut microbiome profile. Despite the fact that previous pesticides are associated with metabolic disease, and that glyphosate is known to alter the gut microbiota which can impact energy and glucose homeostasis, no study has ever examined whether exposure to glyphosate can result in development of obesity and/or diabetes. One of the main roles of the gut microbiota is bile acid metabolism, and studies suggest that alterations in bile acid signaling represent a plausible link between the gut microbiota and regulation of metabolic homeostasis via changes in Farnesoid X receptor (FXR) signaling. These facts, coupled with our preliminary data, led to the hypothesis that exposure to glyphosate shifts the gut microbiome, leading to altered intestinal bile acid signaling that contributes to impairments in energy and glucose homeostasis. This hypothesis will be tested in 3 aims: 1) assess if exposure to glyphosate during different developmental timepoints promotes metabolic dysfunction in male and female mice on a chow or high-fat diet, 2) determine the role of the gut microbiome in the effects of glyphosate exposure on metabolic homeostasis, and 3) identify the impact of altered bile acid signaling via glyphosate exposure in impaired metabolic homeostasis. The proposed study will be the first ever to provide mechanistic insight of the effects of glyphosate exposure on metabolic homeostasis. This proposal will provide valuable data leading to further research examining how environmental pesticide usage can affect human health, and possibly identify microbial targets to offset the detrimental effects of environmental chemical use.

NIH Research Projects · FY 2026 · 2025-05

ABSTRACT Patients with high-risk hematological malignancies may be cured using allogeneic hematopoietic cell transplantation (HCT); however, HCT carries a significant risk for mortality. Social adversity accounts for increased risk for morbidity and mortality following HCT in both adults and children. Our group has identified that in adult recipients, not only is this risk disproportionately worse among HCT recipients of low socioeconomic status (SES), but it is worse among recipients receiving hematopoietic cells from donors of low SES. Further, we have demonstrated that up-regulation of a stress- and SES-related transcriptome profile – termed the “conserved transcriptional response to adversity” (CTRA) – within adult HCT donors and recipients may be a biological contributor to cancer outcomes disparities. However, it is unknown whether low donor SES and donor/recipient stress-related immunobiological factors, such as CTRA expression and biological aging (both linked to poorer outcomes in cancer and HCT patients), pose a prognostic risk to pediatric HCT recipients. Despite our novel findings in adults, they cannot be extrapolated to pediatric patients because pediatric patients are diagnosed with cancer that is biologically unique from adults and they experience stress and illness differently than adults. The goal of this research is to extend our understanding of whether the immunobiologic mechanisms underlying the comorbidity of social health disparities in adult cancer and HCT extend to the biologically and psychosocially unique pediatric cancer population, providing a critical link for designing interventions to reduce cancer disparities. The primary aims of this proposal are to: 1) quantify how donor and recipient SES are associated with pediatric HCT outcomes; 2) evaluate how HCT donor and pediatric recipient SES affects biologic indicators of stress (CTRA, biological aging); and 3) determine the relationship between donor and recipient stress biology factors and clinical outcomes in pediatric HCT patients. Our overarching hypothesis is that SES- related immunobiologic risk factors will be associated with pediatric recipient and donor SES, and that both will be associated with inferior pediatric HCT outcomes, including disease-free survival, transplant-related mortality, relapse, graft-versus-host disease, and overall survival. The research plan employs molecular biology to investigate immunobiologic factors underlying health disparities by collaborating with the federally funded Center for International Blood and Marrow Transplant Research. We will leverage the expertise of a multidisciplinary investigator team by using clinical (N=1716 donor/recipient pairs) and biological (N=946 each for donors and recipients) data for donors and recipients in the pediatric HCT population. By identifying SES-related immunobiological risk factors for adverse pediatric HCT outcomes, we have the opportunity to optimize HCT outcomes and address potential biological mechanisms of cancer disparities. The proposed work will define the gene regulatory understanding of SES disparities in pediatric cancer treatment outcomes, providing critical data to design interventions for improving outcomes across the age continuum.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY To increase smoking cessation rates from the status quo (7.4% of people who smoke [PWS] quit smoking each year in the U.S.) and curb cancer, the U.S. Food and Drug Administration (FDA) is considering the implementation of two cigarette product standards. The first is the FDA’s proposed menthol ban (MB). The second is a nicotine reduction standard (NRS). Based on published literature encompassing modeling studies, behavioral intent estimates, and expert elicitation, as well as our team’s preliminary data, the MB is anticipated to motivate 7.3% to 17.7% of PWS menthol cigarettes to quit and the NRS is anticipated to motivate 46.8% to 57.5% of all PWS to quit. These levels of quitting above the status quo will mean that quitlines and other state- based cessation initiatives will be severely under-resourced to meet the needs of PWS. Our research is thus highly significant as our overarching objective is to ensure that the U.S. is fully prepared to maximize smoking cessation during and following the implementation of cigarette product standards by providing state departments of health, tobacco quitline operators, as well as state policy and law makers, with state-specific estimates of the number of PWS who will quit smoking in response to cigarette standards and the number of quitline enrollees. We will also provide state-specific estimates for populations at higher risk for tobacco-related disease and death which can be leveraged to purposively plan for equitable resource distribution. Additionally, the added benefit of mass media campaigns, which will likely be used to introduce the cigarette standards and promote smoking cessation and cessation resources, will be forecasted. A constituent advisory council (CAC) comprised of state public health professionals and representatives of national non-profits and advocacy organizations with interests in tobacco control will guide our efforts and help ensure that end users of the estimates understand the methods, assumptions, and limitations while providing opportunities to maximize the utility of the estimates. The aims of this three-year project are as follow: Aim 1: To estimate, for each U.S. state, the number of and fold increase in PWS, both overall and in priority populations, who will quit smoking and enroll in the quitline in the year following the MB and the NRS. Aim 2: To estimate the added number of PWS who would quit and enroll into quitlines if mass media campaigns are implemented alongside the MB and the NRS for each state and in priority populations. Aim 3: To conduct a constituent-centered design process, involving CAC inputs and usability assessments to inform the development of a public portal for disseminating the estimates. Our research is consistent with the NCI’s Tobacco Control Research Branch scientific priorities including research on “tobacco cessation interventions at individual, system, and population levels” and “tobacco control interventions for underserved and at-risk populations.” It is aligned with the recently released Department of Health and Human Services draft cessation framework which will be a roadmap to “drive further progress toward smoking cessation and to deliver equitable outcomes for all persons in America.”

NIH Research Projects · FY 2026 · 2025-05

Abstract: Nursing homes (NHs) care for a growing proportion of adults with serious mental illness (SMI) such as schizophrenia, leading some to call NHs “de facto mental health care.” Despite legislative efforts to reduce institutionalization for those with SMI, the prevalence of SMI in NHs has increased by approximately 80% in the last 10-years. Those with SMI have significantly greater odds of also having comorbid Alzheimer’s disease and related dementias (AD/ADRD) compared to those without SMI. Individuals with SMI and comorbid AD/ADRD are a particularly vulnerable group because SMI can complicate the identification and treatment of dementia, and SMI symptoms cause distress and amplify dementia-related behaviors and disabilities. The prevalence of SMI alone and SMI with comorbid AD/ADRD varies by race/ethnicity, with Black, Indigenous and people of color (BIPOC) having higher diagnosed rates of SMI. These concurrent trends reflect healthcare disparities, with NHs often serving as the provider of last resort in the absence of other viable options. To address these disparities, we need an evidence base for high-quality equitable NH care in these complex care situations. To properly develop such an evidence base, it is vital to understand the extent of SMI prevalence alone and SMI with comorbid AD/ADRD in NHs and assess quality outcomes for those with SMI alone and SMI with comorbid ADRD by race/ethnicity. We also need to identify modifiable organizational factors that can facilitate care for these groups. Yet, research on SMI in NHs is nearly a decade old and relies largely on federally mandated NH clinical assessment data (the Minimum Data Set, MDS). The MDS measures physical and cognitive health for care planning and may misrepresent SMI estimates. To address this gap, we will create a new, integrated dataset—MDS in combination with mental health screenings mandated on hospital discharge (Preadmission Screening and Resident Review, PASRR) and Medicaid/Medicare claims—for a comprehensive analysis of SMI, AD/ADRD, and health disparities in NHs. This application has three specific aims. In Aim 1, we will assess patterns of prevalence for SMI, AD/ADRD, and SMI with AD/ADRD in NHs over time (2013-2019 vs 2021-2022). We will generate longitudinal estimates of SMI with AD/ADRD in NHs and estimate how rates differ for those with and without AD/ADRD and by race/ethnicity. In Aim 2, we will estimate quality of life, a key person-centered measure, and quality of care for those with SMI with and without AD/ADRD (2011-2019 vs 2021-2022). In Aim 3, we will conduct qualitative case studies, including facility observations in 10 high- proportion SMI NHs of with varying proportions of residents with AD/ADRD and racial/ethnic composition (identified from Aim 1), coupled with 50 resident and 50 staff interviews. In meeting these aims, we will address a critical need for evidence on the prevalence, care needs, and organizational barriers to care for two NIH priority populations: NH residents with SMI, with and without ADRD, and BIPOC older adults.

NIH Research Projects · FY 2025 · 2025-05

Project Summary/Abstract There is now an urgent need to develop more clinically relevant tests, or medical device development tools (MDDT), that are alternatives to clinical studies to help accelerate the translation of new dental materials. In this biphasic R61/R33 application, we propose a MDDT, in the form of an accelerated fatigue test calibrated by clinical data, for assessing the clinical performance of resin composites. The method explicitly predicts the survival probability of composite restorations as a function of time, through some easy-to-perform cyclic fatigue and biofilm tests on a simple yet clinically representative model composite restoration. Our immediate goal is to have this MDDT qualified by the FDA for use by dental materials manufacturers, while our long-term goal is to extend the method and application of this tool to other medical devices. Our strategy for qualifying the proposed MDDT contains the following specific aims: Phase 1, Aim 1 Confirm repeatability of accelerated fatigue test for model resin-composite restorations. The fatigue test using conventional materials will be repeated multiple times. The resulting survival probability curves are expected to lie within the 95% interval of each other. Phase 1, Aim 2 Assess viability and repeatability of calibrated biofilm model for producing recurrent caries in debonded specimens. Debonded specimens will be challenged using a clinically-calibrated biofilm model. Recurrent caries is expected to be produced consistently in the specimens and the clinical time for it to occur following debonding can be predicted within the required confidence intervals. Phase 2, Aim 3 Determine if laboratory model can accurately predict service life of a wide range of composite restorations using prospective clinical data. Prospective clinical data for different classes of restorations will be collected for calibration and validation of the laboratory model. The calibrated model is expected to be able to accurately predict the clinical performance of different classes of restorations. Phase 2, Aim 4 Determine if laboratory model can accurately predict service life of a wide range of composite restorations using retrospective clinical data. Retrospective clinical data will be collected from the BigMouth Dental Data Repository to further validate the model for life predictions. The recalibrated model is expected to be still capable of accurately predicting the service life of the restorations. Phase 2, Aim 5 Assess viability and repeatability of accelerated fatigue and biofilm tests for assessing resin composites with caries prevention and remineralization properties. Specimens made of materials with or without antibacterial properties will be challenged using the calibrated fatigue and biofilm models. Resin composites with antibacterial agents are expected to take longer to develop recurrent caries, and the results are repeatable.

NIH Research Projects · FY 2025 · 2025-05

ABSTRACT TDP43 is considered a key target for drug discovery in frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and other TDP43 proteinopathies, including Alzheimer’s disease and related dementias (ADRD). The pathophysiology of TDP43 proteinopathies involves a loss of native function (RNA binding and splicing regulation) and a toxic gain of function (cytoplasmic mislocalization and toxic aggregate formation). Despite years of research, current small molecule discovery efforts targeting TDP43 dysfunction have not yielded strong inhibitors or successful clinical translations. Historically, TDP43 therapeutic strategies have focused on reducing its toxic gain of function. Our proposal, in contrast, aims to prevent the loss of TDP43’s native function. Recent high-impact publications have provided critical new insight into how we might accomplish this. It is now understood that TDP43’s RNA binding requires N-terminal domain (NTD) multimerization, and that pathological loss of NTD-NTD interactions is the key step preceding cytoplasmic mislocalization and aggregation. The goal of this proposal is, therefore, to identify novel small molecules that stabilize functional, NTD-dependent TDP43 multimers to restore TDP43 function and rescue TDP43-associated pathologies. Our high-throughput screening pipeline, using engineered fluorescence lifetime (FLT)-based FRET biosensors, specifically monitors NTD-dependent TDP43 multimerization in living cells. We present strong and extensive preliminary data to support our proposal. A pilot screen of the 2,684 compound Selleck library identified multiple promising hits previously known to bind and effect TDP43. We demonstrate the full pipeline on one of those hits, which stabilizes nuclear TDP43 multimers, rescues TDP43 mislocalization and aggregation, improves neuronal cell health and partially rescues motor function in a C. elegans model of TDP43 proteinopathy. These data strongly support the premise of our targeting strategy, the robustness of our HTS pipeline, and instill confidence in the promise of our proposed campaign. We will screen the 50,000-compound CNS-SetTM library, curated for BBB penetration, in an inducible neuronal cell line. Using a range of cell-based and biophysical assays we will identify two kinds of promising small molecules that stabilize NTD-dependent multimers: 1) compounds that directly bind to the TDP43 NTD; or 2) compounds that act through an indirect mechanism of action. To enrich the pool of direct acting compounds, we will also perform in silico docking screens of over 500,000 compounds targeting the NTD-NTD dimeric interface. Hit compounds from both screens will advance through the pipeline, which includes functional assays to monitor TDP43 splicing regulation, TDP43 mislocalization and aggregation, neurite length (a measure of cell health) in both 2D neuronal culture and 3D neurospheres, and a C. elegans movement assay. Lastly, we will engineer iPSC-derived motor neurons to express the TDP43 biosensors, providing an improved physiological model of disease for future refinement of the most promising leads.

NIH Research Projects · FY 2026 · 2025-04

ABSTRACT Promoting weight-related health is vital to cardiovascular health and a public health priority. The Project EAT (Eating and Activity over Time) research has informed a paradigm shift regarding how to address weight- related health. Specifically, findings have shown the need to address the full spectrum of weight-related health, including weight status, dietary intake, physical activity, body image, disordered eating (e.g., binge eating, unhealthy weight control practices), and eating disorders, in addition to social determinants of these outcomes. The socio-environmental contexts of adolescents and young adults today (i.e., those who make up Generation Z born between 1997-2012) have dramatically changed since Project EAT began following adolescent Millennials (i.e., those born between 1981-1996) in 1998. For example, there have been vast changes in technology and young people are being exposed to a proliferation of image-based social media (e.g., TikTok) with mixed messages about weight-related health (e.g., new weight loss medications, body positivity). If we are to effectively promote weight-related health and health equity across ethnicity/race and socio-economic status in the next generation of young people, it is crucial to understand the most salient issues facing today’s adolescents and young adults. The ultimate goal of this R35 is to promote the broad spectrum of weight-related health in the next generation of adolescents and young adults. To achieve this goal, the R35 will integrate research, community partnerships, and training. For the first time, Project EAT will collect data on a national sample of 2000 Gen Z adolescents and young adults. Additionally, we will leverage the existing Project EAT Millennial-generation cohorts by collecting data from both cohort members and their Gen Z adolescent and young adult children (expected n=1000 parent-child dyads), for an intergenerational study across two generations of young people. We will also conduct qualitative data collection for a deep understanding of the weight-related issues facing Gen Z young people; rapid response surveys to assess the impact of socio-environmental influences in real time; and innovative substudies for in- depth explorations of timely topics. The result will be the most comprehensive dataset to date on weight- related health among diverse adolescents, young adults, and their parents. To ensure that our data are used to make a positive difference, we will work in partnership with two Community Advisory Boards; one comprised of diverse adolescents and young adults and the other comprised of professionals (e.g., health care providers). We will also integrate training throughout the research program to ensure that future scientists are prepared to address weight-related health in young people, particularly those from marginalized backgrounds. This R35 aligns with the NHLBI Strategic Vision. It will support a highly dedicated and productive researcher, along with a strong team, to carry out a timely, impactful, and innovative program of research and training to significantly advance science, enhance weight-related health, and work toward greater health equity.

NIH Research Projects · FY 2026 · 2025-04

Project Summary Osteoclasts are large multinucleated cells that secrete acid and proteases to resorb bone. Understanding the molecular events that regulate osteoclast activity during periodontal disease is critical to treating bone loss during inflammatory diseases. Reversible modifications to DNA such as histone acetylation, methylation, phosphorylation and ubiquitylation alter the access of transcriptional machinery to DNA and regulate gene expression. Lysine-specific demethylase 1 (LSD1) confers transcriptional repression by demethylating H3K4 or activating transcription by demethylating H3K9. The role and targets of LSD1 during osteoclast differentiation are unknown. Results from our work with LSD1;LysM-Cre (LSD1cKO) conditional mice begins to fill this knowledge gap. LSD1cKO mice have smaller osteoclasts and increased BV/TV compared to LSD1WT mice. Bulk RNA-SEQ of femur-derived osteoclast precursors from LSD1cKO mice indicate that genes in the IFN-b pathway are upregulated compared to LSD1WT cells. Unlike those from the femur, osteoclasts generated from the LSD1cKO mandible were not significantly different in size compared to their wild type littermates suggesting a difference in skeletal site regulation by LSD1. Our data demonstrates significant bone loss in LSD1WT mice but no significant bone loss in LSD1cKO mice in a ligature induced periodontitis model. In support of this, TNF- a, an inflammatory cytokine that induces osteoclast differentiation after priming by TGF-b, was unable to induce osteoclast differentiation in mandible derived cells suggesting a mechanism for the inability of LSD1cKO mice to lose bone in ligature induced periodontal disease. The central hypothesis is that LSD1 demethylates residues at H3K4 to inhibit expression of genes involved in the IFN-b pathway thus allowing inflammatory cytokines to induce osteoclast differentiation. In the first aim we will gain mechanistic insights by conducting an in-depth investigation of ligature induced periodontitis in mandible derived osteoclast precursors from LSD1cKO mice. We will confirm our initial data that LSD1cKO mice are resistant to bone loss during ligature induced periodontitis disease through micro-CT, histology, and ELISA of various cytokines. Additionally, we will perform bulk RNA- and ATAC-SEQ of mandible-derived preosteoclasts from un-ligated and ligated LSD1WT and -cKO mice. This data will allow us to determine skeletal site-specific changes in mandible derived osteoclasts during ligature induced periodontitis. In our second aim we will determine if LSD1 expression is necessary for innate immune training resulting from ligature induced periodontitis by performing single cell sequencing of bone marrow cells from LSD1WT and LSD1cKO mice. To complement our single cell sequencing we will also perform single cell ATAC-SEQ of bone marrow cells from LSD1WT and cKO mice who have undergone innate immunity training. Epigenetic modifications are modifiable, potentially reversible and represent a promising group of treatments for periodontal disease.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Methamphetamine (meth) addiction is a large and growing public health concern that is inadequately managed with available therapeutics. This proposal addresses this need by furthering our understanding of a promising new anti-addiction therapeutic strategy. Meth induces inappropriate dopamine (DA) release from neurons of the mesolimbic DA pathway. Restoration of DA signaling homeostasis may be achieved by targeting the G protein- coupled receptor (GPCR) neurotensin receptor 1 (NTSR1). NTSR1 modulates DA signaling via action at putative NTSR1/D2 DA receptor complexes. The efficacy of peptide NTSR1 agonists in animal models of meth use have made clinically useful, small molecule NTSR1 ligands highly desirable. NTSR1, like other GPCRs, signals through both G protein- and β-arrestin-mediated pathways. Recently, we developed and characterized a novel class of small molecule NTSR1 ligands, typified by compound SBI-553, which activate β-arrestin without stimulating G protein signaling. This type of functional selectivity or biased signaling presents an opportunity to produce more directed physiological action and reduce unwanted side effects. Promising data suggests that SBI- 553 attenuates the reinforcing effects of meth in mice without the hypotension and hypothermia characteristic of balanced NTSR1 ligands. At present, the mechanisms by which β-arrestin-biased NTSR1 ligands block meth effects are unclear and the cell type(s) on which β-arrestin-biased NTSR1 ligands act on is unknown. The objectives of this application are to elucidate the molecular mechanism by which β-arrestin-biased NTSR1 ligands achieve β-arrestin recruitment to the NTSR1 and to identify the cell type(s) in the nucleus accumbens (NAc) at which they act to attenuate meth-induced behaviors. My central hypothesis is that is that β-arrestin- biased NTSR1 ligands stimulate receptor-β-arrestin association via a G protein-independent, GPCR kinase 2 (GRK2)-dependent mechanism and attenuate meth-induced behaviors via action on D2-expressing medium spiny neurons (MSNs) in the NAc core. I will test this hypothesis by pursuing two aims, using SBI-553 as a tool compound. I will first (1) elucidate the biochemical mechanism by which NTSR1 ligands recruit β-arrestin, using recently developed GRK- and G protein-subtype-specific-null cells. I will then (2) identify the cell type on which NTSR1 ligands act in the NAc to attenuate meth addiction-like behaviors, visualizing NTSR1-expressing cells in and projecting to the NAc using virally-mediated fluorophore expression and assessing the ability of SBI-553 to attenuate meth-induced locomotion and conditioned place preference in mice lacking NTSR1 selectivity in D2 MSNs. Pursuit of these aims requires interdisciplinary training in molecular biology and systems neuroscience. Therefore, I have assembled expert collaborators into an interdisciplinary mentoring committee, led by Drs. Lauren Slosky (Sponsor) and Kevin Wickman (Co-Sponsor). Together, we have crafted an individualized training plan that will provide me with the foundational scientific and professional skills necessary to reach my long-term goal of running an independent laboratory and studying the neurobiological basis of addiction.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY The stereotypic and relatively simple circuitry of the cerebellar cortex, with its highly conserved nature throughout evolution makes the cerebellum a very attractive circuit to understand fundamental neuronal mechanisms by which the brain performs input-output transformations that are needed not only for motor function but a spectrum of non-motor functions. A unifying view of the computations performed by the cerebellar cortex that incorporates its dominant parasagittal and transverse architectures has proved elusive. Recordings of cerebellar neuronal activity across multiple folia at relatively high spatial and temporal resolution are limited. Further, given the cerebellum’s involvement in several motor and non-motor processes, it is crucial to make these recordings in freely behaving mice in which the wide repertoire of behaviors is not impeded. Here, we propose to engineer a miniaturized ultra-widefield micro-camera array microscope (MCAM) capable of imaging a large area (24mm2) of the cerebellar cortex with cellular resolution. This MCAM combines several innovations, including a transparent polymer window implant for cellular resolution imaging, an array of epi-fluorescence micro-camera optics, along with complementary genetic approaches for sparsely labeling Purkinje cell populations in the cerebellum. In AIM 1, we will design and build an MCAM to be compatible with a cerebellum polymer skull implant developed by our collaborative team. Experiments will be conducted in head fixed mice to refine and optimize the opto-mechanical components of the MCAM. In AIM 2, we will deploy MCAM in freely behaving mice in open field arenas and iteratively refine the design of structural and optical elements to ensure robust motion and light artifact free imaging in freely behaving animals. We will then validate the utility of the cerebellum MCAM to measure cerebellar wide Purkinje cell activities and encoding of error signaling in ladder rung walking.

NIH Research Projects · FY 2026 · 2025-04

SUMMARY Microbes, specifically bacteria, are known to influence the host tumor microenvironment during cancer development. Bacterial proteins perform biochemical functions directly, and indirectly, interacting with host cancer cells, regulating the expression of genes and pathways associated with tumorigenesis. Mass spectrometry (MS)-based metaproteomics offers a powerful means to characterize functional proteins that contribute to microbe-host interactions in cancer. However, metaproteomic analysis is limited by the low abundance of microbes compared to host cells within the tumor microenvironment. Current approaches for enrichment (e.g., differential centrifugation) only modestly increase detection of microbes, while culturing samples to boost bacterial abundance suffers from loss of unculturable microbes and their in vivo. An approach to efficiently enrich microbes directly from clinical cancer samples, such as tissue biopsies and fluids, and enable deep metaproteomic analysis, would transform our ability to investigate the mechanisms by which non-host microorganisms influence carcinogenesis and treatment. To address this challenge, we propose to develop and optimize a novel approach for enriching microbes from clinical cancer sample (CS) specimens, by developing a novel approach based on bio-orthogonal non-canonical amino acid tagging (BONCAT), coupled with cell sorting enrichment and sensitive MS-based metaproteomics. Our interdisciplinary team, which includes clinical and translational cancer research partners, brings the necessary expertise and access to clinical samples necessary for developing, optimizing, and demonstrating effectiveness of our approach. Our work will pursue these Aims: Specific Aim 1. Optimize and evaluate CS-BONCAT in samples of known composition; Specific Aim 2. Optimize and demonstrate proof-of-concept using CS-BONCAT to enable metaproteomic analysis of clinical cancer samples. We will focus on optimization in brush biopsy samples from oral cancer patients, and further demonstrate effectiveness in evaluating bacterial metaproteomes associated with colorectal and ovarian cancers from clinical samples. We will evaluate the effectiveness of our optimized approach through quantitative performance measures, ensuring CS-BONCAT will be useful for the cancer research community. We will promote adoption of CS-BONCAT by cancer researchers as part of a complete, clinical metaproteomics workflow through accessible online and on-demand multimedia resources. Once completed, we will deliver a transformative approach to better understand microorganism contributors to tumorigenesis, impacting diagnosis, prevention, and treatment for many cancer types.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Visual Snow Syndrome (VSS) is a poorly understood neurological condition whose primary symptom is the constant perception of flickering specks, like television static, superimposed on the visual world. VSS can be debilitating, interfering with daily life activities such as reading and driving. The cause of this condition remains unknown, and there are currently no effective treatment options. Our proposal builds on our recent discovery that a method called visual adaptation can temporarily alleviate visual snow symptoms. This exciting revelation gives us a powerful new tool for understanding the neural basis of visual snow. In this proposal, we will test the hypothesis that VSS is caused by excess spontaneous neural activity within visual brain areas. To do so, we will compare behavioral tests of visual perception using adaptation in people with VSS versus normally sighted control participants, as well as non-invasive measurements of neural activity (functional magnetic resonance imaging) and brain chemistry (magnetic resonance spectroscopy). Understanding where and how spontaneous neural activity leads to visual snow percepts will pave the way for new treatment strategies, objective tests, and biomarkers for VSS, which may in turn improve quality of life, diagnosis, and evaluation of treatment efficacy in this disorder.

NIH Research Projects · FY 2026 · 2025-03

Project Summary Peripheral artery disease (PAD) results in the progressive reduction of blood flow to peripheral body parts including the lower limbs. The resulting ischemic muscle triggers an increased arterial pressure during lower limb movements that is due to an exaggerated exercise pressor reflex (EPR). The EPR is a neural feedback mechanism that leads to a physiological increase in blood pressure upon muscle contraction. When the EPR is exaggerated in PAD, such that even low levels of muscle contraction (e.g., elicited by walking) cause abnormally high blood pressure responses. This significantly contributes to the high risk of cardiovascular morbidity and mortality in patients with PAD. Therefore, exercise, which has been shown to be beneficial for improving muscle function and repair in patients with PAD cannot be safely prescribed to the patients. This emphasizes the need for therapies that can normalize the EPR. The mechanically sensitive arm of the EPR mediates its exaggeration in PAD, as has been shown by rodent femoral artery ligation (FAL), a well-established model of PAD. FAL chronically sensitizes the mechanically sensitive receptors e.g., Piezo2, but the mechanism is unknown. Preliminary studies from our lab show that Piezo2, in part, mediates the exaggerated EPR. The ischemic muscles of patients and rodent models with PAD exhibit increased expression of pro-inflammatory genes and immune cell infiltration. The effect that the resulting inflammatory cytokines from the ischemic muscle has on the muscle mechanosensitive afferent neurons and their resident ion channels is unknown. Previous findings have reported a signal transduction pathway that begins with an inflammatory mediator and culminates in the heightened activity of a mechanosensitive channel in somatosensory neurons. Therefore, the hypothesis of this proposal is that the pro-inflammatory signals from the ischemic muscle increase the expression and activity of Piezo2 channels in mechanosensitive afferent neurons. To test this hypothesis, the proposed aims (Aim 1) will determine the effect of proinflammatory mediators on the activity and expression of Piezo2 channel and other mechanosensitive channels in mouse dorsal root ganglia (DRG) sensory neurons and hiPSC-derived sensory neurons (hiPSC-SN). The effects of proinflammatory mediators in the absence of ischemia on Piezo2 and other mechanosensitive channels’ expression and activity will also be investigated in vivo. To establish a definitive cause-and-effect relationship between muscle inflammation and Piezo2 sensitization, the proposed experiments involve macrophage depletion under ischemic conditions. The effects of this depletion on the activity and expression of Piezo2 and other mechanosensitive channels in the DRG will be investigated. The resulting findings will offer insights into the interplay between neural and immune responses in PAD, potentially leading to novel therapeutic strategies to better managing the cardiovascular risks associated with PAD, especially during exercise. Beyond the immediate aims, these findings could inform research into other cardiovascular diseases where ischemia and inflammation play critical roles.