Mayo Clinic Rochester

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Corticobasal syndrome (CBS) is a neurodegenerative disorder characterized by impaired motor and higher cortical function. Pathologies underlying CBS are heterogeneous; ~60% have a 4-repeat (4R) tauopathy (CBS- 4R) and 20-30% have Alzheimer’s disease (CBS-AD). It has been shown that molecular pathology influences patterns of brain atrophy in CBS, yet little is known about biological disease mechanisms underlying CBS and how mechanisms are related to molecular pathology. This R01 will focus on assessing the biological mechanism of neuroinflammation in CBS. Neuroinflammation plays a key role in the pathogenesis of different neurodegenerative diseases, including AD and 4R tauopathies, and has been linked mechanistically to damage of the white matter which is a key feature of CBS. The first aim of the grant will use the PET ligand 1C-ER176 to assess the distribution of neuroinflammation in the brain and Neurite Orientation Dispersion and Density Imaging (NODDI) to measure white matter microstructure. The second aim will measure biomarkers of neuroinflammation from blood plasma, such as plasma glial fibrillary acidic protein and proinflammatory cytokines. We will prospectively recruit 80 CBS patients, with each participant undergoing clinical testing, MRI diffusion tensor imaging, ER176, Aβ and tau-PET, and a blood draw. The Aβ and tau PET will be used to classify CBS patients with (CBS-AD) and without (CBS-4R) biomarker-confirmed AD. We will determine whether patterns of ER176 uptake, NODDI abnormalities, and blood plasma metrics differ between CBS-AD and CBS-4R and whether they differ compared to 30 healthy controls and 30 patients with amnestic AD. We will also assess relationships between these different outcome measures and determine whether they are related to markers of disease severity. These first two aims will determine the role of neuroinflammation and white matter microstructure damage in CBS and whether neuroimaging and plasma metrics can be used as indirect biomarkers of AD in CBS. Forty CBS patients will be brought back after two years to allow for the assessment of longitudinal relationships. As we are unable to determine the exact molecular pathology underlying CBS-4R during life, we will further this work in aim 3 by assessing our disease mechanisms of interest in an autopsy cohort of 90 CBS patients with known pathology. We will measure burden of activated microglia and astrocytes, myelin and tau proteins from brain tissue and determine whether burden differs across the three most common pathologies underling CBS-4R (corticobasal degeneration n=30, progressive supranuclear palsy n=30) and CBS-AD (n=30). Findings from aim 3 will complement and help validate findings from our clinical cohort in aims 1&2. This grant is highly significant as results will help elucidate the mechanistic role of neuroinflammation and white matter damage in CBS and determine the value of neuroimaging and plasma measures as biomarkers of disease and pathology. This work may also provide potential mechanistic treatment targets for CBS and biomarkers to help in the selection/stratification of patients for clinical trials.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Dihydropyrimidine dehydrogenase (DPD) deficiency, caused by mutations within DPYD, has been studied mostly in the context of 5-fluorouracil (5-FU) toxicity and its role as a pharmacogene. However, a rare pediatric disorder with severe early onset symptoms, pediatric DPD deficiency, is also linked to genetic variation within DPYD. The molecular mechanisms that contribute to disease onset and associated symptoms are unknown, nor have any effective therapeutic avenues been identified, likely owing to the lack of mechanistic knowledge. Therefore, in the proposed studies, I will use induced pluripotent stem cell (iPSC)- derived cerebral organoid models of pediatric DPD deficiency to identify the mechanisms linking DPD deficiency with the outward symptoms of the condition. The overall goals of the proposed studies are to define disease etiology, determine molecular mechanisms that lead to disease onset, and to identify potential therapeutic targets. We hypothesize that dysregulation of excitatory and inhibitory signaling within the brain contributes to seizure onset and epilepsy due to excitotoxicity and a decrease in β-alanine inhibitory signaling, along with anatomical structural changes across development and differences in cellular composition. We further hypothesize that the symptoms of this disorder could be relieved by correcting genetic variation within DPYD. To address this hypothesis, we will identify differentially expressed genes and dysregulated pathways at bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) levels to determine molecular mechanisms contributing to the disease. We will investigate the potential for dysregulation of gene expression via epigenetic mechanisms and perform functional studies of organoid signaling. Finally, isogenic cell line models will be established to determine if the molecular and functional phenotype of organoids derived from affected patients is specifically dependent on DPYD genetic variation. Overall, these data will describe the etiology of pediatric DPD deficiency, determine molecular mechanisms and pathways contributing to symptom onset, and aid in therapeutic target identification for disease treatment. These studies will provide broad implications into the role of DPYD in neurological development and developmental mechanisms contributing to pediatric genetic epilepsy onset.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY/ABSTRACT Focal bone marrow biopsies of the posterior iliac crest are the gold standard for diagnosing multiple myeloma, yet they do not reflect the spatial and genomic heterogeneity of the disease. Almost 25% of such patients do not have adequate samples for cytogenetic assessment need for risk stratification. This inconsistency in bone marrow sampling could result in falsely reassuring prognoses for patients with aggressive disease. Whole-body imaging presents an unrealized opportunity to derive image features in the bone marrow that reflect the cytogenetic diversity of clonal plasma cells. Several advanced imaging modalities are used for diagnosis and disease management. An alternative approach is to optimize one imaging modality for these tasks. Recently FDA approved photon- counting detector (PCD)-CT has technological advancements that permit simultaneous bone marrow composition quantification and lytic lesion detection throughout the whole skeleton. In addition, the quantitative accuracy of the spectral data can be used to determine changes in bone marrow and intralesional fat fraction, an indicator of treatment response. This proposal’s specific objective is to develop imaging based cytogenetic risk stratification models and a quantitative PCD-CT mechanism to accurately measure bone marrow composition. In Aim 1, we will develop and validate a deep- learning (DL) imaging-model for multiple myeloma cytogenetic risk stratification. In Aim 2, we will develop and validate physics-informed DL-assisted material decomposition to derive imaging biomarkers of multiple myeloma. In Aim 3, we will determine the clinical feasibility of the DL cytogenetic risk prediction model and imaging biomarkers for multiple myeloma prognostication and assessing response to therapy. This PCD-CT protocol will be a “one-stop shop” multiple myeloma tool for disease detection, prognostication, and treatment response assessment. The innovation of this proposal includes our development of an imaging protocol that leverages the many technical improvements of PCD-CT, AI image processing, and AI modeling to develop biomarkers from bone marrow composition. Secondly, a PCD-CT-based AI risk prediction model will be positioned to supplant focal invasive approaches that may not offer a comprehensive assessment of the entire heterogeneity of disease burden.

NIH Research Projects · FY 2025 · 2025-04

PROJECT SUMMARY/ABSTRACT The Mayo Clinic in Rochester, MN seeks funding to acquire the Bruker BioSpec 70/20 magnetic resonance (MR) imaging scanner, featuring a 7.0 Tesla magnet and a 20 cm horizontal bore. This instrument will significantly advance our research capabilities by addressing existing gaps in preclinical imaging. The chosen bore size and system configuration are deliberately selected to accommodate a wide range of small animal models, from zebrafish, mice (capable of imaging multiple mice simultaneously) to adult rats, essential for ongoing studies in neuroscience, cancer research, cardiovascular diseases, and beyond. This flexibility is crucial for implementing advanced imaging applications such as MR elastography, which requires extra space for actuators within the bore in contact with the subject to generate mechanical waves in soft tissues, enhancing our research capabilities in mechanical tissue properties from head to toe. The horizontal configuration of the BioSpec 70/20 is strategically justified to overcome physiological and technical limitations experienced with obsolete vertical NMR systems, such as organ shift due to gravity, which affects the consistency of quantitative imaging results. Horizontal positioning also facilitates easier access to the subject during scans, crucial for dynamic contrast-enhanced MRI and functional MRI, where precise and repeated interventions are required. Equipped with a high-performance gradient system and a 16-channel receiver, the BioSpec 70/20 will enable sophisticated quantitative imaging techniques essential for cutting-edge research. These include high- resolution diffusion tensor imaging for neurology studies, arterial spin labeling for assessing cerebral and tissue blood flow, and advanced cardiac imaging to capture the fast dynamics of small animal hearts. The system's superior gradients and slew rates are critical for applications requiring high signal-to-noise ratios and rapid acquisition times, such as diffusion-based cytometry and functional imaging of neuronal activity. The broad, long-term objectives of acquiring this system include enhancing our understanding of disease mechanisms and therapeutic responses at a microstructural level across multiple research programs. This system will support significant advances in liver disease research by enabling high-resolution imaging to evaluate fibrosis and inflammation, brain disease research through precise imaging of neurodegeneration, and nephrology and cardiovascular research by allowing detailed assessments of cardiac function, renal function and vascular morphology. In conclusion, the acquisition of the BioSpec 70/20 MRI system will transform the Mayo Clinic’s research landscape, bridging the gap between preclinical findings and clinical applications, and maintaining our leadership in biomedical research. This investment will not only advance our current projects but also pave the way for new discoveries and innovations in medical science.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY/ABSTRACT Primary aldosteronism (PA) is the most common cause of secondary hypertension, accounting for up to 15% of cases. Compared to primary hypertension, PA is linked to a 12-fold increased risk of adverse cardiovascular and renal events and increased mortality. Despite guideline recommendations for screening and the availability of screening tests and effective treatments, only 2% of at-risk individuals undergo PA screening. Further, the small proportion of individuals who are evaluated for PA often undergo screening too late, after they have already developed preventable cardiovascular and renal complications. However, the factors driving low and delayed PA screening rates have not been thoroughly investigated. This project will identify patient, clinician and health care system factors contributing to inadequate and delayed screening following an organized Implementation Framework to inform the development of future interventions that can improve the frequency and timeliness of PA screening. The long-term objective of this project is to ensure timely, evidence-based care for all individuals at risk of PA. In Aim 1, we will establish current patterns of PA screening by leveraging linked datasets, encompassing insurance claims and electronic health records of enrollees in private and Medicare Advantage health plans within the OptumLabs Data Warehouse (OLDW), connected to a 100% sample of Medicare fee-for-service beneficiaries (M-FFS). Significantly, the OLDW-M-FFS data originates from primary care practices (~70%), and non-academic institutions (~80%), mirroring real-world practices. Innovative machine learning techniques will be employed to model and identify factors associated with the frequency of PA screening and the duration of hypertension before testing. In Aim 2, we'll use a mixed-methods approach to explore factors behind the underutilization of evidence-based PA screening. Surveys and interviews with patients, clinicians, and practice leaders will be conducted across three large healthcare systems (University of Florida, Mayo Clinic, University of Michigan) and 10 regional sites, including primary care and rural practices. Finally, Aim 3 will use a Delphi-based implementation mapping approach to identify feasible and acceptable strategies targeting specific factors related to PA screening through collaboration with representatives from patient groups, clinicians, and health systems. By the end of the study, we'll have identified factors contributing to inadequate and delayed PA screening, offering a comprehensive, multilevel understanding of barriers and facilitators. Moreover, we'll propose mitigation strategies that are acceptable and feasible to important stakeholder groups from different settings. These findings will lay the foundation for developing and testing interventions to support evidence-based PA screening, improving health outcomes and reducing the burden of preventable morbidity and mortality associated with PA.

NIH Research Projects · FY 2025 · 2025-02

Project Abstract Cellular senescence is a key driver of many age-related diseases, yet its in vivo characterization remains challenging due to cellular heterogeneity and the lack of universal biomarkers. Deep learning classifiers based on morphological features hold promise for senescence detection, but existing models are unable to accurately identify individual senescent cells in complex tissue environments. As part of a SenNet-funded Technology development award (TDA), we have developed SenoQuant, an advanced AI-based analysis tool for multimodal imaging datasets. Using SenoQuant, we integrated single-cell spatial proteomics technologies (4i and CODEX) to analyze senescence-associated markers in human skin. From these data, we trained a deep learning classifier capable of identifying p21+ senescent cells at single-cell resolution using only DAPI staining, achieving 87% accuracy. Unlike conventional classifiers trained on in vitro datasets, our model is the first to leverage spatial omics data to capture the complexity of senescent cells in situ. Building on this success, we aim to enhance the accuracy and expand the scope of our classifier to detect a broader range of senescent cell types (senotypes). Utilizing omics datasets from aged human skin and lung, including SenNet’s benchmarking project comparing spatial omics technologies within the same tissue, we will develop more robust models. Additionally, we will integrate our classifier into SenoQuant, providing researchers an easy-to-use, no-code required solution to analyze DAPI-stained images and automatically quantify senescent cell burden. These advancements will have profound implications for both fundamental research and translational applications. By enabling cost-effective, high-throughput senescent cell detection, our work will accelerate drug discovery, biomarker development, and diagnostics, ultimately advancing our understanding of aging and age-related diseases.

NIH Research Projects · FY 2026 · 2025-02

Abstract This project will develop a novel gene therapy for bone healing based upon new insights from our laboratory on the osteogenic properties of transgenic bone morphogenetic protein-2 (BMP-2), its modulation by inflammatory mediators, especially interleukin-1 (IL-1), and the biology of the healing of large osseous segmental defects. A validated rat model will be used in which a 5 mm critical size, segmental defect is surgically created in the femur. Both female and male animals will be used. BMP-2 is a highly osteogenic morphogen. Recombinant, human (rh) BMP-2 is used clinically in bone healing but its potency is weak, necessitating the use of milligram amounts of rhBMP-2. These are expensive and produce a variety of side effects, some of them serious. Prior work by our group has shown that transgenic BMP-2 delivered by an adenovirus vector is 2-3 log orders more effective than rhBMP-2 in healing rat segmental defects but that its effectiveness is limited by an inflammatory response to the adenovirus and, in particular, the local synthesis of IL-1 which reduces the effectiveness of BMP-2. By inhibiting chondrogenesis, IL-1 inhibits endochondral ossification and drives osteogenesis down the intramembraneous pathway. We have shown that, in this model, the intramembraneous route produces bone of inferior quality. In the proposed research we will develop an effective, affordable, clinically expedient gene therapy for healing critical size, osseous defects based on the use of adeno-associated virus (AAV), a less inflammatory vector, to deliver BMP-2 to the defect site. Because our laboratory focuses on research translation, we evaluated different serotypes of AAV to identify a serotype that transduced both human and rat mesenchymal stromal cells (MSCs). Finding none, we engineered AAV8 to include a RGD sequence to enable integrin binding and confirmed that this novel serotype transduced both human and rat MSCS, and transduced cells within the femoral defect in vivo. We thus propose to use AAV8-RGD in this project. In Specific Aim 1, vector encoding a green fluorescent protein-luciferase (GFP-luc) marker gene will be implanted into the defect on the same collagen sponge that is used clinically to deliver rhBMP-2. The level and duration of transgene expression will be measured by an in vitro imaging system (IVIS), enabling us to identify a dose that efficiently transduces cells within the defect with transgene expression persisting for at least 1-3 weeks which our prior data suggest is optimal for bone healing in this model. In the second part of this aim, AAV8-RGD will be engineered to encode either BMP-2 alone or BMP-2 and IL-1 receptor antagonist (IL-1Ra) in a bicistronic vector. The two constructs will be compared in their ability to heal the defect and an optimal dose identified. In Specific Aim 2, the quality of the regenerate will be assessed by mechanical testing and micro-computed tomography. Histology will determine whether the new bone form intramembraneously or by endochondral ossification. ELISA and RT-PCR will be used to measure expression of IL-1a, IL-1b and human and rat BMP-2. In Specific Aim 3, single cell RNA sequencing and in situ hybridization (RNAScope) will be used to identify transduced cells and locate them within the defect.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT: The current application is an important step towards accomplishing the applicant’s career goal of becoming an independent translational investigator of exercise benefits to human health. Towards that goal, the applicant’s focus is to understand mechanisms of type 2 diabetes (T2D) and its complications. Muscle insulin resistance is a precursor to the development of T2D. Muscle is the primary tissue for insulin mediated glucose disposal, and loss of muscle mass contributes to insulin resistance. Therefore, maintaining muscle mass is key for regulating insulin sensitivity. Resistance exercise training (RET) enhances muscle mass and strength, and improves insulin sensitivity in people with T2D, but mechanisms of RET are unclear. The overarching goal of this application is to identify mechanisms of RET on enhanced metabolism. Synthesis of new protein machinery for improves metabolism in response to exercise training, but it is unclear which metabolic machinery are synthesized. Additionally, emerging data indicate post-translational modifications (PTMs), especially phosphorylation and acetylation, are key intracellular signaling mechanisms for enhancing insulin sensitivity with exercise, and may explain the improvement in insulin sensitivity with resistance exercise training that occurs before the accretion of new muscle proteins. Our preliminary data show that acetylation of glycolytic and contractile proteins are reduced by RET, which we propose enhances glycolytic protein function for rapid ATP supply, thus enhancing insulin sensitivity. In Aim 1, we will utilize an innovative approach to measure synthesis rates of individual muscle proteins using stable isotope labeling in primary human myotubes to determine which proteins have increased synthesis rates in response to RET. In Aim 2, hyperinsulinemic- euglycemic clamps and muscle biopsies will be performed before and after 2 weeks of RET in sedentary people to determine if glycolytic and contractile protein deacetylation or phosphorylation is associated with insulin sensitivity. Together the results from Aims 1 and 2 will unveil new mechanistic targets for understanding how RET influences metabolism. An understudied yet promising molecular target of RET effects is an isoform of the transcriptional coactivator PGC-1α, PGC-1α4. PGC-1α4 is upregulated by RET in humans, and regulates muscle hypertrophy, glycolysis, and insulin sensitivity, but the role of PGC-1α4 in RET-induced muscle protein synthesis is unknown. Using C2C12 myotubes, Aim 3 will determine individual protein synthesis rates, mRNA expression, and post-translational modifications in response to PGC-1α4 overexpression. The results from these studies will reveal downstream targets of RET on muscle glucose metabolism for future investigation, providing a foundation for the applicant’s long-term career goal of establishing a translational research laboratory investigating exercise- mediated effects on metabolism. The individually tailored training plan, outstanding research environment, and multidisciplinary mentoring team provides the applicant an opportunity to learn new research techniques and successfully complete the proposed research projects to develop as an independent translational investigator.

NIH Research Projects · FY 2025 · 2025-01

PROJECT SUMMARY Alzheimer's disease (AD) is a major public health problem affecting an estimated 6.7 million Americans. However, ~25% AD patients present with atypical non-amnestic clinical features such as visual, language, behavioral, executive, or motor difficulties. Furthermore, not all patients that present with these clinical phenotypes show evidence of amyloid and tau on positron emission tomography (PET). To date, there have been no reports on the diagnostic utility and performance of blood plasma biomarkers in atypical AD patients. There is an urgent need to address this to allow blood plasma biomarkers to be incorporated into clinical practice to improve diagnosis and reduce diagnostic delays, and in clinical trials to aid patient selection and provide disease outcome measures. The overall goal of this R03 is, therefore, to determine the diagnostic utility of plasma biomarkers and their relation to aspects of pathophysiology in atypical AD. This R03 will leverage existing blood samples, and clinical and neuroimaging data from 210 patients recruited into R01-AG50603 (PI Whitwell) to address the following specific aims: 1) To assess the value of blood plasma measures as diagnostic biomarkers in atypical AD. Here we will assess whether plasma biomarkers would be useful diagnostic biomarkers in atypical AD patients, if they could differentiate atypical AD patients from healthy controls and from patients that present with these clinical syndromes but do not have AD. 2) To assess the value of blood plasma measures as useful disease biomarkers/outcome measures in atypical AD. Here we will assess whether plasma biomarkers could be useful disease markers and whether they are related to clinical outcomes and other aspects of brain pathophysiology, including amyloid and tau burden, brain metabolism and brain volume. This research proposal is innovative because it investigates the utility and performance of these plasma biomarkers in atypical AD patients, who, despite being a part of the AD continuum do not present with memory loss but presents with deficits in non-memory domains and distinct neuroimaging signatures. This is important because current AD trials typically emphasize memory dysfunction as key criteria, which atypical AD patients do not fulfil. Hence the inclusion of plasma biomarkers as pre- selection tools in AD treatment trials will allow the inclusion of these patients. Another regard in which this research proposal is innovative is its focus on identifying the relationship between plasma markers, neuroimaging biomarkers and aspects of brain pathophysiology in atypical AD patients. This is important as it will establish how plasma biomarkers relate to meaningful outcomes in atypical AD patients during clinical trials. Ultimately, this R03 will have a significant impact on public health as atypical AD affects ~1 million Americans.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Epilepsy impacts 1% of the US population with a third experiencing drug-resistant epilepsy. FDA-approved treatments like anterior nucleus of the thalamus deep brain stimulation, and thalamic responsive neurostimulation show great promise, however, rarely achieve seizure freedom. Thalamic neuromodulation is limited by a generic approach to electrode targeting and stimulation parameter selection, which does not account for highly variable patient specific seizure network (SN) structure and excitability. Our hypothesis is that optimal thalamic neuromodulation requires a highly personalized approach, with SN-specific electrode targeting, and short-latency biomarkers for efficient data-driven optimization of stimulation parameters. The objectives of this research are to 1) delineate and measure precise causal connections within brain networks (effective connectivity) using single pulses of stimulation delivered through stereotactic intracranial EEG (sEEG) leads, and 2) characterize thalamic neuromodulation induced changes in network excitability using short-latency electrophysiology biomarkers. Here, we will employ clinical intracranial stereotactic EEG (sEEG) that includes a thalamus electrode, and single pulse and repetitive high frequent stimulation to map, characterize, and modulate brain networks. We aim to 1) map thalamocortical effective connectivity using single pulse electrical stimulation during sEEG (3-4 thalamus stimulation sites, and approx. 200 recording locations per individual); 2) characterize the temporal structure of thalamocortical evoked potentials in non-seizure and seizure networks using a data- driven computational machine-learning approach (identify specific features that distinguish normal from seizure networks); and 3) characterize thalamic high frequency stimulation induced changes on network excitability, and the timescales of effects. This work aims to develop a highly personalized approach to thalamic neuromodulation, with seizure network specific electrode targeting and data-driven stimulation parameter optimization. Lastly, we will use an ethics framework to gather and integrate patient perspectives on precision neuromodulation to ensure that efforts align with patient priorities. My career development objectives are to gain expertise in: 1) multimodal brain network mapping, integrating electrophysiology and imaging techniques (SA1), and 2) advanced signal processing and machine- learning methods for data-driven feature classification (e.g. distinguish normal from seizure networks (SA2); quantify stimulation induced changes in excitability (SA3)). I will develop independent expertise with flexible neuromodulation systems (g.tec, NeuraLynx, Cadence) (SA1, 3). Further, I will pursue comprehensive training in translational research, clinical trial conduct, and grant writing, equipping me for the shift to an independent research career. This career development award is pivotal for my progression towards independent RO1 funding and provides the foundation for clinical trials in personalized thalamic neuromodulation for epilepsy.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Patients with glioblastoma (GBM) are routinely treated with radiation (RT), temozolomide (TMZ), and glucocorticoids. However, these treatments often result in long lasting treatment-related lymphopenia (TRL) that is associated with shorter survival. In addition, lymphopenia is associated with unresponsiveness to checkpoint inhibitors. Here, we explore a novel approach to mitigate TRL in order to enhance response to immunotherapy and improve survival in GBM. Interleukin 7 (IL-7) is a hematopoietic growth factor and homeostatic cytokine that preferentially supports the growth and survival of the B and T lymphocytes. NT-I7 is a novel long-acting form of recombinant human IL-7 fused with hybrid Fc. We recently reported that NT-I7 significantly prolonged survival in glioma murine models through increasing cytotoxic CD8 T cells and decreasing regulatory T cells in the tumor. The survival advantage from NT-I7 is CD8 dependent in our model. Additionally, we conducted a first in-human phase I/II clinical trial to evaluate the safety and effect of NT-I7 on absolute lymphocyte counts (ALC) in patients with gliomas following standard RT and TMZ therapy. We found that NT-I7 is well tolerated and significantly increased ALC. Immunophenotyping of peripheral blood suggested predominately CD8 expansion following NT-I7 administration. In addition, preliminary data from an immune resistant CT2A murine glioma model demonstrated that combination of NT-I7 with anti-PD-1 blockade increased survival. Thus, we have developed a new phase II study with a safety run-in cohort evaluating the safety and efficacy of neoadjuvant and adjuvant NT-I7 plus pembrolizumab in patients with recurrent GBM. Here we are requesting funding for obtaining and processing specimens and for conducting proposed correlative studies associated with this trial as outlined in Aim 1. In addition, we will be conducting preclinical studies to dissect the mechanisms of NT-I7 immunotherapeutic effect. We hypothesize that NT-I7 can enhance immune response through antigen specific priming CD8 response and improve anti-tumor efficacy of checkpoint blockade in GBM. In Aim 1, we will collect pre- and post-treatment tumor tissues and peripheral blood to conduct comprehensive immuno-profiling using state-of-the-art CyTOF and Hyperion Imaging Mass Cytometry. Additionally, we will assess CD8 T cell infiltration within the CNS and evaluate the predictive performance of peripheral CD4 and CD8 Tscm as a biomarker of therapeutic efficacy. In Aim 2, we will dissect the mechanisms of NT-I7 on enhancing CD8 T cell trafficking and infiltration into the CNS in glioma murine models. Our group has generated novel transgenic mice that enable conditional silencing of the MHC class I molecules, H-2Kb on specific cell types. We will employ these transgenic mice to define the specific antigen presenting cell subsets (macrophages, microglia, and dendritic cells) contribute to the generation of distinct brain infiltrating CD8 T cell responses with NT-I7 treatment.

NIH Research Projects · FY 2026 · 2025-01

SUMMARY Although preclinical studies have implicated inflammation as a main driver of atherosclerotic disease for the past two decades, its clinical relevance has only been recently validated in proof-of-concept trials. Immune checkpoint proteins, including co-stimulatory and co-inhibitory proteins, are master regulators of the immune response and were originally described to allow cognate interactions between T cells and antigen presenting cells (APCs). Lately, it has become clear that immune checkpoint proteins are expressed on a plethora of immune cells, including macrophages. The sequence, the location and the extent of these interactions condition the very establishment of an immune response and its resolution or chronicity. Understanding the role of immune checkpoint proteins in CVD is crucial, as immune checkpoints exert cell-type specific actions and signaling in atherosclerosis and can therefore be targeted specifically. We have identified an important role for the co-stimulatory immune checkpoint protein Glucocorticoid Induced TNF-Related Protein (GITR) in atherosclerosis. In human atherosclerotic plaques, we found that GITR expression is associated with a vulnerable plaque phenotype. Although GITR is well-known to be expressed on T cells, our preliminary data show that macrophage GITR plays a key role in atherosclerosis. Macrophages in plaques start expressing GITR in intermediate and advanced stages of atherosclerosis and Cite-seq analysis of the mouse atherosclerotic aorta showed that GITR+CD68+ cells display the transcriptome of inflammatory macrophages. GITR-/-ApoE-/- mice display a reduction in atherosclerosis and develop a stable plaque phenotype, due to a reduction of monocyte recruitment and macrophage activation. Deficiency of GITR did not affect regulatory or effector T cells. Likewise, LysM-GITRflflApoE-/- mice, but not CD4-GITRflflApoE-/- mice, develop less atherosclerosis. Deficiency of GITR on macrophages reduces their migration, TNF production, ROS levels and mitochondrial stress. Elevated plasma levels of sGITR, which we found to be released by macrophages and not T cells, are associated with the presence of CVD. We hypothesize that GITR-signaling in macrophages drives atherosclerosis, and that targeting (macrophage) GITR is a safe immunotherapeutic approach that will ameliorate ASCVD, as GITR deficiency affects macrophage biology, but not T cell function. We propose to unlock GITR’s full translational potential as biomarker and immunotherapeutic target for atherosclerosis. In aim 1, we will detail GITR’s macrophage specific effects and mechanisms in atherosclerosis. In aim 2, we will test the translational potential of our newly designed GITR inhibitors using a systemic and macrophage targeted nanobiologic approach. In aim 3, we will test the potential of sGITR as biomarker for CVD. Knowledge on cell-type specific actions of immune checkpoints warrants cell targeted immune checkpoint- based therapeutics that attenuate atherosclerosis-specific inflammatory pathways and will cause limited immune-related side effects, an essentiality to render immunotherapy a relevant treatment modality for CVD.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract Chronic pain is experienced by more than 30% of older adults (>65 years of age), many of whom receive prescription opioids despite well-described adverse effects including gastrointestinal distress, constipation, physical dependence, and respiratory depression. More recently, longitudinal observational studies led by our group and others have highlighted that prescription opioids are associated with accelerated cognitive decline in older adults, including increased risk for mild cognitive impairment or dementia. However, two critical gaps remain in our understanding of the relationship between prescription opioids and cognition. First, existing observational studies are unable to adequately distinguish the effects of opioids from those of underlying chronic pain necessitating opioids (i.e., confounding by indication). Second, the biological mechanisms driving the relationships between opioids and cognition are unknown. We find in prior work that prescription opioids are associated with decreased white matter integrity in major axonal pathways, including the corpus callosum and other pathways integral to cognitive and emotional processing. These findings are consistent with preclinical studies showing the opioids impair myelin production by oligodendrocytes. However, as with cognition, these observational data cannot be used to distinguish the potential causative effects of opioids from the effects of underlying pain. The overall purpose of this project is to test the hypothesis that opioid-mediated impairments in myelin production and/or other direct or indirect effects on axonal integrity mediate opioid- associated cognitive impairment. We will conduct a single-center, double-blinded, placebo-controlled trial including 200 participants with chronic pain secondary to osteoarthritis. The primary aim is to determine whether exposure to prescription opioids is associated with brain structural changes on magnetic resonance imaging (MRI), with the primary outcome of white matter integrity as measured by fractional anisotropy of the corpus callosum. The secondary outcome will be global cognition. Exploratory outcomes include several patient-centered outcomes (mental health, physical function, quality of life, sleep). All participants will receive evidence-based, tiered interventions to treat their pain under the direction of the study team (experts in pain management for older adults). In addition, they will be randomized to receive either opioids or placebo over a 6 week treatment period with titration of study medication based on pain scores per a defined protocol. All participants will undergo MRI imaging at enrollment and again at 12-months to evaluate the primary outcome. Participants will also undergo neurocognitive testing and assessment of exploratory patient-centered outcomes (e.g., quality of life). Our team has the requisite experience and expertise to perform this innovative research, whose findings will have a major impact on clinical practice and shared clinical decision making, regardless of study results.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Prenatal inflammation is observed in pregnancy complications, especially those complicated with preterm birth (PTB). Prenatal inflammation is a major cause of neonatal mortality and morbidity with significant impacts on neurodevelopment as well as lung and immune system development. PTB affects 10-12% of births in the United States. The cellular process behind the subsequent altered placental inflammation is not fully understood, complicating attempts to treat or prevent it. Thus, the objective of this grant is to investigate the mechanisms through which placental resident macrophages, namely Hofbauer cells, are involved in the placental impact of prenatal inflammation. Hofbauer cells are the predominant immune cell type within the placenta; these macrophages are known to release pro-inflammatory cytokines when stimulated. The central hypothesis that the pro-inflammatory profile at the maternal-fetal interface with prenatal inflammation is primarily driven by Hofbauer cells will be addressed in two specific aims. First, the Hofbauer cell inflammatory profile in physiological birth (Term) vs. pathological pregnancies (PTB) will be determined. Second, the Hofbauer cell- specific contribution to the altered inflammatory profile, as is observed in the placenta following pathological prenatal inflammation, will be modeled in in vitro and in vivo models using pathogen-associated molecular patterns (PAMP) stimulation. This project recognizes the complex dynamics of contribution to inflammation and considers all cell types, and their spatial distribution, within the placenta in inflammatory contribution. Thus, spatially resolved techniques will be used to study the Hofbauer cell contribution to inflammation. Our models include primary cell suspensions combined with a rodent model. Ultimately, this work will contribute to improved understanding of the impact of prenatal inflammation at the maternal-fetal interface, the role of Hofbauer cells in response, and potential for targeted anti-inflammatory therapy. Completing the planned education outlined in goals for fellowship training and this project will contribute to my overall formation as an independent physician scientist with a career in advancing the research and care for women’s health.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Our Translational Training in Respiratory Disease and Repair T32 seeks to train the next generation of basic, translational and clinician scientists capable of working together to advance respiratory medicine toward approaches that fully restore respiratory function in the setting of disease and dysfunction. We request support for 5 postdoctoral trainees who will be mentored by an interdisciplinary and highly collaborative faculty of 26 individuals spanning basic (Physiology and Biomedical Engineering, Biochemistry and Molecular Biology) and clinical (Anesthesiology, Pulmonary Medicine, Allergy, Cardiology, Surgery, Radiology) departments and divisions within the Mayo Clinic College of Medicine and Science. Research and training conducted under this program will span basic to clinical aspects of respiratory biology, physiology, and medicine. The basic research thrust will train mentees to identify novel targets and approaches to defend, repair and regenerate respiratory function in the setting of disease and dysfunction. A translational thrust focused on technology development and therapeutic approaches will prepare trainees to generate novel tools and techniques needed to break through current barriers limiting our understanding of, and capacity to reverse, acute and chronic respiratory conditions. The clinical research thrust will bridge behavioral, clinical and translational studies and will focus trainees on the unmet needs of patients while providing them with rich access to clinical data and biospecimens. It will also allow trainees to experience and/or participate firsthand in implementation of novel findings (technological or therapeutic) into clinical practice. Cross-cutting themes interwoven with these programs will include Respiratory Biology Across the Lifespan spanning neonatal diseases and lung development to aging-related disease and functional decline, and Human Disease Modeling which will develop novel approaches to study living human cells and tissues as essential tools for bridging bench to bedside. The resulting T32 program will combine exceptional physical resources, a rich and collaborative intellectual environment, and an interdisciplinary and translational emphasis to train the next generation of scientists and clinicians to tackle the most challenging unmet needs in respiratory disease and repair.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT Light chain (AL) amyloidosis is a rare plasma cell disorder. It is caused by abnormal misfolding of monoclonal immunoglobulin light chains causing extracellular deposition of amyloid, which ultimately results in organ dysfunction and death. The treatment goal in AL amyloidosis is elimination of the production of the amyloidogenic light chains by means of anti-plasma cell therapies, which can allow for organ recovery and extended survival. The phase III randomized ANDROMEDA study, which showed superiority of daratumumab- CyBorD over CyBorD induction in the rate of complete hematological response and overall hematological response rate, established the standard of care for newly diagnosed AL amyloidosis as daratumumab-CyBorD. However, the study continued with daratumumab maintenance for up to 18 cycles in those receiving daratumumab-CyBorD induction, in a non-randomized manner, thus providing no proof of the need for maintenance therapy in this disease or for its optimal duration. Our main objective in this study is to assess the optimal duration of maintenance in the post-Andromeda era. The proposed study is a phase II randomized study where patients achieving adequate hematological response to daratumumab-CyBorD induction will be randomized in a 1:1 ratio to single agent daratumumab maintenance of 6 months (experimental arm), versus 18 months of daratumumab maintenance (control arm). The study will have a pragmatic trail design with the use of broadened eligibility criteria to allow participants at different stages of the disease to take part. In Aim 1, the primary assessment of efficacy will be event-free survival (EFS). In Aim 2, we will assess secondary efficacy endpoints including hematological response; measurable residual disease (MRD) assessed by next generation multiparametric flow cytometry; depth of organ response; adverse events (especially infections and IVIG use); time to next therapy, and overall survival. In Aim 3 we will assess patient-reported quality of life assessed in a longitudinal manner throughout maintenance and after maintenance completion using the PROMIS29 questionnaire and selected items from the PRO-CTCAE questionnaire. The study will be conducted at Mayo Clinic campuses in Arizona, Florida, and Minnesota with 96 patients planned to be accrued to meet the statistical design for a non-inferiority study. The study’s key strength is its design as a pragmatic trial, thus reflecting real world practice. As part of that, we will allow treatment by the local medical doctor with interval visits to the Mayo Clinic campus for efficacy and safety assessments. We bring a research alliance in plasma cell disorders between the three Mayo Clinic campuses. Lastly, MRD testing and quality of life assessment are innovative tools in clinical research in AL amyloidosis, and will be assessed longitudinally in this study.

NIH Research Projects · FY 2026 · 2024-12

Abstract This proposal aims to investigate the mechanisms underlying PARP inhibitor (PARPi) resistance in prostate cancer and identify potential strategies to overcome this resistance. Prostate cancer is a prevalent cancer in men, and recently, PARPi has been approved to treat metastatic castrate- resistant prostate cancer (mCRPC) patients whose disease has stopped responding to second- generation anti-androgens and whose cancers are homologous recombination deficient (HRD). While some patients treated with PAPRi show promising results, a significant percentage of patients do not respond to these drugs even with HRD. In addition, acquired resistance inevitably develops. Thus, it is critical to identify mechanisms contributing to PARPi resistance. We have discovered that a specific isoform of histone methyltransferase NSD3, called NSD3S, is overexpressed in PARPi-resistant prostate cancer cells. Based on our preliminary data, we hypothesize that NSD3S plays a crucial role in driving PARPi resistance through its influence on replication fork dynamics. Furthermore, we have found that the NSD3S is regulated by a CRL E3 ubiquitin ligase whose misregulation contributes to NSD3S high expression in PARPi-resistant cells. We propose three specific aims to test these hypotheses. Aim 1 aims to investigate the mechanistic role of NSD3S in regulating DNA replication dynamics and its contribution to PARPi resistance. Aim 2 focuses on understanding the mechanisms responsible for NSD3S upregulation in PARPi-resistant lines. Aim 3 aims to explore new approaches based on our results to overcome PARPi resistance in prostate cancer using in vitro and in vivo models. Successful completion of this study would not only provide insights into the mechanisms of PARPi resistance and replication fork dynamics driven by NSD3S but also have implications for the development of precision medicine approaches in prostate cancer treatment.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT RESEARCH: Aging is the single greatest risk factor for a multitude of morbidities. While multifactorial, a central mechanism of aging is cellular senescence, a complex, context-dependent cell fate with important roles in both, physiological and pathological processes. The acute generation and subsequent elimination of senescent cells is usually a physiological, beneficial process associated with accelerated tissue regeneration after injury, but the aberrant senescent cell accumulation is linked to a wide range of pathologies, morbidities, and shortened healthy life spans in mice. The mechanisms governing physiological senescent cell elimination, or their pathological accumulation with age are incompletely understood, particularly in the human context. T cells have emerged as one of the crucial players in controlling and killing senescent cells, however, how senescent cells engage and activate T cells to elicit T cell activities and cytotoxicity is largely elusive. In this proposal, I investigate molecular mechanisms of T cell-mediated surveillance of senescent cells under both physiological and aging conditions. In Aim 1, I will define how various types of senescent cells deploy their secretome to sensitize human T cells toward activation, survival, and retention. Aim 2 will assess co-stimulatory and co-inhibitory interactions between senescent cells and T cells, crucial prerequisites of effective T cell activity or inhibition. In Aim 3, I will perform translational studies in human kidney specimens to elucidate spatially resolved T cell surveillance of renal senescent cells as well as mechanistic studies in isolated primary renal cells. CANDIDATE: This proposal integrates my Ph.D. expertise in cellular senescence with my post-doctoral work on T cell aging and allows me to build an independent, unique research niche. However, to realize this goal, I require additional protected time and new research and professional skills. Here, I describe a detailed plan for my transition to independence. The research during the K99 phase will be conducted at Mayo Clinic, the world’s top-ranked hospital and an ideal institution for translational, human research on aging. The objectives of this proposal are to i) gain additional mentored research and career training to build an independent translational research program dedicated to age-related T cell dysfunction contributing to pathological senescent cell accumulation in humans; ii) perform a series of experiments to uncover molecular mechanisms of T cell engagement by senescent cells under optimal conditions and delineate the impact of T cell aging on senescent cell immune evasion. Completion of the proposed aims allows me to build a strong foundation on T cell surveillance of senescent cells enabling me to discover key mechanisms of senescent cell immune escape. This will leave me well-positioned to become an independent investigator, securing competitive funding, advancing the field of senescence immunosurveillance, and contributing towards my long-term research goal of promoting healthy aging through the development of immunotherapies targeting pathological senescent cells.

NIH Research Projects · FY 2026 · 2024-12

Given the heterogeneity and aggressiveness of TNBC, it is likely that successful novel targeted therapies will continue to rely on identifying subsets of TNBC patients most likely to respond based on robust predictive biomarkers. Compared to other subtypes, TNBC exhibits extensive epigenomic misregulation. In our preliminary and published data, we identified a subset of TNBC with elevated DNA methyltransferase 3A (DNMT3A) that exhibits unique sensitivity to DNMT inhibitors (DNMTi). We have shown that in TNBC, DNMTi induce degradation of DNMTs through the E3 ligase TRAF6. We developed a DNMT3A IHC clinical assay and found that up to 80% all TNBC tumors express DNMT3A, and ˜30% exhibit moderate-strong staining. DNMT3A+ was associated with poor clinical outcomes independent of tumor stage, nodal metastases and immune infiltration. Building upon our preliminary data, this proposal seeks to evaluate further the preclinical and clinical activity and mechanisms of action of DNMTi + chemoimmunotherapy in DNMT3A+ TNBC, and to clinically evaluate biomarkers with predictive and pharmacodynamic utility, with a focus on DNMT3A IHC and other biomarkers in relevant pathways. Historically, enthusiasm for DNMTi has been hampered by limited efficacy in previous clinical trials, mostly in ER+ breast cancer. There is little clinical information on these agents in TNBC. Emerging evidence and our preclinical data suggest that DNMTi exhibit combinatorial effects with taxanes and immunotherapy. We hypothesized that the addition of DNMTi to chemoimmunotherapy would be beneficial in patients with DNMT3A+ TNBC. At the mechanistic level, although identified as a major mechanism of DNMTi action, how the viral mimicry pathway regulates DNMTi activity in TNBC remains unclear and requires further elucidation. Our preliminary data identified ZNF101 as a new regulator of the viral mimicry pathway to regulate IFN-induced gene expression in TNBC. Our proposed Aims are intended to further evaluate biomarkers and mechanisms of drug action in samples collected from a prospective phase I trial supported through the NCI CTEP (NCT05673200), where we are evaluating an oral DNMTi (ASTX727) in combination with paclitaxel and pembrolizumab in patients with metastatic TNBC, including the subset of DNMT3A high tumors (Aim 1), and to evaluate ZNF101 and viral mimicry pathway involvement in anti-tumor activity (Aim 2) and anti- tumor immunity induced by DNMTis (Aim 3). The results will be further tested in biospecimens collected from a completed trial, NCT02957968, which evaluated IV decitabine + paclitaxel and pembrolizumab. While DNMTi have been evaluated before in unselected breast cancer, the innovation in our project is the biomarker-driven approach based on novel mechanisms of action described by our group. If successful, our finding will significantly impact a large number of TNBC patients, as it may allow us to: (1) Gain novel insights into DNMTi activity in TNBC, (2) repurpose DNMTi in patients most likely to benefit based on biomarkers and (3) enhance the therapeutic efficacy especially in metastatic TNBC patients who have progressed on standard of care.

NIH Research Projects · FY 2026 · 2024-11

Project Summary Antibiotic resistance is a global health emergency that threatens advancements in modern medicine. Bacteria employ several mechanisms to evade the action of antibiotics, including efflux, reduced permeability, inactivation of antibiotics, and mutations to target proteins. Therapeutics that block resistance mechanisms would serve as adjuvants to antibiotics in the fight against pathogenic bacteria. One such class of resistance blockers are efflux pump inhibitors (EPIs), which are a promising therapeutic since these membrane transport proteins provide one of the broadest mechanisms of antibiotic resistance. Our team discovered Fab inhibitors of efflux pumps that block drug expulsion by inserting their CDRH3 loops into the substrate binding pocket. This finding and other discoveries of protein EPIs have been facilitated through display technologies, such as phage display and mRNA display. These screens require stable and pure efflux pumps and constitute a rather time-consuming process since they involve sample optimization prior to the screen. Moreover, the identified hits do not always correspond to inhibitors since screens are designed to detect binding and not function. The goal of this proposal is to develop a high-throughput screening approach to discover protein-based EPIs to block antibiotic efflux without the need for sample optimization. In our assay, the efflux pump is co-expressed with a library of Fabs in E. coli. Antibody expression is directed to the periplasm, such that binding occurs from the outside, a requirement to avoid membrane permeability in Gram-positive bacteria. Next, bacteria are treated with a fluorescent dye, which can be transported by the efflux pump and bind to DNA. Hence, E. coli harboring inhibited efflux pumps show greater fluorescence while uninhibited ones display reduced fluorescence. This feature enables bacteria to be sorted based on their fluorescence by using flow cytometry to obtain the identity of the binder. In Aim 1, we will explore several parameters with the goal of establishing the assay into a robust tool to be used for discovering protein EPIs. In Aim 2, we will use the method to screen against efflux pumps from pathogenic bacteria where no such specific inhibitor has been developed. By accomplishing the goals of the project, we will establish a high- throughput method for identifying protein-based EPIs, thereby expediting the discovery process.

NSF Awards · FY 2024 · 2024-10

In daily life, people grasp and hold an object with their hands, such as a hammer or an egg, frequently and dexterously. These tasks require different levels of steady grasp force and exert different sensations on the fingers and palm. This raises questions of how the brain regulates sustained grasp force and processes sensory input from different parts of the hand. This project will investigate cortical oscillations using high-density electrode grids while human subjects perform sustained hand grasp tasks and feel tactile stimuli such as touch and vibration. Novel computational algorithms will be developed and applied to the neural data to predict the produced grasp force and differentiate tactile inputs to the hand. This project will provide novel knowledge regarding the organization of sensorimotor cortex activity in relation to grasp force and tactile sensations. Brain regions that show unique activity in response to touch and vibration will then be stimulated with electrical pulses to elicit artificial sensations. Insights gained from this project will play a critical role in the development of closed-loop neuroprosthetics that can replicate natural hand function. Despite considerable progress regarding our understanding of the neural bases of sensorimotor behavior, there is very limited knowledge about the neural dynamics of sensory and motor cortical circuits during the generation of sustained complex hand function, such as grasping and tactile exploration, which are essential for common daily activities. A better understanding of the spatio-temporal neural dynamics associated with sustained complex hand movements and somatosensory processing is a necessary requirement for the construction of more efficient closed-loop neuroprosthetics. Utilizing advanced electrode technology, this project will record cortical activity with high-density electrocorticography (ECoG) grids, then decode multichannel data with computational intelligence for the identification of oscillatory patterns of the sensorimotor cortex during the execution of sustained hand grasp function. The high-density ECoG grids will provide recordings of brain activity across a large cortical space and with sub-centimeter resolution. Simultaneously, tactile sensory inputs--such as vibration and touch--will be delivered to different fingers and palm. The project will examine to what extent the cortical oscillations can be used to predict the produced grasp force and distinguish between different prolonged somatosensory inputs to the hand. The project will also develop a real-time system for the mapping cortical activations online, then stimulate cortical regions using channel suites and temporal patterns mimicking the ECoG modulations using a computer-in-the-loop system. The project will integrate neuroscience, neurosurgery and biomedical engineering expertise, to uncover spatio-spectral dynamics of somatosensory and motor cortical oscillations, and decode these patterns for the control of closed-loop hand neuroprosthetics. Outcomes will enable the design and development of neuroprosthetics more akin to the natural function of the hand. This project is funded by Integrative Strategies for Understanding Neural and Cognitive Systems (NCS), a multidisciplinary program jointly supported by the Directorates for Biology (BIO), Computer and Information Science and Engineering (CISE), Education and Human Resources (EHR), Engineering (ENG), and Social, Behavioral, and Economic Sciences (SBE). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-10

This project seeks to address the critical need for computational hardware capable of supporting artificial intelligence studies in pathology based on large-scale clinical data collection efforts currently underway at the Mayo Clinic in Rochester, MN. We are in the process of digitizing a vast clinical data repository to meet the clinical objectives of the Department of Laboratory Medicine and Pathology (DLMP), which carries enormous potential for innovative and unparalleled research in pathology. However, to fully leverage this treasure trove of data, significant investments in computation must be made. This project’s novelties are to develop a shared computational resource for pathology research based on the combined experience of the investigators in the Division of Computational Pathology and AI within DLMP and the ongoing data collection activities. Upon completion, this project will drive the advancement of knowledge throughout healthcare, leading to innovative breakthroughs that benefit both academia and the broader scientific community. Although our group contributes to the clinical application of AI in DLMP, the research itself cannot and should not be solely driven by the specific clinical needs of the department, and therefore we must augment existing strategies with the computational instrumentation needed to establish research capabilities around our rapidly growing data sets. The project involves utilizing an existing environment at Mayo to install GPU- and CPU-based computational servers dedicated to the proposed work and connected to the rapidly growing clinical data store. Local data storage for rapid computational processing is also part of the funded computational environment, and together will support data reuse, data exploration, and modern machine learning strategies to streamline data annotation and labeling. 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 2024 · 2024-10

PROJECT SUMMARY The 2024 Fusion conference on “Epithelial mesenchymal interactions in lung development and fibrosis.”, will be held October 04-07, 2024, in St. Julians, Malta. The 2024 Lung Fusion comes at a critical time, because post- acute COVID-19 syndrome including chronic consequence of severe lung injuries will be coming into focus, heightening our need to understand and combat the dysfunctional repair and remodeling that follows severe injury. According to statistics from the World Health Organization, the global burden of lung disease continues to rise, with >4 million deaths annually worldwide attributed to chronic respiratory diseases, including pulmonary fibrosis and ARDS. While basic scientific research is making substantial strides forward in understanding molecular, cellular and tissue level mechanisms driving respiratory diseases, translation of these findings toward early detection and effective repair and restoration of lung function in chronic respiratory diseases remains a major barrier. Meeting this challenge requires the integration of knowledge from experts spanning lung development, molecular and cell biology, genomics and epigenomics, physiology, bioengineering, matrix biology as well as physicians and translational experts immersed in the diagnosis and treatment of human disease. Lung Fusion 2024 will bring diverse experts together to disseminate and debate the latest findings in the fields of lung development, injury, and repair, and to formulate new ideas, collaborations and approaches that will translate biologic discoveries toward meaningful advances in respiratory medicine. A major emphasis of the Lung Fusion conference is to strengthen the pipeline of scientists and clinicians focused on lung development, injury, and repair. Funds from this R13 will be specifically targeted to promote participation in the conference by women, under-represented minorities and people with disabilities, graduate students, postdoctoral fellows, and early career investigators. The unique attributes of the Fusion (open scientific exchange, secluded location to maximize engagement, tradition to share unpublished data, abundant time for discussion) provide an opportunity for formal and informal interactions and collaborations that are likely to have significant and sustained impact on the field. The 2024 “Epithelial mesenchymal interactions in lung development and fibrosis” conference will thus promote accelerated progress in understanding and treating chronic lung diseases and help to ensure the vitality and growth of a diverse pipeline of clinicians and scientists capable of addressing the growing burden of lung diseases.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT In rheumatoid arthritis (RA), delaying initiation of treatment for ≥12 weeks is associated with irreversible joint damage due to greater difficulty in achieving remission, but navigating the hurdles of the US healthcare system in this short timeframe can be challenging. Time-consuming logistical steps must be carried out to be evaluated by a qualified specialist, establish a diagnosis, and start antirheumatic drug therapy. These difficulties are exacerbated for rural residents due to the closure of rural hospitals nationwide extending the distance to healthcare facilities and the time to travel and obtain care. Additionally, there is very little information about the timing and accuracy of RA diagnosis and their associated effects on outcomes for rural residents of the US. The growing rheumatology workforce shortage further aggravates these issues, as <10% of rheumatologists practice in rural or micropolitan areas yet 30% of the US population lives in these areas. Our goal is to improve outcomes in patients with RA by reducing healthcare disparities. We aim to (1) identify rural healthcare disparities in the diagnosis and treatment of early RA, (2) develop and validate an AI algorithm to enable early identification of RA, and (3) assess long-term outcomes in patients with RA living in rural vs urban areas compared to those without RA. We are uniquely positioned to address these objectives as ours is the only population-based, longitudinal RA inception cohort in the US, and we will extend our cohort to the expanded Rochester Epidemiology Project catchment area, comprising 27 mixed rural-urban counties in MN and WI (60% rural). This area includes 73 rural communities where 17 medical facilities have closed in the past 5 years. In addition, we have the only well- curated database of patients with incident RA, as we manually screen all potential cases of RA to ensure they meet the American College of Rheumatology/ European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria for RA. This is essential for RA research because the diagnostic codes for RA (especially seronegative RA) are often inaccurate. This research will provide real-world evidence regarding the magnitude of healthcare disparities in rural residents with RA. Our AI algorithm to facilitate early recognition of RA will improve clinical practice in three meaningful ways, 1) reducing underdiagnosis of RA in rural primary care settings, 2) facilitating timely initiation of anti-rheumatic therapies to reduce joint damage and improve long- term outcomes, and 3) optimizing referrals to rheumatology specialty care to reduce the impact of the workforce shortage. This work will be foundational for the development of a pragmatic clinical trial testing implementation of a clinical decision support tool to reduce disparities in early identification of RA. Furthermore, evaluating long- term outcomes and identifying patient subgroups with the worst outcomes is an important step toward developing interventions to bridge these gaps in healthcare delivery.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT Chronic Obstructive Pulmonary Disease (COPD) is one of the top five causes of disability among middle-aged US adults. Exercise-based pulmonary rehabilitation (PR) programs are often recommended for COPD patients to alleviate symptoms of breathlessness, fatigue, physical function, and overall quality of life. However, the benefits of physical activity-based interventions are typically not sustained over a long period of time in COPD, and adherence to physical activity interventions is poor. In addition, few longitudinal studies on physical activity of COPD patients use objective measures of physical activity. Symptoms of COPD can lead to increased sleep disturbances resulting in increased daily fatigue, lower physical activity, and negative mood, which in turn worsen COPD symptoms. We recently demonstrated the effectiveness of our novel home-based PR program consisting of 12 weeks of weekly health coaching calls and objective remote monitoring to increase the physical activity of COPD patients. However, the underlying behavioral mechanisms that contribute to a higher likelihood of successful and sustainable increases in daily physical activity in COPD patients participating in such programs are not understood. With COPD prevalence and its’ associated co-morbidities quickly accelerating in the aging population, it is critical to understand the underlying mechanisms responsible for improving health outcomes, and to translate that knowledge into clinical practice. It is our overarching hypothesis that modifiable habitual behavioral patterns play a significant mitigating role in slowing the progression of COPD symptoms. The proposed project will bridge these mechanistic gaps in knowledge and allow us to better refine and individualize our novel PR program to optimize improvements in physical activity and subsequent health benefits across the COPD population. The goal of this study is to investigate how patterns of physical activity, sedentary behavior, sleep and cognitive components of mood and self-efficacy affect the physical activity outcomes produced by our home-based physical activity intervention (R01 HL140486, PI: Benzo) by applying algorithms to a wrist-worn accelerometer (developed in R21 AR66643, PI: Fortune) in combination with daily survey-based measurements. The following steps will be taken to address this important need: we will determine the associations of the underlying (1) patterns of physical activity and sedentary behavior with changes in physical activity elicited through PR, (2) patterns of sleep behaviors with changes in physical activity, fatigue and mood elicited through PR, and (3) behavioral processes with changes in physical activity elicited through PR. This project is innovative in its approach of utilizing our novel wearable sensor-based algorithms, and survey measurements combined with our novel home-based PR intervention to further the understanding of the mechanistic interplay of multi-factorial behavioral aspects that lead to increased likelihood of successful outcomes from participation in our novel PR program. Our results may critically inform the optimization of PR programs for this prevalent condition.