Mayo Clinic Rochester

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT Many people hesitate to contribute their biospecimens and data, including genomic data, for research because they believe that misuse is likely. Biobanks have a tricky problem – that they must engender trust with specimen contributors that they will protect biospecimens and data while simultaneously aiming to get biospecimens and data to the investigators who can most use them. Most biobanks report underutilization of their stored biospecimens and data (including genomic information) for reasons including underdeveloped, unharmonized data management technologies. Without metadata to link permitted conditions for sharing and reuse, biorepositories risk sharing resources which were impermissible to share or contributing to resource inefficiencies by not sharing. The long-term goal of this research program is to respect and protect biospecimen contributors’ autonomous choices and to promote transparency in how those choices are made knowable across biorepositories’ information systems and expressed to individual investigators. The overall objective of the proposed research is to empirically validate one or more standards-based models which make permissions for biospecimen sharing and reuse understandable to machines. This study will include examination of four information models and will be achieved through a single specific aim: to evaluate four established machine-interpretable models for expressing permissions, restrictions, and obligations for biospecimen and information sharing and reuse. Our rationale is: before biospecimen management applications implement a model for labeling biospecimens and information resources according to permissions, restrictions, and obligations which govern their reuse, that model must be vetted for accurate representation of real-world consent forms and policy documents. This aim will be achieved through identifying and annotating sentences from at least 20 consent forms which express permission or constraint regarding biospecimen and data sharing and reuse, those sentences will be deconstructed according to the entities and processes within each model, and the models will be evaluated in terms of their consistency, completeness, conciseness, and interoperability. Additionally, the deconstructed sentences will be applied to each model’s response lists (or value sets) and evaluated in terms of their integration with the model and coverage of the concepts. The proposed research is innovative because it will be the first empirical validation of existing, potentially in-use models using real-world consent forms. The proposed research is significant because more robust models have the potential to enhance responsible stewardship of biospecimens and information, protect specimen contributors’ autonomous choices, and engender trust between those contributors who gave consent and the individual investigators who require permission to use biospecimens in research.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT This grant proposal describes a research project that aims to improve the performance of deep learning models for pathology detection in chest radiographs. Racial and ethnic minority groups in the United States experience higher rates of illness and death across a wide range of health conditions. With the adoption of Artificial Intelligence (AI) and Deep Learning (DL) in healthcare, there is growing concern about increased differences through the use of algorithms. To address this issue, the research team proposes to leverage generative modeling to better represent underserved and understudied groups in training data. Specifically, they will train DL models that detect 14 pathologies from publicly available chest radiographs with patient age, sex and race information. They will use Denoising Diffusion Probabilistic Models (DDPMs) to create synthetic data and augment the dataset with more diverse images. The research team expects that engineered image synthesis will train DL models that reliably detect chest pathologies without being biased on race or sex. To achieve this goal, they have proposed three aims: 1) Establish a baseline for pathology detection in chest radiographs; 2) Augment the real radiographs with synthetic chest radiographs representing minorities; and 3) Assess the impact of synthetic data on model performance. The proposed research leverages the power of DL image generation algorithms to potentially improve the performance of pathology detection in chest radiographs. Additionally, the generative model will be released publicly as a foundational model for researchers without access to the required computational resources to train such models. This approach has the potential to improve healthcare outcomes for underserved populations and advance this field of AI research.

NIH Research Projects · FY 2024 · 2024-09

ABSTRACT More than 10 million Americans are affected by osteoporosis, and an estimated 40 million Americans are at risk of osteoporosis from decreased bone mass. In addition to primary osteoporosis affecting post-menopausal women and the elderly, secondary osteoporosis from conditions such as plasma cell disorders, lupus and hyperparathyroidism also increases the risk of skeletal fractures. The spine is a prevalent site for osteoporotic fractures resulting in substantial morbidity due to debilitating consequences such as pain and immobility. Current diagnostic approach for osteoporosis evaluation such as dual-energy x-ray absorptiometry (DXA) lack the spatial resolution to characterize trabecular microarchitecture, a crucial marker of bone quality. Considering the high socioeconomic burden related to skeletal fragility, there is an unmet clinical need to develop a quantitative bone characterization technique that can comprehensively measure cortical and trabecular microstructures in vivo. Photon-counting detector (PCD) CT has been recently introduced for clinical use. We have demonstrated numerous technical and clinical benefits of PCD-CT for musculoskeletal imaging. A single PCD-CT scan offers both high spatial resolution (110 µm) and spectrally resolved x-ray data which are beneficial for characterizing trabecular morphometry and volumetric bone density. The long-term goal of our work is to extract imaging biomarkers of bone quality for routine assessment of skeletal fragility and guide timely initiation and monitoring of pharmacologic therapies in patients at high risk of osteoporotic fractures. The objective of this proposal is to demonstrate the clinical utility of PCD-CT in characterizing bone quality in the vertebrae of patients undergoing pharmacologic therapy for osteoporosis. We propose to meet this objective by first developing and validating a quantitative spine PCD-CT imaging methodology using cadavers and compare the results to a high-resolution reference standard (micro-CT) in Aim 1, and clinically translate the imaging methodology in Aim 2 to demonstrate in vivo bone quantification in osteoporotic patients. The significance of our proposed technique is that it will enable accurate characterization of bone quality on a clinically available CT system for direct or opportunistic bone quality assessment.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Immune checkpoint blockade has revolutionized the therapeutic landscape of patients with metastatic cancer. However, despite remarkable outcomes in some patients, only a minority achieves complete and durable clinical response. To overcome this, combination of radiotherapy and immune checkpoint blockade has gained popularity to turn up the heat on cold tumors. While tumor irradiation can elicit an immunogenic cell death triggering tumor antigen presentation and T-cell priming, immune checkpoint blockade can enhance the expansion of tumor-reactive T cells which culminates with regression of distant non-irradiated metastases, referred as “abscopal effect”. The synergy of radiotherapy and current immune checkpoint blockade has shown to improve oncological outcomes in some patients but rates of abscopal effect remain scarce. Our long-term goals are to develop new effective therapeutic combinations to boost abscopal response and improve clinical outcome of patients with advanced cancers. To that end, there is a critical need to shed the light on the underlying mechanisms of poor response to radiotherapy. Our group has generated compelling functional evidence implicating the immune checkpoint molecule B7-H3 as a key mediator of tumor immune evasion that may act both locally by impairing T cell-mediated cytotoxicity and systemically through release of immunomodulatory tumor-derived extracellular vesicles (tdEVs). The overall objectives in this application are to gain a better understanding of the role of B7-H3 In local and systemic antitumor immunity and evaluate the therapeutic potential of targeting B7-H3 function with immune checkpoint inhibitors. In line with this, our central hypothesis is that tumor B7-H3 acts as a “don’t touch me” signal which inhibits the cytotoxic function of CD8 T cells. We will test this hypothesis through two aims. In Aim 1, we will dissect the mechanisms of B7-H3-induced CD8 T cell dysfunction. To that end, we will use proximity labeling technologies and time-lapse imaging of T-cell mediated cytotoxicity. We will also employ immunocompetent mouse models humanized for B7-H3 to evaluate the safety and therapeutic efficacy of a newly developed B7-H3 inhibitor. In Aim 2, we will elucidate the mechanisms of systemic immunosuppression mediated by B7-H3+ tdEVs in response to radiotherapy using genetically engineered mouse tumor cells and in vivo proximity-dependent biotinylation. We have assembled a multi- disciplinary team with complementary expertise in extracellular vesicle biology, radiation oncology, tumor immunology and proteomics to validate B7-H3 as a therapeutic target to boost abscopal response in patients with advanced cancers treated with radiotherapy.

NIH Research Projects · FY 2025 · 2024-09

Diffuse midline glioma (DMG) is a lethal pediatric brain tumor without a cure and with a poor prognosis. The H3K27M mutation is present in 80% of DMG patients and is the primary driver of the disease. Therefore, targeting this oncohistone using mRNA-based gene therapies may represent a promising treatment option. However, mRNA as a drug needs to overcome the blood-brain and blood-tumor barriers to reach the tumor site, which is difficult due to the location of DMG in the brain stem. During my postdoctoral fellowship, I have developed non- toxic lipid nanoparticles (LNPs) that can effectively deliver mRNA to DMG tumors in vivo. This proposal aims to further optimize and evaluate the efficacy of these LNPs in delivering mRNA, explore the mechanism behind their delivery, and develop a new therapeutic approach targeting the H3K27M gene in DMG. In Aim 1, I will test the delivery of mRNA with different bases modifications and LNP chemistries to maximize LNP transfection and protein translation in DMG mouse models. In Aim 2, I will test the hypothesis that microglia take up LNPs and repackage them in extracellular vesicles that are subsequently delivered to DMG cells ‘in relay’. In the independent phase (Aim 3), I will explore LNP-mRNA-based gene therapy approach to target oncohistone H3K27M in DMG. Altogether this proposal aims to advance our understanding of DMG and establish a reliable and effective nucleic acid delivery approach for DMG. Completing the proposed project will allow me to build a strong scientific foundation under the mentorship of Profs. Kathryn A. Whitehead (lipid nanoparticle expert), Ian F. Pollack (pediatric brain tumor expert) and Drew Weissman (mRNA expert). An interdisciplinary advisory team has carefully been assembled, consisting of Prof. Robert S. Langer for translational drug delivery expertise, Profs. Maria G. Castro, Carl Koschmann and Sameer Agnihotri for DMG biology and mouse model expertise, Prof. Xiaoming Hu for microglia expertise and Prof. Samira Kiani for gene therapy expertise. Together, this research proposal, mentorship team, advisory committee and institutional support from Carnegie Mellon University will lay the scientific groundwork and provide the necessary training to reach my ultimate goal of successfully starting my independent academic career.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT In this proposal, we will quantify disparities in incidence, short- and long-term outcomes, and barriers to post- partum care in women with hypertensive disorders of pregnancy (HDP) according to various demographic factors and socioeconomic (SES) status indicators. HDP includes a broad spectrum of subtypes associated with varying degrees of morbidity. Incidence of HDP and its complications are higher in rural areas and socioeconomic status (SES) likely plays a moderating effect, but this has not been well-studied due to challenges in determining individual-level SES. Our overall goal is to develop targeted strategies to improve the cardiovascular health of women after HDP. This proposal strongly aligns with Goal 1 of the 2019-2023 Trans-NIH Strategic Plan for Women's Health Research "Advancing Science for the Health of Women”, which aims to understand chronic conditions understudied among women and/or that disproportionately affect populations of women who are understudied, underrepresented, and underreported in biomedical research – specifically, women in rural areas and women who have low SES. We will use a novel indicator of SES, the HOUsing-based Socioeconomic Status (HOUSES) index, which is an objective, scalable, standardized, and individual-level SES measure that predicts multiple health outcomes. Our hypothesis is that SES may be an important modifier of risk, with low SES causing a multiplicative increase in HDP incidence and outcomes, regardless of place of residence.The following 3 aims are proposed to understand the intersection between rural residence and SES in HDP. The first aim is to determine if SES is a significant moderator in the relationship between urban/rural status and the incidence of HDP and its subtypes. We will quantify the incidence of HDP subtypes in a 27-county region of the Upper Midwest, which has a large rural population, using electronic health record data from 2000 to 2021 and test for interactions between urban/rural status and SES. The second aim is to determine if SES is a significant moderator in the association between urban/rural status and the risk of short and long-term complications of HDP. Using HDP cases identified in the first aim, we will identify any cardiovascular and cardiometabolic diagnoses that develop after delivery and characterize acute care and post-partum visits in the first year after delivery. We will test for interaction between rural/urban status and SES and conduct a comprehensive cost analysis. The third aim will be to assess key barriers to care for high-risk women with HDP complications through qualitative semi-structured interviews. We will interview 30 demographically diverse women with adverse outcomes after HDP using the Health Belief Model to understand barriers and facilitators of access to post-partum care. By combining the results of this qualitative aim with the results from Aim 1 and 2, we can develop effective interventions that target high-risk populations in rural areas and improve the care of women with HDP in the reproductive era and beyond.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Psychiatric disorders remain a leading cause of disability in the US and are associated with increased morbidity and mortality. Early detection and treatment is essential to improving long-term outcomes, yet a substantial proportion of patients with psychiatric complaints experience long diagnostic odysseys before receiving an appropriate diagnosis and initiating effective treatment. “Learning health care systems” aim to short-circuit this slow process by leveraging the diagnostic, treatment, and utilization patterns left behind in “big data” (e.g., clinical, genomic, and social determinants of health) to more efficiently and accurately match the right patient with the right diagnosis/treatment, at the right time. Furthermore, over the past several years, a new paradigm– precision medicine–has moved to the forefront of biomedical research and clinical practice. Precision medicine has been defined as “an approach to disease treatment and prevention that seeks to maximize effectiveness by taking into account individual variability in genes, environment, and lifestyle.” Since its inception in 2018, the mission of the PsycheMERGE network has been to advance precision psychiatry in a learning health care system framework. This application, which was developed collaboratively by PsycheMERGE Network members, represents an opportunity for profound advancement of both basic and translational research in precision psychiatry. We propose extending our foundational efforts to now address barriers to scalability, utility of genomic data, clinical application, and translation to clinical practice in a precision psychiatry paradigm. Specifically, Aim 1 creates a nation-wide federated transfer-learning platform for the development of generalizable and bias-aware algorithms. Aim 2 integrates state-of-the-art methods to perform inclusive trans-ancestry genomic analysis of biobank samples and further innovates by leveraging the breadth and depth of medical record data to discover novel biology that can further inform precision psychiatry paradigms. Aim 3 addresses the application of algorithms by focusing on two use cases including (a) differential diagnosis between bipolar disorder 1 and other mood disorders, as well as (b) probabilistic treatment response to antidepressants for acute depressive episodes. Lastly, Aim 4 uses mixed methods to assess the feasibility, utility, and attitudes towards precision psychiatry tools. Our combined sample of clinical EHR data exceeds 29 million individuals and of those, nearly 2 million also have genetic data already available for analysis across the twelve sites included in this application. A cross-cutting theme throughout the application is the intentional focus on equitable performance of algorithms, innovative integration of social determinants of health, and inclusive methods for genomic analyses. The sites included are also representative of many diverse communities across the United States including the East and West Coasts, the South, and the Midwest. This application represents a major step towards equitable precision psychiatry and brings the field closer to the goals outlined in the updated NIMH Strategic plan.

NIH Research Projects · FY 2025 · 2024-09

Dr. Ciara O’Sullivan is a medical oncologist focusing on clinical and translational research in breast cancer (BC) and developmental therapeutics. Her research has been supported by an American Society of Clinical Oncology Career Development Award and intramural funding at Mayo Clinic (MC). She develops and conducts clinical trials designed to test new drugs and overcome drug resistance, predominantly in endocrine resistant and HER2-positive (HER2+) BC. Another focus is individualizing systemic treatment for early stage HER2+ BC. She is a member of the Alliance Breast Committee and the MC Institutional Review Board (IRB). She led/is leading 17 NCI sponsored trials and three multisite investigator-initiated trials. Specifically, she is study chair of an FDA registration trial, CompassHER2 RD (CompassHER2 Trials Examining Escalating and De- Escalating Therapy in HER2+ Breast Cancer: Optimizing Treatment in Residual Disease [NCT04457596; A011801]), was PI of ACCRU-BR01, A Phase I/II Trial of Abemaciclib and T-DM1 in Women and Men with HER2+ Advanced or Metastatic Breast Cancer Who Progressed on Treatment with a Taxane, Trastuzumab and Pertuzumab (NCT04351230; closed prematurely in 2022) and Co-PI of PROMISE (A Prospective Study to evaluate the role of Tumor Sequencing in Women Receiving Palbociclib for Advanced Hormone Receptor (HR)-Positive, Breast Cancer [NCT03281902]). She has developed an initiative with MC patient advocates which aims to improve BC care through education and patient-centered clinical trials. Dr. O’Sullivan plans to support the NCTN in the next 5 years through: 1. Continued leadership of A011801, including efforts to optimize trial accrual; 2. Completion of PROMISE trial objectives; 3. Leadership of active industry sponsored trials at MC, as well as upcoming trials; 4. Continued work with BC patient advocates to develop patient focused clinical trials, addressing barriers to research participation ; 5. Acquiring the necessary skillset to become a leader in the MC and Alliance BC Disease Groups. Dr. O’Sullivan aims to improve care for BC patients through personalization of systemic treatment options, investigation of novel therapeutics, development of prognostic and predictive biomarkers and her BC advocacy endeavors. Her long-term goal is to be an internationally recognized Professor of Medical Oncology, maintaining a clinical practice with a research focus on endocrine resistance in HR+ BC, HER2+ BC and BC Advocacy. She is committed to being of service to the NCTN by developing, leading and recruiting patients to NCI sponsored clinical trials, supporting IRBs and scientific review committees, and serving on NCI scientific committees. These activities and the derivatives of her proposed work are aligned with the NCI mission of conducting high-quality cancer research to advance knowledge and improve quantity and quality of life for all oncology patients.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Tissue-specific genes are underutilized as disease targets. Tissue-specific genes show narrow expression, play key roles in maintaining tissue homeostasis and are thought to be good drug candidates. Thus, targeting of dysfunctional tissue-specific genes can provide a safer therapeutic approach due to the reduced risk of side effects. However, identifying which tissue-specific genes are critical in disease is a bottleneck in drug discovery. We hypothesize that key tissue-specific genes have the ability to spread perturbations in a protein-protein interactome and can be identified by their context specific functionality. This approach offers a paradigm shift from conventional analyses that uniquely focus on one-gene expression levels. We recently proposed Gene Utility Model (GUM) which hypothesizes that it is how a gene is utilized in protein-protein interaction (PPI) network dictates its importance in disease development. We will use information flow of a gene within a PPI network to represent the gene utility in a given biological state. Under this scenario, genes with high information flows (i.e., high gene utilities) in a disease state, instead of gene expression level, are deemed to play more important roles in disease development. Thus, this application seeks to increase the clinical utility of NIH Common Funds datasets by employing state-of-the-art systems biology approaches to precisely and reliably identifying tissue-specific druggable functional genes (TS-DFGs). We will construct a prototype for Common Fund Gene Utility Compendium by leveraging four NIH Common Fund datasets: Genotype Tissue Expression (GTEx), Library of Integrated Network-based Cellular Signatures (LINCS), Illuminating the Druggable Genome (IDG), and 4D Nucleome (4DN). We will focus on three disease types, liver cancer, nonalcoholic fatty liver disease (NAFLD), and Alzheimer's disease (AD) as proof-of-concept studies. In Aim 1, we will uncover highly utilized tissue-specific genes across multiple normal tissue types and three selected disease types. We will then construct utility karyotype to indicate chromosomal regions enriched with highly utilized genes. In Aim 2, we will employ selectivity, controllability, and suitability as criteria to score druggability for TS-DFG candidates with respect to liver cancer, NAFLD, and AD. Druggable utility networks (DUNs) with respect to each disease type will be constructed to assess the distribution of highly score TS-DFGs in a PPI network and signaling pathways. The constructed prototype of the Common Fund Gene Utility Compendium will promote innovative research to enhance the usage and provide added clinical value for the NIH Common Fund datasets by offering a new paradigm shift for target and drug discovery. Our long-term goal is to enlarge this compendium by including more diseases across different tissue types to facilitate integrative pan-tissue analyses and drive drug discovery.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT The gastrointestinal (GI) epithelium directly senses components of foods we eat, which contain a variety of nutritive and non-nutritive stimuli. These stimuli come from foods with a range of osmolality from zero (water) to >1,500 mmol/kg-H2O for some of the saltiest foods. GI epithelial cells are not only first to sense luminal osmoles, but these cells, along with the kidney tubular cells, encounter the largest osmole swings of all cells in the body. In functional and motility GI disorders, such as irritable bowel syndrome (IBS), which affect 10 - 20% of the US population, non-nutritive aspects of diets such as osmolality are often first line therapies. For example, FODMAPs (Fermentable Oligo-, Di-, Monosaccharides and Polyols) are targeted for elimination in IBS diets. FODMAPs are also highly osmotically active – they are known to drive luminal volume shifts which may lead to symptoms. Both hypo- and hyper-osmotic stimuli invoke downstream signaling that regulates GI motility and systemic physiologic responses. The enteroendocrine cells (EECs) are specialized sensory epithelial cells that interact with luminal stimuli, both nutritive and non-nutritive, and these cells are capable of regulating both local and systemic physiology including GI motility. While EECs are traditionally considered to be nutrient sensors, our lab discovered an EEC subpopulation that transduces mechanical signals, thereby opening the door to EECs being sensors of non-nutritive stimuli. Literature has shown that EEC receptor activation drives two main signal transduction pathways: calcium (Ca2+) and cAMP which lead to release of a range of signaling molecules, including serotonin (5HT). To investigate how EECs sense hyper and hypoosmotic stimuli respectively, our lab is manipulating EEC receptors: V1aR, VRAC, and Piezo2. In VRAC proteins, Ca2+ signaling drives Cl- currents. Understanding osmo-transduction will provide mechanistic insights into commonly used clinical therapies. The overall goal of this proposal is to uncover the mechanisms by which osmolality is sensed by EECs and how osmotic stimuli may engage EEC signal transduction to alter release of signaling molecules and systemic GI physiology. The hypothesis is that EECs transduce osmotic stimuli in location and subtype-specific ways - via cytoplasmic Ca2+, Cl- and cAMP, through osmoregulatory proteins, and secrete signaling molecules to modulate GI motility. Aim 1 investigates the cellular pathways by which EECs transduce osmotic stimuli. Aim 2 investigates the osmotically induced extracellular release of signaling molecules by EECs and subsequent changes in GI motility. The results of this work are poised to bridge knowledge gaps in EEC osmo-transduction, as well as inform broader osmosensing mechanisms in sensory epithelia. The proposed work will be carried out in an environment that provides expert knowledge towards achieving the specified goal, including collaborations with experts in visceral signal transduction, organoid work, and osmolality. This proposal includes a comprehensive training plan by which the PI will gain valuable skills in the study of molecular osmo-transduction on clinically relevant questions. Along with research activities, the plan also includes clinical training and shadowing activities to prepare the PI for her transition to the next stage of training as a future surgeon-scientist.

NIH Research Projects · FY 2025 · 2024-09

SUMMARY Pancreatic cancer (PDAC) is particularly lethal, due in part to a resistance to therapies and a high incidence of metastasis. The overall goal of our research program is to define the molecular mechanisms regulating tumor progression and metastasis of PDAC, thereby identifying new therapeutic strategies to improve patient survival. This proposal focuses on an activator of the invasive cytoskeletal machinery, the proto-oncogene Vav1, which is a GTP exchange factor and activator of the potent Rac/Cdc42 small GTPases that regulate actin dynamics. Vav1 is aberrantly expressed in a subset of pancreatic tumors and correlates with a poor prognosis. Here we have identified a novel role for Vav1 in the regulation of glutamine metabolism that we believe contributes to cellular energy levels, thereby integrating a potent pro-invasive factor with an essential metabolic axis in PDAC. Vav1 promotes the conversion of glutamine to glutamate via the enzyme glutaminase (GLS1). Further, we have identified novel mechanisms by which the glutamine/glutamate axis contributes to tumor progression and metastasis through both localized energy production and through paracrine signaling by both glutamate and inflammatory cytokines. Our substantial preliminary data support the hypothesis for this proposal that ectopic expression of the Rac/Cdc42 exchange factor Vav1 regulates glutamine metabolism to link nutrient status to actin dynamics, invasion, and proliferation. Using a combination of cell biology, live cell fluorescence microscopy, biochemistry, and in vivo models, we will test this hypothesis by investigating how Vav1 amplifies glutamine catabolism (Aim 1), and how glutamate production drives tumor progression and metastasis in pancreatic tumor cells (Aim 2). Successful completion of this research will provide fundamental mechanistic advances in our understanding of the metabolic dependencies of PDAC, identify therapeutic vulnerabilities for patients with Vav1- positive tumors, and establish novel links between cytoskeletal signaling and glutamine metabolism.

NIH Research Projects · FY 2025 · 2024-09

Summary Intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver cancer after hepatocellular carcinoma (HCC), is an aggressive malignancy with dismal overall prognosis. While frontline combination of chemotherapy with immune checkpoint inhibition (ICI) has been a major recent advance in therapy for patients with unresectable iCCA, there remains an unmet critical need to improve the current median progression free survival of about 8 months. With data supporting the need for a pre-existing immune response in the tumor for ICI response, here we propose to add high-dose conformal external beam radiotherapy (EBRT) followed by intra-tumor injection of autologous dendritic cells (DC) to dual PD-L1 (atezolizumab)/TIGIT (tiragolumab) blockade to further enhance the immune stimulatory effect. Radiation can induce inflammatory tumor cell death that can be favorable for tumor neoantigen presentation. Injection of autologous DC after EBRT would be a novel method of boosting in vivo tumor antigen uptake and presentation to expand tumor-reactive cytotoxic T cells. We have treated subjects with unresectable liver tumors (HCC and iCCA) in a pilot study with this EBRT and DC approach with promising response and acceptable toxicity (no grade ≥ 3 toxicity). Three of the 8 subjects had partial response, including an iCCA patient with ongoing response at 48 months. Both emergence of new T cell receptor (TCR) clones and expansion of existing TCR clones, including clones with tumor reactive and cytotoxic profile, have been observed, suggesting this combination could enhance tumor reactive cytotoxic T cell response. However, many of the TCR clones also have early exhaustion signal with upregulation of multiple checkpoint receptors including PD-L1 and TIGIT. Thus, combining DC injection with atezolizumab and tiragolumab may help further enhance the cytotoxic functions of these TCR clones. We hypothesize that combining EBRT followed by intratumor DC injections with atezolizumab and tiragolumab can improve the PFS for patients with unresectable iCCA and that the effect is mediated by systemic expansion of a tumor reactive T cell repertoire. We will test the hypothesis through 2 aims. 1) Assess the clinical efficacy of this combination therapy in a phase II study with a safety run-in phase. PFS will be the primary endpoint. 2) identify the effect of this novel combination immunotherapy on tumor reactive T cell repertoire. We will use scRNAseq and TCRseq to identify TCR clonal expansion and transcriptome profile of the TCR clones in the blood and tumor, with a focus on tumor reactive TCR clones. We will also use scRNAseq and flow to profile the changes of other immune cells in the tumor and blood. Finally, we will use imaging cytometry to examine the tumor and immune spatial relationship in the tumor. Our study will not only identify the clinical activities of this novel combination therapy but also use state-of-the-art technology to improve our understanding on the mechanism of action and potential resistance to this immunotherapy.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Despite a characteristic indolent course, a substantial subset of follicular lymphoma (FL) patients has an early relapse with a poor outcome. Thus far, efforts to identify factors that predict survival have been unsuccessful. However, we and others have demonstrated the prognostic relevance of the tumor microenvironment (TME) in FL and provided initial evidence for the role of specific genetic alterations in shaping different environments with highly dissimilar clinical courses. Yet, the crosstalk between malignant B cells and other immune cells of the TME is poorly understood, as is the role of molecular alterations in modulating this interplay. This underscores the urgent need to improve our understanding of how tumor-immune interactions may drive lymphomagenesis and represent therapeutic vulnerabilities. Through massive genetic and transcriptomic sequencing, we found that FL patients with increased expression of IRF4, an NF-kB target with a critical role in B cell differentiation, display dysregulated immune signatures and an immunosuppressive TME with a poor prognosis. We hypothesize that increased IRF4 expression disrupts the immune synapse between B cells and T follicular helper (TFH) cells while promoting suppressive T follicular regulatory (TFR) cells, in part by preventing induction of selection molecules such as CD40 and PDL1, and in part by rewiring cytokines release. To test our hypothesis, we propose three specific aims. In Aim 1, we will use novel transgenic mouse models with overexpression and deletion of irf4 to investigate whether and how IRF4 controls tumor immunity in normal and malignant B cells by integrating single-cell transcriptional and translational (CITE-seq) analysis. In Aim 2, we will use high dimensional cytometry (CyTOF), spatially resolved proteomics (CODEX), and CITE-seq in the same mouse models to define the effect of B cells with different IRF4 status on TFH cells. In Aim 3, we will use single-cell transcriptomic and proteomic tools to elucidate the role of TFR cells in response to B cells differently expressing IRF4. The findings of all aims will be validated in human FL samples. Building on her substantial prior laboratory and clinical experience in B cell lymphoma, Dr. Patrizia Mondello will lead these studies under the dual mentorship of Dr. Stephen Ansell, a leader in immunotherapy and TME in lymphoma at Mayo Clinic, and Dr. Laura Pasqualucci, a world expert in the genetics and epigenetics of B cell lymphoma at Columbia University. Mayo Clinic offers an exceptional environment for cultivating a developing career in translational cancer research. To achieve the long-term goal of becoming a successful independent investigator, Dr. Mondello has developed a structured curriculum of activities aimed at broadening her knowledge base, expanding her technical repertoire, and developing leadership skills. She has also assembled an advisory committee of leading scientists. In completing her proposed plan with this team, Dr. Mondello will be prepared to compete for R01 funding and to launch a translational research program studying the dysregulation and therapeutic targeting of chromatin modifiers and transcription factors and their effect on the TME in lymphoma.

NSF Awards · FY 2024 · 2024-09

The RET site at the Mayo Clinic in Rochester, MN will be centered on promoting AI fluency in healthcare, particularly among school districts in rural Minnesota. Rural Minnesotans lack many of the opportunities afforded to other high school students in the state, and exposure to emerging tools will help encourage them to pursue careers in healthcare and AI and, more generally, will train them as patients to better understand the nature of their care and the role that AI is poised to play. A key focus of this experience will not only be the technical underpinnings of AI but also its role in society, risks associated with its application in a high-stakes area like healthcare, implementation challenges, and ethics/privacy implications. High school teachers will conduct research over a 7 week period under the guidance an AI researcher working in the healthcare space and will select a project that is aligned with their goals. In parallel, they will use these experiences to craft a curriculum in collaboration with Mayo Clinic education specialists. Importantly, they will work closely with other high school teachers in the program, both past and present, to share insights about their research and curriculum development efforts, as well as the challenges they face in their school districts. Mayo Clinic education researchers will follow up with participants of this program to evaluate outcomes and to assist with further refinements to the program and to the teachers’ implementation. This evaluation will help to inform future iterations of the program as well as enable broad dissemination outside Minnesota to guide educational paradigms in this emerging area. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Acamprosate and naltrexone are major medications used in the treatment of alcohol use disorder (AUD). However, response to treatment with these drugs is variable, with only ~50% of patients achieving optimal outcomes. As a result, it would be important to identify molecular mechanisms underlying individual variation in AUD drug treatment outcomes. That information could potentially facilitate the development of individualized AUD pharmacotherapy regimens as well as the development of novel AUD therapeutic agents. During the current funding cycle, we performed a series of “Pharmaco-Omic” studies designed to identify biomarkers associated with acamprosate response for AUD patients enrolled in our Mayo Clinic Center for Individualized Treatment of Alcohol Dependence (CITA) clinical trial—one of the largest acamprosate AUD clinical trials and one for which we have generated a series of multiple omics datasets. Using those data, we identified novel biomarkers associated with variation in acamprosate treatment outcomes. Those biomarkers included, for example, the FNDC4 gene and a series of other genes—genes which we now propose to study further by performing functional studies of the AUD biomarkers that we have already identified and to extend those studies to include a series of protein biomarkers for both AUD drug response and AUD pathophysiology. Finally, we will also expand our studies to include the application of iPSC-derived brain organoids from both our AUD patients and control subjects to make it possible to identify genes and biological pathways that contribute to acamprosate and naltrexone treatment response. In summary, the studies proposed in this application represent a systematic attempt to identify and study molecular mechanisms underlying and associated with variation in AUD drug treatment response phenotypes and AUD clinical outcomes in response to drug therapy. Our use of “multiple omics” to study samples from AUD patients treated with these drugs, followed by “functional omic” studies of those samples and concluding with the generation and study of patient-derived brain organoids generated from the same patients make this series of studies truly unique and—based on our preliminary data—highly promising for the identification of novel candidate genes and pathways. The results of the proposed studies would represent a significant step toward greater understanding of the biology of acamprosate and naltrexone treatment response in AUD, potentially leading to the development of better and more effective AUD drug therapy, an outcome that would represent a significant advance in the treatment of this disorder.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Gastrointestinal (GI) symptoms, especially constipation, affect >50% of persons with PD (PwPD). However, these concepts are exclusively based on tertiary care studies that used incomplete definitions of constipation. Our population study found that constipation preceded the motor symptoms of PD by up to 20 or more years. Our proposal is predicated on the integrated, multi-hit hypothesis that environmental exposures, especially in genetically vulnerable persons, are perpetuated by an inflammatory gut microbiome and epigenetic changes, resulting in accumulation of misfolded α synuclein in the gut and its transfer to the central nervous system, followed by enteric and central neurodegeneration, GI and anorectal dysfunctions, and GI symptoms in PD. This proposal will assimilate the bigger-picture cellular networks that drive disease processes, enteric neuropathology, brain-gut dysfunctions, and the clinical phenotype in PwPD-C and without constipation (PwPD- noC). We have assembled a multi-disciplinary team from the Departments of Gastroenterology, Neurology, Physiology, and Radiology and the Center for Individualized Medicine at Mayo Clinic, Dr. Gary Miller (Columbia University), and Dr. Rodger Liddle (Duke University) to compare brain-gut dysfunctions (Aim 1), omics-based disease signatures (Aim 2), and the exposome (Aim 3) in 60 PwPD-C, 60 PwPD-noC, and 30 healthy controls. When integrated with the clinical phenotype, this information will identify biomarkers and pathways that predispose to constipation in PwPD. Aim 1 will compare neurological and GI clinical features, in vivo GI functions (GI transit and anorectal functions), enteric neuropathology (α-synuclein deposition in EEC and neurons and neuronal loss) and neuroimaging abnormalities (18FFDG-PET and MRI) in PwPD-C, PwPD-noC, and healthy controls. Aim 2 will discover changes in gut microbial composition and dynamics associated with PD-C by assessing the fecal metagenome (Aim 2a) and the colonic mucosal transcriptome (Aim 2b) and epigenome (Aim 2c). Aim 3 will identify signatures associated with PD-C in and across the peripheral blood exposome and metabolome. We will identify exogenous chemical exposures (e.g., pollutants and pesticides) representing the exposome and endogenous small molecule metabolites representing biological pathways or the metabolome using cutting-edge high-resolution mass spectroscopy platforms and environmental questionnaires. Integrated with the epigenome and transcriptome, Aim 3 will likely enrich our understanding of the risk factors for PD.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT To survive, human behavior must adapt to ever-changing contexts. This includes movement, which requires constant coordination and adjustment of a motor network made of distributed brain regions. These regions can be categorized into two classes: the primary motor nodes (M1) in which activation of distinct regions leads to distinct movement types, and non-primary nodes (e.g. PMv, PMd, SMA) which inform M1 prior to movement execution. Among the 800,000 strokes in the U.S. each year, the most common deficits are related to disruption of this motor network. Current post-stroke rehab tools, such as neurofeedback therapy, assume that these motor areas act together, but if true, this interdependence severely limits treatment of patients as damage to the network can’t be overcome. Recent findings challenge this assumption by showing that non-primary regions, like M1, send direct projections to the spinal cord and the classical primary motor area contains non-primary cortex. Thus, the functions of M1 and non-primary nodes may overlap more than previously thought. This raises the possibility that non-primary areas could substitute for M1, allowing damaged networks to use new motor patterns to bypass dysfunctional nodes. Thus, there is a critical need to better understand the interdependence of the motor network. This can be experimentally carried out by measuring the ability of non-primary nodes to act independently of M1. Our hypothesis is that non-primary motor nodes can indeed be modulated independently of M1 when provided custom feedback, resulting in altered network connectivity. To test this, we will use stereoelectroencephalography, a method of intracranial monitoring for patients with epilepsy that records from the entire brain to 1) identify the innate human motor network using motor BCI, 2) reinforce M1 decoupling from the rest of the network using custom imagery brain computer interfaces and 3) measure the connectivity changes resulting from this BCI-driven adaptation using electrical stimulation. In addition to the scientific discoveries afforded by this proposal, it will also serve to assess the clinical validity of sEEG-based neurofeedback as a potential post-stroke motor therapy.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Irritable bowel syndrome (IBS) is estimated to affect 1 in 6 U.S. adults and results in significant morbidity and health care utilization. Studies over the last decade have highlighted proteases as important peripheral mediators in the pathophysiology of IBS, especially in inducing barrier dysfunction and visceral hypersensitivity. Post-infection IBS (PI-IBS) is a defined subset of IBS where an acute injury results in subsequent development of long-standing gastrointestinal symptomatology. Twenty percent of those suffering from intestinal infection may be at risk for PI-IBS as shown in our study from a large cohort of prospectively followed Minnesota residents. Our studies have demonstrated that impaired inactivation of luminal proteases due to absence of specific intestinal microbes is critical to the pathogenesis of PI-IBS. Our preliminary studies in humanized mouse models of PI-IBS associated high proteolytic activity (PA) have demonstrated that fecal microbiota transplantation (FMT) from a donor that has low PA and presence of key microbes like Alistipes putredinis can reverse the high PA state. Based on these and other findings from PI-IBS patients, we hypothesize that targeted FMT where recipients have high PA and donors are specifically selected based on their microbiota composition and low PA, will be safe and efficacious for improvement of symptoms in PI-IBS. We propose a pilot, randomized, double-blind, placebo-controlled clinical trial where PI-IBS patients will be administered either a single FMT from the donor or from their own stool (autologous control). In Aim 1, we will determine efficacy defined by a ≥50-point improvement in IBS symptom severity score at 12 weeks post-FMT. We will determine microbiota engraftment at 12 weeks and assess predictors of successful response to the FMT. In Aim 2, we will determine effects of autologous and donor FMT on fecal metabolome and in vivo colonic permeability. We hypothesize that successful FMT will be associated with changes in fecal metabolome that support inhibition of PA as well as improvement in colonic permeability. This trial will provide robust pilot and feasibility data to support larger trials investigating PA-based FMT approaches in broader cohorts of IBS patients. In addition, the microbiota assessment will provide additional supportive data for commensal microbes that support suppression of PA. In future, these data can allow development of simplified microbial consortium for treating high PA states. The study team has the expertise in translational studies and clinical trials for neurogastrointestinal disorders. Additionally, an investigational new drug approval from the FDA as well as IRB approval have been obtained.

NIH Research Projects · FY 2025 · 2024-09

SUMMARY In most individuals, exercise counters the onset and progression of chronic diseases (e.g., type 2 diabetes, cardiovascular disease, cognitive decline, and cancers), geriatric syndromes (e.g., frailty), and disability, even when introduced in later-life. However, the physiological effects conveyed by exercise are highly variable across individuals. In line with RFA-AG-24-045, this application builds on a robust scientific foundation and will use innovative, multidisciplinary approaches to critically test the central hypothesis that biological mechanisms of aging are modulators of exercise response heterogeneity (ERH) in older adults. Our proposal centers on cellular senescence and epigenetics as causes of ERH in two distinct, clinically meaningful co-primary outcomes: physical function and insulin sensitivity. Senescence is a cell fate that contributes to age-related tissue pathology and impairs regeneration. Recently, we characterized hallmarks of cellular senescence in human skeletal muscle and observed negative associations with measures of physical function and insulin sensitivity. We have also demonstrated that circulating biomarkers of cellular senescence are associated with deficits in physical function and are responsive to exercise training. Epigenetic modifications effectively govern transcriptional programs that regulate cellular homeostasis and adaptations to stimuli. DNA methylation (DNAm) at CpG sites is a key epigenetic modification that changes radically with advancing age. In skeletal muscle, age-associated alterations in DNAm affect the expression of genes central to functional and metabolic adaptations to exercise. Based on these observations, we will conduct a randomized, two-site clinical trial of a 6-month structured progressive resistance training intervention (n = 200) and a health education intervention (HE) (n = 100) to define the ERH in physical function (Specific Aim 1) and insulin sensitivity (Specific Aim 2) in community dwelling older (³ 65 years) women and men with evidence of mobility limitations. We will use state-of-the-art molecular profiling to rigorously examine cellular senescence and DNAm in skeletal muscle in parallel with their blood-based biomarkers. Through predictive approaches to treatment effect heterogeneity, we will examine how these biological mechanisms, key clinical variables (sex, BMI, comorbid conditions, medications, depression, and fatigue), and behavioral factors (nutrition, habitual physical activity, sleep, fatigue, and depressive symptoms), and their interactions, mediate ERH.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT The prevalence and burden of chronic kidney disease (CKD) is increasing worldwide. Patients who undergo radical or partial nephrectomy for kidney cancer resemble the general population with comorbidities, but with the difference that a majority undergo pre- and post-surgery abdominal imaging. Despite successful surgical tumor removal, there is a concern for future progressive CKD. Following nephrectomy, the unaffected kidney undergoes compensatory hypertrophy, and the degree of hypertrophy and kidney function decline depend on the comorbidity burden and the amount of the removed kidney tissue. With the recent advances in artificial intelligence (AI)--based quantification of kidney volumes from CT scans, there is an opportunity to evaluate automated imaging biomarkers as prognostic tools. There are also algorithms that quantify the number and volume of simple parenchymal cysts and many radiomic/texture features. The Co-Principal Investigators in this program are uniquely equipped for the proposed studies. Dr. Denic has expertise in kidney micro- and macro- anatomy and advanced biostatistical skills. Dr. Kline has expertise in AI and developing advanced image processing techniques. The central hypothesis of this proposal is that macrostructural findings on imaging of the retained (non-operated) kidney after radical or partial nephrectomy are prognostic for progressive CKD. In Aim 1, we will determine whether the degree of compensatory hypertrophy in the retained kidney after nephrectomy predicts progressive CKD. Using a recently created deep learning algorithm we developed, we will quantify the kidney, cortex, and medullary volumes in pre-surgery and follow-up CT scans (at median 1-year post-surgery). From these volumes, we will calculate the degree of compensatory changes in kidney volumes and assess their association with baseline comorbidities and microstructural measures. Finally, we will develop models to predict progressive CKD. In Aim 2, we will first optimize and finalize training of the model to quantify cysts and their size in CT images and develop postprocessing steps to separate cortical from medullary cysts. We will then develop models to assess whether the number and size of cysts (overall, cortical, medullary) in the retained kidney in pre-surgery scans, and changes in number and size of cysts (overall, cortical, medullary) in the retained kidney over 1-year post-surgery, can predict progressive CKD. In Aim 3, we will determine whether novel radiological imaging texture features on pre-surgery scans are reflective of microstructural measures of nephron size and nephrosclerosis and whether kidney texture features on follow-up CT scans predict progressive CKD. This research program will be facilitated by Mayo Clinic’s outstanding clinical and research environment at all three sites dedicated to improving patient care. The goal is to develop a tool that can guide clinical decision-making in everyday practice, and that can help clinicians in improving their care of patients at an individual level by assessing the future risk of CKD.

NIH Research Projects · FY 2023 · 2024-08

PROJECT SUMMARY Relapse prevention is a major goal in the treatment of alcohol use disorder (alcoholism), as many alcoholics return to alcohol use even after a prolonged period of successful abstinence. The chronically relapsing nature of alcoholism is thought to be exacerbated by the intensification of alcohol craving during abstinence. However, the brain mechanisms causing this intensification process remains unknown. Like alcohol craving provoked by environmental stimuli signaling alcohol (‘alcohol cues’) in recovering alcoholics, cue-provoked alcohol seeking in rats is known to intensify during abstinence. We have found that alcohol ‘cue-reactive’ neurons (expressing the activation marker Fos) in the nucleus accumbens (NAc) core drive this behavioral intensification, thereby identifying these neurons as neural targets functionally linked to cue-provoked alcohol seeking. We also found that these ‘cue-reactive’ neurons undergo unique transcriptional adaptations during abstinence (including those linked to alcoholism/drug addiction) that are largely distinct from adaptations in adjacent ‘non-reactive’ neurons. While these results provide gene targets specific to behaviorally functional neural units, we have so far identified such adaptations (across relatively short abstinence) in rats that were well-trained to self-administer alcohol but were not subjected to physical dependence-inducing procedures. These ‘non-dependent’ rats will thus likely model ‘casual drinkers’ but perhaps not patients with alcoholism. Indeed, alcoholics are known to report greater cue-provoked craving than non-dependent drinkers and show different patterns of neural cue- reactivities. Similarly, cue-provoked alcohol seeking in rats with or without a history of physical dependence is known to be controlled by different brain mechanisms. However, no study has yet characterized abstinence- induced intensification of alcohol seeking in animals with dependence histories. We thus next used chronic intermittent alcohol vapor exposures to induce physical dependence and found that rats with histories of dependence show greater cue-provoked alcohol seeking and greater intensification of this behavior than non- dependent rats during prolonged abstinence. These ‘dependent’ rats will thus likely better model the intensification of alcohol craving in recovering alcoholics than ‘non-dependent’ rats, thereby providing more relevant mechanical insights into the chronically relapsing nature of alcoholism. Based on the premise above, this R21 project will test the central hypothesis that “transcriptional adaptations unique to alcohol cue-reactive neurons in NAc core drive the intensification of cue-provoked alcohol seeking in alcohol dependent rats undergoing prolonged abstinence”. We will use neural activity-specific transcriptional profiling (Aim 1) and gene rescuing (Aim 2) to selectively target alcohol ‘cue-reactive’ – rather than ‘non-reactive’ – neurons. The results will determine which transcriptional adaptations are functionally linked to the intensification of alcohol seeking in dependent rats undergoing prolonged abstinence. Such knowledge may help identify novel therapeutic targets for developing anti-relapse medication to counter intensifying alcohol craving in recovering alcoholics.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Asthma is characterized by chronic, non-resolving lung inflammation; however, there are endogenous inhibitory mechanisms that normally promote the resolution of lung inflammation. The long-term objective of our research is to understand the bronchial epithelial cell (BEC)-mediated inhibition of lung inflammation in asthma. Transmembrane protein 178 (Tmem178) mediates a novel endogenous inhibitory mechanism in asthma. Our preliminary data showed that TMEM178 gene expression in BECs decreased as asthma severity increased. In addition, we found that Tmem178 inhibits adenosine triphosphate- and allergen-induced [Ca2+]i responses, store- operated calcium entry (SOCE), and interleukin (IL)-33 release in BECs. Furthermore, the genetic loss of Tmem178 led to more severe lung inflammation, airway hyperresponsiveness, and airway collagen deposition in a murine model of asthma. Finally, we identified TMEM178 variants associated with severe clinical phenotypes in asthma patients. Based on our preliminary data, we hypothesize that the Tmem178-mediated endogenous inhibitory mechanism in BECs is dysregulated in asthma, resulting in downstream lung inflammation, AHR, and tissue remodeling. In this project, we will test this hypothesis by complementary approaches using BEC cultures and mouse models of asthma together with whole-genome sequencing, RNA sequencing, and clinical data from diverse asthma cohorts. In Aim 1, we will test the hypothesis that Tmem178-mediated inhibition of calcium responses is disrupted in asthmatic BECs. We will analyze calcium imaging from normal and asthmatic BECs and organotypic cultures of normal and asthmatic BECs. In Aim 2, we will test the hypothesis that the targeted genetic loss of Tmem178 in epithelial cells results in more severe lung inflammation, airway hyperresponsiveness, and airway collagen deposition. We will analyze Tmem178fl/flShhCre mice in a murine model of asthma. In Aim 3, we will test the hypothesis that TMEM178 variants are associated with TMEM178 expression and [Ca2+]i responses in BECs and severe asthma phenotypes in patients. We will analyze existing whole-genome sequencing, RNA sequencing, and clinical data from diverse asthma cohorts, and use CRISPR/Cas9 editing to generate and study TMEM178 variants in BECs. The results of our proposed research will characterize the role of Tmem178 in BECs and asthma pathogenesis, thereby providing a rationale for the development of novel therapies to resolve inflammation in the asthmatic lung.

NIH Research Projects · FY 2026 · 2024-08

The United States incarcerates more people per capita than any other developed democracy. Persons behind bars retain a fundamental, Constitutionally-protected right to receive community-standard healthcare. A multitude of factors prior to confinement, such as low educational attainment, exposure to violence, housing insecurity, and history of childhood trauma, likely contribute to the poor health status of the U.S. prison population. As a consequence of harsh sentencing practices of the 1980s and 90s, 1 in 7 adults in prison is serving a life sentence. This means our prison population is aging at an unprecedented rate. Incarcerated people face earlier disease onset and faster progression than community-dwelling, age-matched peers. This translates to an increasingly frail and medically complex prison population, with high rates of cardiovascular disease, cancer, and dementia. When an incarcerated person’s needs exceed the prison’s healthcare capabilities, they transfer to a hospital in a neighboring community. Yet vanishingly little is known about these encounters. Multimorbidity, high prevalence of familial estrangement, poor advance directive completion, shackling, correctional officer presence, stigma, and heterogeneous correctional policies all contribute to these ethically fraught hospitalizations. The proposed work will address key knowledge gaps about the clinical, geriatric, ethical dimensions of need for hospitalized incarcerated older adults. Aim 1 will leverage a unique dataset from a 5-state hospital network, spanning 25 years and thousands of hospital admissions to define prevalence and temporal trends in factors such as age, delirium and advance directive completion. Aim 2 will apply state-of-the-art qualitative methods to characterize the experience of hospitalization for an incarcerated older adult from multiple vantage points: patient, family, correctional officer and bedside nurse. Aim 3 will apply a sophisticated analytic lens to evaluate prevalence and contents of state and federal policies pertinent to the hospital care of older adults. The candidate, Dr. Erin Sullivan DeMartino, is clinician-ethicist in Mayo Clinic’s Division of Pulmonary and Critical Care Medicine with a track record of high-impact original research publications and a GEMSSTAR award from NIA. She has engaged a world-class mentorship and advisory team. Her primary mentor, Dr. Jon Tilburt, is a visible and established empirical bioethics investigator committed to the development of junior colleagues. Dr. DeMartino has recruited a team of internationally recognized co-mentors and advisors with diverse backgrounds, offering expertise in geriatrics, correctional health, ethics, and qualitative and quantitative methods both for the aims and the career development plan. Dr. DeMartino has outlined a rigorous training plan, drawing upon the vast resources of Mayo Clinic and national methodologic, geriatric, and leadership development opportunities. Mayo Clinic’s Kogod Center on Aging and Biomedical Ethics Research Program provide an unparalleled setting for execution of the proposed research and development activities and for Dr. DeMartino’s emergence as an independent investigator at the forefront of aging and policy research centered on vulnerable populations.

NIH Research Projects · FY 2026 · 2024-08

Project Summary/Abstract Hepatic encephalopathy (HE) is a complication of cirrhosis characterized by cognitive, psychological, and motor dysfunction that is associated with decreased quality of life and poor survival. Unfortunately, current treatments for HE only have modest efficacy in preventing overt (or clinically apparent) HE episodes. Novel therapies are desperately needed to alleviate the burden of HE, and targeting the microbiome is a promising therapeutic pathway. HE is thought to result from translocation of bacterial products across a permeable intestinal epithelium, which bypass the dysfunctional liver and reach the brain. Dr. Bloom’s preliminary work shows that specific gut bacteria are associated with impaired intestinal barrier function and may influence HE. Despite this initial work, there is limited data regarding the most promising microbiome targets for HE treatment – a gap that Dr. Bloom plans to address in this proposal. Her central hypothesis is that microbiome-targeted therapies can treat and prevent HE. Her aims are to 1) identify host and microbiome features associated with future overt HE, and 2) compare mechanisms of microbiome-targeted therapies to treat minimal HE. In order to accomplish Aim 1, she will conduct a prospective cohort study that will enroll 150 patients with cirrhosis: 75 patients with a history of overt HE and 75 patients with no history of overt HE but at high risk. At baseline, she will collect microbiome and host data. She will then prospectively follow all patients for 6 months to identify interval overt HE, while collecting serial microbiome and host data. In order to accomplish Aim 2, she will conduct a pilot clinical trial in 60 patients with cirrhosis and minimal HE. She will randomize patients to 1) lactulose (standard of care), 2) polyethylene glycol (used as alternative to standard of care), or 3) potato starch. She will evaluate microbiome composition and function and cognitive function before, during, and after therapy. The primary outcome will be change in stool short-chain fatty acids with treatment. These proposed studies will identify host and microbiome features closely associated with HE and determine the impact of HE therapies in reversing HE-associated microbiome features. During the K23 award period, Dr. Bloom will acquire knowledge and skills in three core research domains: rigorous clinical trial design, microbiome sequencing analysis, and statistical modeling. She will achieve these training goals through hands-on mentorship, a Masters in Public Health, other formal didactics, several regular group meetings, and attending academic conferences. Dr. Bloom will specifically learn how to perform clinical trials of microbiome-targeted therapies, analyze metagenomic sequencing to interpret bacterial community composition and function, and develop multi-dimensional models that include multi-omics (microbiome and metabolome) and longitudinal data to better understand the pathogenesis of HE and mechanism of microbiome-targeted therapies. Through this K23 career development award, Dr. Bloom will achieve her long-term goal of becoming an independent clinical and translational investigator who can design and lead trials of microbiome-targeted therapies for HE.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Dr. Parikh is a consultant in the Division of Hematology, Department of Medicine at Mayo Clinic in Rochester, MN, and holds the rank of Associate Professor of Medicine with the Mayo Clinic Alix School of Medicine. Dr. Parikh is also a member of the CLL Disease Team and the Lymphoid Malignancies Disease Group of the Mayo Clinic Comprehensive Cancer Center. Since joining on staff at Mayo Clinic, his clinical and research efforts have focused on chronic lymphocytic leukemia (CLL). Dr. Parikh’s overall goal is to improve the care of patients with CLL through the development of novel clinical trials in collaboration with the National Clinical Trials Network (NCTN). To further his objectives, Dr. Parikh proposes with this R50 application to: 1) complete the ECOG-ACRIN trial “EA9161: A Randomized Phase III Study of the Addition of Venetoclax to Ibrutinib and Obinutuzumab Versus Ibrutinib and Obinutuzumab in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL)”, and the Alliance for Clinical Trials in Oncology clinical trial “A041702 A Randomized Phase III Study of Ibrutinib Plus Obinutuzumab Versus Ibrutinib Plus Venetoclax and Obinutuzumab in Untreated Older Patients (≥65 Years of Age) with Chronic Lymphocytic Leukemia (CLL)”; and participate in the final outcome analysis, correlative biomarker analysis, and drafting of abstracts and manuscripts; 2) develop the study protocol and serve as the National PI for the next ECOG-ACRIN-led frontline CLL protocol titled “EA9231: Measurable Residual Disease Guided Frontline Therapy in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Patients <70 Years”. In addition to writing the study protocol and activating the study, Dr. Parikh will also be responsible for completing the final analysis, and publish relevant abstracts and manuscripts that will result from this work; and 3) serve as the Mayo Clinic PI for the next Alliance in Clinical Trials in Oncology clinical trial that will test the utility of measurable residual disease in older patients (>65 years) with previously untreated CLL. Additionally, in his role as the Chair of the CLL Disease Team and Vice Chair of the Lymphoid Malignancies Disease Group of the Mayo Clinic Comprehensive Cancer Center, Dr. Parikh oversees the strategic plans for all clinical trials in CLL across the Mayo Enterprise, including NCTN-sponsored trials. Dr. Parikh also participates and actively collaborates on several correlative studies that are being conducted on samples collected from CLL patients enrolled on ECOG-ACRIN trials across the country. Dr. Parikh views the opportunity to submit this application for the NCI Research Specialist (Clinician Scientist) R50 award as a significant and critical opportunity to continue his career goal of developing, implementing, and completing the most cutting-edge and state-of-the-art clinical trials in CLL conducted by the NCTN.