University Of Minnesota

NIH Research Projects · FY 2025 · 2021-01

PROJECT SUMMARY/ABSTRACT The respiratory control system displays a remarkable capacity for neuroplasticity, imparting flexibility of breathing in response to changing physiological or environmental conditions across the lifespan. Gonadal hormones (estrogens, progestins, androgens) exert powerful modulatory effects and directly influence the development of neuroplasticity in other neural control areas. Yet, the role of gonadal hormone signaling in the development respiratory neuroplasticity has not been clearly defined. The overarching hypothesis guiding this proposal is that gonadal hormone signaling within the spinal cord is necessary to enable expression of respiratory neuroplasticity through regulation of spinal microglia. Five important preliminary findings support this hypothesis. First, while estrogens and progestins are typically associated as the principal gonadal hormones in females, whereas androgens are considered the primary gonadal hormone in males, it is in fact estradiol in both sexes that is required to permit respiratory neuroplasticity. Second, testosterone is aromatized to estradiol directly within the spinal cord to elicit plasticity in males. Third, the estrogen receptor isoforms (ERα, ERβ and GPER) essential for enabling respiratory plasticity are unique in females and males. Fourth, estradiol supplementation or the pharmacological activation of spinal estrogen receptors is sufficient to rescue plasticity following removal of the gonads in both sexes. Fifth, treating the spinal cord with a localized anti-inflammatory, or reducing the population of CNS microglia (using a CSF1R inhibitor), is sufficient to restore respiratory neuroplasticity in rats of both sexes following removal of the gonads, indicating a role for spinal microglia in the estrogen-induced recovery of plasticity. Using rigorous neurophysiologic measures of respiratory neuroplasticity in combination with estrogen receptor pharmacology, targeted gene manipulation by siRNA knockdown, flow cytometry, mass spectroscopy, and protein biochemistry, we will dissect the role of spinal estrogen receptor signaling for expression of respiratory neuroplasticity. Three specific hypotheses will be tested: 1) Spinal ER signaling is necessary for induction of respiratory neuroplasticity in female and male rats; 2) Spinal estrogen signaling is sufficient to restore respiratory plasticity when sex steroid levels are systemically reduced; and 3) Estrogen permits respiratory plasticity through modulation of spinal cord microglia. These studies address a critical gap in our basic biological understanding of respiratory neural function; how sex hormone signaling enables development of respiratory neuroplasticity. In addition, our results will directly inform ongoing translational studies targeting mechanisms of respiratory neuroplasticity for therapeutic benefit.

NIH Research Projects · FY 2026 · 2020-12

Heart disease, cancer and diabetes are three of the 10 leading causes of death in the United States (US) and all are diet-related diseases. Latinos are the largest immigrant population in the US but they share an uneven burden of chronic disease including risk for cardiovascular disease, obesity and diabetes. Understanding the factors related to disease risk and developing culturally-appropriate population-level interventions are critical to reduce health disparities. Yet, such research is often stymied by the lack of measurement tools that are specific, appropriate, and valid for diverse populations; poor measurement tools cloud our understanding of disease-risk factors and may lead to inconclusive or wrong conclusions regarding the impact of interventions. High-quality measurement tools are part of the essential infrastructure needed for understanding and evaluating population health and advance the science of diet-related diseases. While myriad factors influence diet-related chronic disease risk, food consumed at home accounts for half of all food expenditures among US adults and represent the most proximal and modifiable factors that influence the foods and nutrients that people consume on a daily basis. However, few valid home food environment assessment tools exist and none have been validated with large, immigrant or low-literacy populations (i.e., limited understanding/use of the written form of one’s native language). In 2008, our team developed and validated a Home Food Inventory (HFI) to assess the healthfulness and obesity risk of home food environments using a checklist format. Our user-administered HFI instrument has been used extensively in the field for NIH-funded studies by our team and many others. Citation benchmarking statistics indicate our validation study article is in the top 2% globally compared to similar articles. Yet, the original HFI can only be used with English-speaking populations, is quite lengthy and paper-based. Our present objective is to further advance the science by developing an accessible home food environment assessment toolkit that includes valid and reliable paper and multi-media electronic tools targeting foods known to impact diet-related health that can be user-administered across literacy levels and in English and Spanish. Our specific aims are to: 1) Reduce the original Home Food Inventory (HFI) into a streamlined HFI-core instrument, maximizing utility and efficiency and minimizing participant burden while retaining foods most impactful on diet-related health; 2) Evaluate the HFI-core (English and Spanish paper versions) by assessing usability, acceptability, validity and reliability, and modify as needed; 3) Develop electronic HFI-core tools (eHFI) that present audio and visual representation of foods for English speakers and Spanish speakers in their native language to overcome language and literacy issues; 4) Evaluate both eHFI tools by assessing usability, acceptability, reliability and validity, and modify as needed; and 5) Facilitate broad use of the instruments through a permanent and easily-accessible storage platform and provide support and a technological assistance platform for future language adaptations and testing.

NIH Research Projects · FY 2024 · 2020-09

Summary Alzheimer's disease (AD) affects over 44 million individuals worldwide, and the number is projected to triple by 2050. However, currently there is no cure for AD. This project aims to develop and apply novel statistical methods, especially deep learning, to advance neuroimaging genetics for AD. It involves novel methodological developments in Aims 1-4, cost-effective applications to the large-scale UK Biobank neuroimaging genetic data for AD (Aim 5), and software development (Aim 6). All four Aims for the methods development tackle emerging impor- tant topics in deep learning with their applications to neuroimaging genetics for AD; although the other three Aims deal with independent topics with their own other broad applications, they in turn serve for Aim 1: 1) Aim 1 applies manually searched deep learning models for automatic feature extraction/phenotyping from neuroimages, by which both the statistical power and biological interpretation of subsequent genome-wide association studies (GWAS) are expected to be enhanced; 2) Aim 2 employs (automatic) neural architecture search (NAS) to more efficiently identify better deep learning models, which are then applied to Aim 1 for enhancing feature extraction/phenotyping and thus boosting the power of GWAS; 3) Aim 3 focuses on explainable deep learning, offering biological insights by localizing and highlighting the most important features extracted by deep learning models that can be used for Aim 1; 4) Aim 4 develops a novel inferential theory for deep learning, which is then applied to rigorously test for the statistical significance of any selected/highlighted features used in Aim 1. In Aim 5, these new methods will be applied to the UK Biobank neuroimaging and GWAS data to identify novel genetic loci and neuroimaging features for AD. As a byproduct, we will develop and distribute software implementing the proposed methods in Aim 6.

NIH Research Projects · FY 2024 · 2020-09

Project Abstract: More than 5 million Americans live with Alzheimer's disease and related dementias (AD/ADRD), and they receive care from more than 16 million family caregivers. Providing high quality care in the community for people with AD/ADRD is a national priority. Persons with AD/ADRD who are enrolled in Medicaid are eligible to receive home and community-based services (HCBS). HCBS programs vary by state but in general include supportive services (e.g., adult day services and personal care). HCBS are provided by states as an alternative to institutional care and are believed to promote the clients’ independence, health, well-being and help avoid or delay more intensive health care utilization (e.g., nursing home admission). But very little is known about the impact of HCBS for people living with AD/ADRD, including whether person-reported outcomes differ for those with and without AD/ADRD, and whether person- reported HCBS outcomes influence use of health care. To determine whether HCBS improve outcomes that matter to clients, we must first better understand the role of these services from the perspective of care recipients (i.e., person-reported outcomes).Toward that end, we propose to use data from the National Core Indicators-Aging and Disabilities (NCI-AD) Adult Consumer Survey collected between 2017-2020 (n>17,000 HCBS respondents each year), which measure HCBS quality and service outcomes from clients’ perspectives. We also propose to link NCI-AD and Medicare and Medicaid claims for respondents in Minnesota (the only state where this linkage is currently possible) to understand the relationship between person-reported HCBS outcomes and health care use. In response to RFA AG-20-037 we propose the following specific aims: 1. Document trends in the HCBS used and/or desired by clients with and without AD/ADRD. We expect that persons with AD/ADRD will indicate a greater desire to use more HCBS than they currently receive compared to those without AD/ADRD. 2. Determine client and state-level factors that promote person-reported HCBS outcomes among persons with and without AD/ADRD. Hypothesis 2a: Persons with AD/ADRD will have significantly poorer person-reported HCBS outcomes than persons without AD/ADRD. Hypothesis 2b: Greater state investment in HCBS relative to institutional care will be associated with significantly more positive person-reported outcomes for clients both with and without AD/ADRD. 3. Determine the association between health plan-level HCBS person-reported quality and health care use (emergency department, hospitalizations, potentially avoidable hospitalizations, and nursing home admission) for persons with and without AD/ADRD. Clients who receive HCBS from high quality plans (based on person-reported outcomes) will use less health care than their counterparts, and this difference will be larger for clients with AD/ADRD. This study has the potential to yield new evidence both for how HCBS influence important outcomes for persons with AD/ADRD, and for the policy-relevant outcome of health care use.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY Understanding the neural circuitry and signaling in health or diseased brain requires new tools that can image neuronal activity and functional connectivity with superior spatiotemporal precision across various scales from individual and population of neural cells and microvessel at microscopic scale, neural circuits and cortical layers/columns, and functional connectivity at mesoscopic (or laminar) scale to neural networks at macroscopic scale and the nervous system level. Functional magnetic resonance imaging (fMRI) based on the blood- oxygenation-level-dependent (BOLD) contrast has gained a prominent position in neuroscience, and it is the only neuroimaging modality that can noninvasively map human neuronal activity and dynamic change to the level of neural computational units, and image functional connectivity and resting-state networks (RSNs) covering the entire brain. However, the fMRI BOLD signal is determined by a complex interplay between vascular and metabolic changes, thus, indirectly reflecting neuronal activity. The inference of underlying neuronal activity on the fMRI BOLD signal can be affected by many unknown factors at microscopic and mesoscopic scales. Although great efforts have been made to study the correlation between fMRI signals and neuronal activity, the neurophysiology origin of the BOLD signal and its specificity in mapping neuronal activity and functional connectivity at cortical lamina level remains elusive. To tackle technical challenges and address critical neuroimaging and neuroscience questions, we have formed an interdisciplinary team with experts in the ultrahigh-field (UHF) fMRI and multi-photon microscopy imaging research fields from two research institutions to develop the world first MRI fully compatible volumetric two-photon microscopy imaging (VTPMI) system, which works in one of the highest field animal MRI scanners at 16.4T Tesla. This novel VTPMI-fMRI multimodal neuroimaging system will make it possible to simultaneously measure key neurophysiological information related to activities and dynamics of excitatory/inhibitory neurons, astrocytes, different sized vessels, and ultrahigh-resolution fMRI data, thus enables delineation of cell- and layer- specific neuronal activity in the living brain. The VTPMI-fMRI technology developed in this project will be employed to study the neuro-vascular correlation and the specificity of resting-state fMRI BOLD signals for mapping the layer-specific functional connectivity in anesthetized and awake brains, with particular emphasis on investigating the roles of inhibitory interneurons. The findings and knowledge from this project will be transformative and beneficial for understanding and interpreting the human fMRI BOLD signals at the fine scale of fundamental computational units.

NIH Research Projects · FY 2024 · 2020-09

Abstract Research into the molecular basis of Parkinson’s Disease has recently undergone a dramatic shift to focus on toxic, early stage oligomers of α-Synuclein (aSyn). Understanding this promising new therapeutic target, a departure from research on insoluble fibrils, now requires biophysical insight about the misfolding of aSyn monomers and subsequent assembly of these toxic oligomers. These oligomer species are far less understood than fibrils, and more difficult to study, presenting a pressing challenge to biophysicists. The specific overall goal of the proposed work is to identify a subset of amino acid interactions within and between aSyn monomers that are most important in the assembly and toxicity of oligomers. Several new high- resolution structures of aSyn fibrils will be used as an exciting starting point to launch detailed investigations into the structural motifs that are present in the early stages of assembly. Based on strong preliminary results, we hypothesize that, despite their relative structural disorder, there exist robust, targetable structural motifs in early stage oligomers that persist through fibrilization. Additionally, a subset of those motifs is essential in determining toxicity: some promote toxic assemblies while others promote cytoprotective assemblies. High-resolution structures of early-stage oligomers will likely never be solved. Absent structures, our data will do the next best thing: it will point to specific motifs and residues that stabilize early-stage oligomers and that should be the focus of directed targeting campaigns. We have established a highly resolved technology (both temporally and spatially), time-resolved FRET, that allows us to study with great sensitivity the early-stages of aSyn aggregation in the cell. We will support these cellular observations with rigorous biophysical studies including 19F NMR, two-color TIRF microscopy and computational modeling. We will also utilize our established small molecule discovery technology in an innovative way to establish whether there are clear structural differences in oligomeric assemblies of the familial variants of aSyn, and whether these assemblies vary in differing neuronal cell lines. In sum, the proposal will provide the field with a significantly deeper understanding of the biophysical basis of aSyn oligomerization and will draw new correlations between key amino-acid residues, folding and toxicity.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY/ABSTRACT Parkinson’s disease (PD) is a neurodegenerative disorder affecting 6-7 million people worldwide. Traditional high frequency, isochronal deep brain stimulation (DBS) is an effective treatment for the motor signs associated with PD. Clinical outcomes, however, vary across centers and within centers across patients. Adverse effects can be induced by “current-spread” to unintended brain areas when the DBS lead is sub-optimally placed which limits clinical benefits. Coordinated reset (CR) DBS is a promising novel DBS approach that has the potential to overcome the limitations of traditional DBS. By alternating lower intensity stimulation delivered in a burst pattern across different contacts of the DBS lead, CR DBS is associated with less current spread, thus reducing the incidence of adverse effects, and improvement in motor signs that persist for days to weeks after cessation of stimulation, i.e. carryover effect. Although the effectiveness of CR DBS has been demonstrated in both preclinical and clinical studies, the selection of CR parameters that provide the greatest carryover effect has been challenging. The optimal target for CR DBS must also be identified. The proposed study using a within-subject experimental design will 1) optimize the critical parameter (cycle rate) of CR DBS, (2) compare the effect of CR DBS in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi), and (3) characterize the changes in cortical and subcortical neuronal activities associated with its therapeutic effect. The nonhuman primate model of PD will be used with each animal implanted with DBS leads in the STN and GPi and high- density Utah arrays placed over the primary motor, dorsal premotor and dorsolateral prefrontal cortices. Objective and quantitative motor assessments will be performed to measure the acute and carryover effect of CR DBS with different cycle rates and in different targets (STN and GPi). The central hypothesis is that the therapeutic effect of CR DBS is greatest when the cycle rate is based on subject-specific pathophysiological biomarkers associated with the PD state. We further hypothesize that CR DBS in GPi will provide greater acute benefits in motor signs and induce significantly longer carryover effects. We predict that motor improvements induced by CR DBS will correlate with a reduction in synchronized neuronal activity within and across cortical and subcortical nodal points in the basal-ganglia-thalamocortical (BGTC) circuit. The results of this study will provide a time efficient approach for the selection of CR DBS cycle rate based on subject-specific biomarker activity in the BGTC circuit, identify the optimal target for CR DBS and enhance our understanding of the mechanism(s) underlying the therapeutic effect of CR DBS. Results of the study will significantly advance the development of CR DBS for the treatment of PD that will enhance clinical outcomes, prolong battery life and induce fewer side effects leading to higher quality of life for PD patients undergoing DBS.

NIH Research Projects · FY 2024 · 2020-09

Project Summary Poor diet and chronic physical inactivity synergize with aging to induce physical decline and cognitive dysfunction. As a result, there is a current push to test various diet and exercise modalities that can improve metabolic health, preserve cognition, and expand health span. Both various forms of caloric restriction and exercise have been shown to provide benefits for metabolism, cognition, and physical function. One popular notion is that fuel oscillations alternating between carbohydrate and fat utilization are beneficial for long term metabolic and cognitive health. A key corollary is that ketone metabolism, triggered by carbohydrate restriction and fat catabolism, may mediate the observed benefits. Indeed, exploiting ketone body metabolism has garnered recent attention as a tool to improve both peripheral metabolism and treat impaired cognition in aging individuals. Rationale for ketone metabolism in brain health originates from the benefits of ketogenic diets or starvation for seizure disorders. Due to the robust stimulation of adipose tissue lipolysis and increased fat oxidation in the liver, exercise is another trigger for hepatic ketogenesis, raising the question of whether the beneficial relationship between brain health and exercise could at least in part be transduced by ketone metabolism. Currently there are large clinical trials testing if ketogenic diets can mitigate or treat cognitive decline and neurodegenerative conditions associated with aging, however, studies investigating mechanisms of action are lacking. This proposal will fill this void by leveraging novel genetic mouse models and cutting-edge approaches to test the central hypothesis that nutritional and exercise-mediated oscillations of integrated ketone metabolism improve neurometabolic health span. Studying mice with selective loss of either hepatic ketogenesis or neuronal ketone oxidation will allow independent dissection of the mechanistic roles of integrated ketone metabolism in mediating the well-described benefits of intermittent fasting (Aim 1) and exercise (Aim 2), which are both established models that provoke ketosis and ketone utilization by the brain, while also improving metabolic and cognitive phenotypes. The specific roles of ketone metabolism on caloric intake; body composition; whole-body energy homeostasis, glucose metabolism, lipid metabolism, and ketone turnover; cognitive function, including memory and executive function; mitochondrial function in brain; metabolic flux (quantified using stable isotope tracers) in brain; as well as the metabolome and transcriptome of discrete anatomic brain regions will all be quantified. Both male and female mice will be examined in mid-life (12 months of age) after chronic Western diet feeding when differences in health span will emerge via cognition, physical function, and metabolic phenotypes. By defining the independent roles of both hepatic ketogenesis and neuronal ketone body oxidation in health span-promoting interventions, the results will optimize therapies to be tested in future clinical trials. Moreover, this work will elucidate specific therapeutic targets linking metabolism, cognition, and physical function in aging.

NIH Research Projects · FY 2025 · 2020-09

Project Summary Diabetes mellitus (DM) occurring after one or more episodes of acute pancreatitis (AP) is an important cause of DM in adults, affecting about 15% of individuals by 2 years after an episode of AP. However, more rigorous data are needed in larger and more diverse populations to define the exact incidence of new DM, risk factors for developing DM, and pathophysiological mechanisms driving AP-related DM. To address this research gap, the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) formed the “Type 1 Diabetes Acute Pancreatitis Consortium” (T1DAPC) in 2020, which subsequently launched the Diabetes Related to Acute Pancreatitis and its Mechanisms (DREAM) study in 2022. The primary aims of the DREAM study are to estimate the prevalence of and clinical risk factors for DM after AP, characterize islet function and endocrine dysfunction after AP, and understand potential immunologic drivers of DM after AP. The University of Minnesota has been a successful clinical site in the T1DAPC, as evidenced by: (1) strong recruitment and exceptional retention (>95%) in DREAM; (2) leadership in the consortium including Co-Chairing the consortium and DREAM protocol (contact P.I. Bellin); and (3) proposals and contributions for ancillary studies and secondary data analyses. We will continue this important work in the next funding cycle of the T1DAPC. Our site-specific Aims for this proposal are: (1) To recruit and retain participants in the DREAM trial and to maintain academic engagement, collaboration, and leadership within the T1DAPC. We will continue to achieve a high level of participant engagement and retention in the DREAM study. (2) To determine whether CT-derived abdominal and pancreatic fat measures predict future development of DM and decline in beta cell function. We will use innovative machine learning approaches to estimate pancreatic, visceral and subcutaneous fat in the DREAM participants on initial CT imaging and determine its value in predicting later DM and beta cell function. (3) To define the role of beta cell function and insulin resistance in DM development after AP. We will use metabolic testing data collected in DREAM to determine metabolic pathways (reduced insulin secretion and/or insulin resistance) driving DM development. The results of DREAM will have a high impact in the clinical care of patients with AP, and are a first step towards developing screening, treatment, and ultimately prevention strategies for AP-related DM.

NIH Research Projects · FY 2026 · 2020-09

ABSTRACT Spinocerebellar ataxia type 1 (SCA1) is a chronic neurodegenerative disease characterized by progressive dysfunction of the cerebellum, impaired movement and cognitive decline. No effective treatments exist for this devastating and fatal disease, creating a pressing need to increase our understanding of SCA1 pathogenesis. SCA1 is caused by the abnormal expansion of glutamine (Q)-encoding CAG repeats in the ataxin-1 (ATXN1) gene. While motor deficits are well studied, the etiology of neurocognitive deficits in SCA1 remains less understood. In the previous funding period, we have made substantial progress in understanding SCA1 cognitive deficits. As executive dysfunction is the prominent cognitive deficit in SCA1 patients, we characterized pathogenesis in the prefrontal cortex (PFC), a brain region key to executive function. Using conditional SCA1 knock–in line, f- ATXN1146Q mice, we investigated the impact of Purkinje cell (PC)-specific expression of mATXN1 on cognitive deficits and PFC pathology. Surprisingly, we found that deleting mATXN1 in PCs caused earlier onset of cognitive deficits and exacerbated PFC dysfunction. Major goals of this competitive renewal are to build upon these findings and undertake further in vivo dissection of the regions and cell types involved in cognitive deficits in SCA1 and delineate underlying mechanisms. Our preliminary observations indicate that deleting mATXN1 in the cortex or microglia ameliorates cognitive deficits in SCA1 mice. We propose to test the hypothesis that mATXN1 expression both in the cortex and microglia contribute to PFC dysfunction, impact cerebello-cortical communication and cortical network connectivity contributing to cognitive deficits in SCA1 mice.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY Alcohol is the most commonly abused substance and Alzheimer’s disease (AD) is the most common neurodegenerative disease. Alcohol abuse is a significant risk factor for the development of AD and this intersection of alcohol abuse and AD presents an enormous public health concern. Chronic, heavy alcohol use is associated with a higher risk of developing AD and accelerated progression of the disease. The clinical phase of AD is preceded by a decades long preclinical phase that is characterized by early deposition of amyloid b (Ab) and neuronal loss in the locus coeruleus (LC), a norepinephrine nucleus in the brainstem. We propose a novel mechanism by which chronic alcohol consumption renders LC neurons vulnerable to degeneration. We recently discovered a novel cellular mechanism that selectively induces mitochondrial oxidant stress in axons. Cytosolic monoamines, including norepinephrine, are metabolized by monoamine oxidase (MAO) enzymes and the electrons generated from this process are directly shuttled into the mitochondrial intermembrane space. This produces increased mitochondrial oxidant stress selectively in axons. We propose that chronic alcohol consumption activates this novel mechanism of axonal mitochondrial oxidant stress leading to a degenerative cascade in LC neurons. Our pilot studies suggest that chronic, intermittent alcohol consumption decreased VMAT2 mRNA and increased axonal oxidant stress in the LC. Importantly, we also showed that Ab pathology was increased in APP/PS1 mice that underwent chronic, intermittent alcohol consumption compared to age-matched water drinking mice. Thus, we hypothesize that chronic, intermittent alcohol consumption decreases VMAT2 expression in the LC leading to increased metabolism of cytosolic norepinephrine by MAO, which then causes axonal mitochondrial oxidant stress. This elevated mitochondrial oxidant stress would then accelerate LC degeneration and Ab deposition in mouse models of AD. We will test this hypothesis using 2 genetic mouse models of AD, APP/PS1 and APP-NL knock- in mice, which develop progressive Ab pathology. A combination of cutting-edge two-photon laser scanning microscopy (2PLSM) in ex vivo brain slices, false fluorescent neurotransmitters (FFNs), genetically encoded redox biosensors, immunohistochemistry, stereological, pharmacological, and genetic techniques will be used to investigate the effects of chronic, intermittent alcohol consumption on VMAT2 expression, VMAT2 packaging of norepinephrine, LC axonal mitochondrial oxidant stress, LC degeneration, Ab pathology, and MAO-dependence. In aim 1, we will determine the effect of chronic, intermittent alcohol consumption on LC axonal mitochondrial oxidant stress. In aim 2, we will determine the effect of chronic alcohol consumption on LC degeneration and Ab pathology. Our proposed experiments will be the first to explore a novel axonal mitochondrial oxidant stress-mediated neurodegenerative mechanism underlying the interaction between chronic alcohol consumption and AD.

NIH Research Projects · FY 2024 · 2020-09

Summary In response to PA-17-088, “Secondary Analyses of Existing Cohorts, Data Sets and Stored Biospecimens to Address Clinical Aging Research Questions (R01)”, we propose integrating existing GWAS summary data of Alzheimer's disease (AD) with existing proteomic and metabolomic quantitative trait locus (pQTL/mQTL) data to identify proteins and metabolites putatively causal to AD. The overarching goal is to both boost statistical power and enhance interpretability for causal inference in the post-GWAS era by leveraging many published large-scale GWAS summary association datasets and omic data. In an emerging and increasingly influential approach called transcriptome-wide association studies (TWAS), by integrating GWAS summary data with gene expression (or eQTL) data, one aims to improve over the current practice of GWAS to not only increase statistical power to identify more genetic variants associated with GWAS traits, but also link the (non-coding) genetic variants to their target genes, thus gaining insights into the genetic basis of common diseases and complex traits. In practice, however, TWAS may fail to identify true causal genes while giving false positives due to the violation of its modeling assumptions (e.g. due to LD or horizontal pleiotropy of SNPs). We first propose three new methods to check possible violations of modeling assumptions in TWAS, then propose two more robust and powerful approaches that improve over the standard TWAS. Next, we extend TWAS to xWAS to integrate GWAS with proteomic and metabolomic traits (i.e. pQTL and mQTL), to identify (putatively) causal proteins and metabolites, analogous to detecting causal genes/transcripts in TWAS. We apply the new (and existing) methods to integrate large-scale GWAS summary data of AD and atrial fibrillation (AF) with pQTL and mQTL to identify putatively causal proteins and metabolites for AD and AF respectively, and to investigate whether AF is causal to AD, thus not only advancing our understanding of the etiology of AD and AF, but also possibly offering modifiable targets for interventions on the two devastating diseases. Finally, we will develop and disseminate publicly available software implementing the proposed analysis methods, e.g. as R packages, to facilitate the wide use by the scientific community.

NIH Research Projects · FY 2025 · 2020-09

Project Summary Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) represent a spectrum of disease, with variable pain burden, often with impaired quality of life and progression to diabetes and pancreatic exocrine insufficiency. The Chronic Pancreatitis Diabetes Pancreatic Cancer (CPDPC) consortium – known in the next funding cycle as the Chronic Pancreatitis Clinical Research Consortium (CPCRC)-- is transforming clinical care for pancreatitis through defining the natural history of disease, developing biomarkers for progression, and ultimately setting the stage for future treatments for affected patients. The University of Minnesota (UMN) brings together a strong multidisciplinary team with Pediatrics, Internal Medicine, and Surgery, and will contribute to the CPCRC through enrollment and retention of patients in consortium studies, academic leadership, and collaboration with other CPCRC sites. The first aim of our CPCRC involvement is to recruit and follow participants in the in the longitudinal cohorts for pediatric pancreatitis (“INSPPIRE-2”) and adult pancreatitis (“PROCEED”) and provide academic expertise and leadership in the consortium. We are unique in our contributions to both INSPPIRE-2 and PROCEED, reflecting our balanced Pediatric and Adult Medicine team. We will capitalize on unique expertise and resources at UMN to propose new ancillary studies for our second and third aims of this proposal. In our second aim we will determine the burden of hypoglycemia and glycemic lability, and adequacy of counterregulatory responses to hypoglycemia in adults with RAP and CP and post-pancreatitis diabetes. This is important because individuals with this form of diabetes are clinically felt to be at increased risk for hypoglycemia but there is surprisingly little evidence in the current literature to support or refute this clinical impression. Understanding hypoglycemia risks and physiology is important in guiding diabetes treatment. In our third aim we will use collected biospecimens and data from the PROCEED cohort to determine differences in diversity indices, distance matrices, and relative abundance and uniqueness of the fecal microbiome in participants with RAP/CP vs those without pancreas disease, and determine if there are signatures of gut dysbiosis in those who develop pain or diabetes as complications of disease. We hypothesize that these unique microbiome patters may serve as a biomarker of disease or contribute mechanistically to disease progression. To accomplish this third aim, we will add new co-investigators to our team with established expertise in microbiome research in the settings of diabetes and gastrointestinal disease. Collectively, this work is clinically significant in defining disease pathophysiology and developing future therapeutic strategies for CP.

NIH Research Projects · FY 2025 · 2020-09

This renewal of our M-ASCEND Program to the NCI Youth Enjoy Science (YES) mechanism leverages 17 years of cancer research-focused mentored education activities at the University of Minnesota (UMN) Masonic Cancer Center and PHDR Program in the Department of Family Medicine. In the next cycle, we will implement our theoretically and community framed program, including a high school engagement year (HS Scholars), a high school summer internship and service-learning component (HS Interns), an undergraduate summer internship (Undergrad Interns), and teacher professional development. In our inaugural cycle, we successfully met our recruitment goals to train and mentor 300 high school and undergraduate students, and 20 high school science teachers. We engaged in continuous quality improvement resulting in high program satisfaction, and evidence of impact on targeted student outcomes (science self-efficacy, identity, and intrinsic utility) and on student persistence in sciences. Notable areas of innovation moving forward include: for HS Interns, a scaffolded research lab experience and service-learning with community mentors to maximize outreach opportunities and support science identity development; for Undergrad Interns, a longitudinal community based participatory research experience that complements their mentored lab training, and for teachers an intensive lab experience aligned to their priorities for building science curricula. We will integrate these innovations to support the academic persistence of 250 high school students attending ten high schools, 50 undergraduate students from across Minnesota, and the professional development of 20 teachers through a multicomponent program combining research mentorship, academic and professional development, and support for science-oriented identity development. Five cohorts of 50 high school students will be recruited to the HS Scholars program comprised of exciting hands-on experiences in Science Saturdays, virtual near-peer mentorship activities and parent programs. Ten students per cohort will be selected to continue to an intensive eight-week summer HS Internship including a mentored research component scaffolded for high school students, and a service learning experience. Ten undergraduate students per year will participate in a nine-week summer internship combining academic and professional development and hands on individual research mentorships. Finally, we will deepen the science-focused skills of 4 high school science teachers per year from collaborating schools through a hands-on research lab experience paired with support to develop curricula responsive to the needs of all learners. As evidenced by our program outcomes thus far, M-ASCEND successfully addresses NCI strategic priorities to strengthen the cancer research workforce and mitigate differential cancer outcomes.

NIH Research Projects · FY 2026 · 2020-09

Project Summary/Abstract IPUMS Multiple Indicator Cluster Surveys (IPUMS MICS) dramatically simplifies ambitious comparative research using UNICEF’s Multiple Indicator Cluster Surveys, which are an essential source of information on the health and well-being of children, adolescents, young adults, and women of reproductive age in over 120 countries. This proposal seeks continued funding to expand, enhance, and maintain IPUMS MICS for cross-national health research. In Phase I of IPUMS MICS, we delivered over 1200 integrated variables from 218 surveys covering 90 countries and attracting almost 400 users. IPUMS MICS has already enabled ambitious research, including whether in-utero exposure to maternal fasting affects child height, via robust testing across a sample of more than 50 countries; the relationship between maternal labor supply and child disability; and how resident grandparents affect child stimulation. Phase II of IPUMS MICS will extend IPUMS MICS’ substantive impact by incorporating the latest surveys, novel modules (e.g., biometric data for children aged 5-9), and new data modalities (i.e., longitudinal and time-diary data). Building on a solid foundation, we will multiply cross-country health research's spatial and temporal scope by increasing interoperability between IPUMS MICS and harmonized data from the Demographic and Health Surveys (IPUMS DHS). We plan further technological innovations to enhance data accessibility through new syntax languages, ease of complex linking, and enhanced variable discovery. We will offer guidance to researchers for conducting complex data analyses that capitalize on novel MICS features, such as research employing GPS sample points and contextual big data. We will also offer researchers free individualized support and expand our user base via webinars, workshops, conference exhibits and presentations, blog posts, and messages to the almost 300,000 IPUMS users. This work will be carried out by a team of highly-skilled researchers with extensive experience in data integration and in substantive research using global health survey data. IPUMS MICS is a cost-effective means of addressing issues central to NICHD’s mission, such as scientifically valid interventions to improve pregnancy outcomes and prevent prematurity, malnutrition, childhood stunting, disease, and developmental delays. By simplifying comparative analyses based on the invaluable MICS data, IPUMS MICS enables groundbreaking research on women and children’s health.

NIH Research Projects · FY 2024 · 2020-09

Project Summary Antimicrobials are critical for medicine, but the problem of antimicrobial resistance (AMR) threatens the effectiveness of these valuable drugs. Widespread use of antibiotics is the main driver of AMR. In human and animal health settings, this makes infections difficult, and sometimes impossible, to treat. Tracking of antimicrobial use (AU) is an essential strategy to combat AMR. There are no systematic, ongoing national- or state-level programs to track AU in dogs and cats in the United States. Measurement of AU is hampered by logistical challenges of accessing prescribing data within and across the many diverse veterinary electronic health record (EHR) systems. Veterinary medicine lacks standard diagnostic coding, as such codes are not required for billing nor disease reporting. Often the details of the patient encounter (e.g., diagnosis, indication for prescriptions) are recorded only in free-text fields of the EHR rather than in easily searchable fields. Methodologies that overcome obstacles to data collection are a critical need in the fight against AMR. The overarching goal of this project is to optimize long-term strategies for collecting and reporting AU data from companion animal practices to understand baseline prescribing behaviors and provide actionable targets for antimicrobial stewardship (AS). Two practical, scalable, and sustainable approaches to track AU in companion animal veterinary practices will be utilized. These include the use of point prevalence surveys (PPS) and the Companion Animal Veterinary Surveillance Network (CAVSNET). PPS have been used by the Centers for Disease Control and Prevention to establish baseline national measures of AU in human hospital and long-term care settings. This project will establish national estimates of AU prevalence in referral and small animal general practices by conducting national PPS in veterinary teaching hospitals and general and referral practices. CAVSNET is a secure passive surveillance system for long-term tracking of companion animal health, disease, and treatment. CAVSNET will gather AU data on a routine basis directly from EHR systems. With these two complementary approaches, we will build a comprehensive national picture of AU in dogs and cats.

NIH Research Projects · FY 2024 · 2020-09

Despite the many initiatives designed to increase diversity among neuroscience researchers, the sad fact is that there has been a decline in the proportion and absolute numbers of minority researchers in the field of neuroscience. This failure is disturbing at a number of levels, but perhaps most notably highlights the inability of more senior investigators to effectively mentor junior investigators in their discipline. The loss of diversity among career scientists means a loss of diversity of thought, which in turn limits the generation of new ideas and scientific progress in the neurosciences. The inability of the multiple training programs to increase diversity is not an indictment of those programs, but rather it illustrates limitations in program approach. As a result, we propose to take a different route to addressing this problem. Our program is based on published findings that underrepresented individuals are lost in the system at transition points in their training, i.e., graduate school to postdoctoral training, postdoctoral training to faculty members, and tenure for young faculty. From self-report data, a principal contributing factor regarding attrition is that individuals feel isolated by not having meaningful ethnic and/or racial peer groups. In this R25 program we propose to take a longitudinal approach to mentoring in which we establish peer groups across each stage of professional development and utilize these peer groups to provide interactive mentoring within a community. We will recruit from across the nation a cohort of trainees from underrepresented backgrounds, consisting of graduate students, postdoctoral fellows, and early stage investigators. For each of these cohorts we will provide longitudinal training in professional skills and mentoring. Through both mentor/mentee and peer-to-peer/peer-to-near peer mentorship structures, we will tailor professional development consistent with the progression of the trainee, while simultaneously creating a network of support amongst its participants. A key element of the program will be to teach the participants in the program how to be effective mentors themselves as a means to maintain the longitudinal development of program participants. Finally, we will provide access to high-level research cores and laboratories to enhance the scientific impact of the participants’ research. Participants will meet in Minnesota for one week each summer for professional training and guidance. For topics that span across career stage, the cohort will work together. There will also be specialized training sessions specific to academic rank. In addition to the on-site summer training, there will be two additional formal training events. In the fall, our trainees and mentors will meet at the annual Society for Neuroscience meeting to participate in both professional development and a social event. In the winter, there will be an on-line video teleconference discussion following the group’s completion of an on-line professional development session. Overall, our goal is to fundamentally alter mentored training, and significantly enhance workforce diversity in the academic pursuit of research on neurological disorders.

NIH Research Projects · FY 2024 · 2020-09

Project Summary/Abstract Neurofibromatosis type 1 (NF1) syndrome is an autosomal dominant cancer-predisposing syndrome afflicting ~1 in every 3,500 persons worldwide with the majority of patients developing benign plexiform and/or dermal neurofibromas. Plexiform neurofibromas constitute a lifelong source of disfigurement, morbidity and mortality, and have the potential to transform to a malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma. In fact, approximately 15% of NF1 patients develop poor prognosis MPNSTs, often in the second or third decade of life. Treatment options for MPNSTs are limited to complicated surgical procedures and classical chemotherapy and, so far, molecular targeted therapies have demonstrated limited efficacy. We desperately need new treatment options for the MPNSTs and methods to prevent them from development. It was recently found that plexiform neurofibromas progress to MPNST via an intermediate, “atypical” neurofibroma (ANF) that in 70% of tumors shows heterozygous or homozygous loss of CDKN2A the gene encoding p16INK4a and p14ARF (Beert et al., 2011; Pemov et al., 2018). Our proposal will address critical unmet needs in this field, including better in vitro and in vivo models of ANF and identification of critical vulnerabilities of these cells. To provide a model for preclinical testing and prevention of ANF to MPNST development, we combined Desert hedgehog (Dhh)-Cre driven biallelic deletion of Nf1 with heterozygous loss of Cdkn2a, creating a unique model of transplantable ANF developing within pre-existing neurofibroma (Chaney et al., submitted). We also combined Dhh-Cre driven biallelic deletion of Nf1 and Pten, generating rapidly developing perinatal ANF-like lesions (Keng et al., 2012). ANF from Dhh-Cre;Nf1fl/fl;Cdkn2a+/- mice grafted subcutaneously into immunocompromised hosts grew, after a delay, providing a more rapid, tractable, transformation system. We plan a complete transcriptome and exome analysis in these models (Aim 1a), and further investigate the model by identifying and validating cell populations and markers altered in mouse and human PNF, ANF, and MPNST in unperturbed tissue sections using a new image analysis method called CO-Detection by IndEXing (Aim 1b). Modulation of the immune environment is increasing used therapeutically. We will therefore define the influence of the nerve microenvironment and immune system on progression from ANF to MPNST (Aim 1c). To identify ANF vulnerabilities, we have completed drug and CRISPR-based genetic synthetic lethality screens in isogenic immortalized human Schwann cells that are NF1 wildtype or were made homozygous for NF1 loss of function mutations using gene editing. Candidate drugs that inhibit PP2A, and other novel targets from the drug screening effort, will be tested for their effects in ANF- like cells in vitro (Aim 2a) and, when successful, in our unique GEMMs (Aim 2b). Similarly, our genetic screening effort will be used to define additional vulnerabilities tested in vitro (Aim 2c) and in vivo (Aim 2d).

NIH Research Projects · FY 2024 · 2020-09

Abstract Neurostimulation, including invasive methods like deep brain stimulation (DBS), is an increasingly important approach to treating mental illness. It offers the possibility of directly targeting specific circuits to reverse circuit dysfunctions that underpin mental disorders. Unfortunately, the clinical efficacy of brain stimulation is still unreliable. DBS, for instance, has extraordinary results in the hands of expert academics, but has not passed a well-controlled US-based clinical trial. The critical barrier is that it is very difficult to study or optimize DBS’ mechanisms of action in psychiatric illness. Animal studies would be ideal for refining stimulation strategies, but the primary species for modeling mental illness are rats and mice. The most promising DBS treatments act on circuits that lack true rodent homologues. We and other investigators have shown that, at multiple brain targets, effective DBS alters neural activity distally, especially in lateral prefrontal cortex (LPFC), which is only found in primates. Non-human primates (NHPs), especially macaques, which have strong LFPC homology to humans, would thus be an excellent model for understanding how DBS works. Macaque studies have yielded major insight in other DBS applications such as movement disorders. In this project, we demonstrate an approach to modeling DBS in non-human primates by focusing on cognitive control. Cognitive control is the ability to regulate one’s own cognition, such as withholding a habitual response in favor of a more goal-aligned option. It is disrupted in depression, obsessive compulsive disorder (OCD), and emerging DBS indications like addiction. Co-PI Widge recently showed that DBS at a well-studied target, the ventral internal capsule/ ventral striatum (VCVS), acts in part by improving cognitive control. That improvement appears to involve PFC activity changes. The challenge is that it is not clear why or through what pathways VCVS DBS improves cognitive control, and thus we lack the ability to optimize the effect. We propose to answer that question by stimulating individual tracts and gray matter nuclei that comprise the VCVS DBS target, in rhesus macaques performing a standard cognitive control task (the Flanker task). During stimulation, we will record single units and local field potentials from multiple PFC structures, identifying mechanisms by which VCVS DBS exerts pro-cognitive effects. Aim 1 maps these mechanisms relative to cortico-thalamic tracts in the internal capsule, while Aim 2 extends that mapping to cortico-striatal tracts and striatal nuclei. These studies are possible through a unique clinical, engineering, and neuroscientific collaboration. Co-I Johnson has developed methods for “steering” electrical neurostimulation to preferentially target structures surrounding a DBS electrode, allowing circuit-targeted neurostimulation without the use of viral/genetic manipulations. His expertise supports our team’s capabilities in macaque cognitive neuroscience (contact PI Hayden), clinical DBS (Widge), and striatal anatomy (co-I Heilbronner).

NIH Research Projects · FY 2025 · 2020-09

Project Summary/Abstract Postpartum smoking relapse rates have remained stagnant for over a decade with more than 50% of those who are able to achieve smoking abstinence during pregnancy relapsing within the first few months after childbirth. Maternal cigarette smoking results in significant increases in a variety of negative health consequences for both mother and child. Second-hand smoke exposure to newborns and infants increases their risk of both acute and chronic illness. Therefore, research to identify safe and novel postpartum smoking relapse prevention intervention is warranted. Our preliminary data indicates that the delivery of exogenous progesterone (Prog) in the early postpartum period reduces several smoking relapse related risk factors (e.g., craving) and was also associated with a higher prevalence of smoking abstinence at 12-weeks postpartum. These observations concur with a wealth of prior literature that demonstrates the protective effects of progesterone on a variety of addictive behaviors. In our other preliminary work looking at non-pregnant premenopausal women, depot medroxyprogesterone acetate or DMPA, which blocks ovulation for 12-weeks which subsequently decreases estradiol levels, was associated with longer previous quit attempts and reduced smoking motives. These observations have shaped our central hypothesis which is that the combination of Prog + DMPA; i.e., increased progesterone and decreased estradiol will prevent postpartum smoking relapse. To examine this hypothesis, we will conduct a double-blind, placebo-controlled, randomized clinical trial that will be implemented by an experienced, transdisciplinary, and productive team of investigators from two sites to enhance the diversity of the study sample and generalizability of the results. We will enroll healthy pregnant women (n=320) who have recently quit smoking and intend to stay abstinent postpartum. Using a 2×2 factorial design, participants will be randomized into one of four assignments: (1) Prog + DMPA, (2) Prog + placebo, (3) placebo + DMPA, and (4) placebo + placebo. Participants will be followed for days to smoking relapse (primary outcome), smoking relapse-related risk factors (e.g., craving), and infant health outcomes from gestational week 36 through 9 months postpartum. This study proposes a safe and innovative intervention to examine the impact of manipulating postpartum physiological to influence the behavior of a new mother which will lead to improved health outcomes for her and her infant. The implications of this novel study will directly advance the current state of the science by expanding on the role of Prog and DMPA in addressing smoking-related behaviors within this highly vulnerable population. Further, should our central hypothesis be supported, the clinical translatability of this intervention is high and may be immediately pursued.

NIH Research Projects · FY 2024 · 2020-08

PROJECT SUMMARY Diseases such as osteoporosis and periodontal disease affect millions of individuals annually in the United States and cost billions in treatment. Osteoclasts are large, multinucleated cells that secrete acid and proteases to resorb bone. Understanding the molecular mechanisms that regulate osteoclast differentiation and activity will provide insight as to how the hyper-active osteoclasts causing pathological bone loss, contributes to osteoporosis and periodontal disease. Reversible modifications to DNA such as histone acetylation, methylation, phosphorylation and ubiquitylation alter the access of transcriptional machinery to DNA and regulate gene expression. Lysine-specific demethylase 1 (LSD1), also known as KDM1A, is the first identified histone demethylase capable of specially demethylating mono- and di-methylated lysine 4 of histone 3 (H3K4me1/2) or lysine 9 of histone 3 (H3K9me1/2). LSD1 confers transcriptional repression by demethylating H3K4 or activating transcription by demethylating H3K9. The mechanism by which LSD1 regulates osteoclast gene expression and differentiation is currently unknown. Preliminary data presented in this proposal demonstrate inhibition of LSD1 activity or expression leads to an increase in mono-methylation of H3K4me1 and an increase in osteoclast differentiation. These preliminary data suggest LSD1 is a repressor of osteoclast gene expression. This proposal aims to characterize the role of LSD1 in regulating osteoclast differentiation in both an animal model and as well as in an in vitro cell culture model (Aim 1) and identifying the osteoclast genes that are regulated by LSD1 (Aim 2). These research goals will be enhanced by the training goals of the application. These training goals include learning techniques such as micro-CT, RNA-SEQ and ChIP-SEQ as well as participation in journal clubs and local and national scientific meetings. Training takes place at the University of Minnesota which offers an outstanding environment for both research and clinical dental training.

NIH Research Projects · FY 2026 · 2020-08

Project Summary Resident memory T cells (Trm) are widely distributed throughout the body, remarkably abundant, and protect against local reinfections and control tumors. Unfortunately, Trm also drive many undesired immune responses including certain autoimmune, allergic, chronic inflammatory, and graft-versus-host diseases. Gaps in understanding resident memory T cell development and poor knowledge of how Trm actually function in tissues is impeding our ability to leverage or manipulate this recently defined cell type for developing new vaccines, cancer therapies, or treatments for many T cell driven diseases. This proposal will develop new mouse and human assays to define how Trm function by amplifying signals through local stromal, hematopoietic, and parenchymal cells. Systemic endocrine consequences of Trm activation will be assessed in vivo. Combinatorial gene editing approaches will expand our understanding of the molecular regulation of Trm induction. And application of a newly developed mouse model, allowing exacting manipulation of antigen responsiveness, will be used to dissect the role of antigen in shaping Trm differentiation during acute and persistent infections or cancer. Collectively, this proposal will identify new strategies for promoting or engineering Trm development, with relevance for protecting against infection or cancer, and new strategies for interfering with Trm function, with relevance for treating inflammatory diseases.

NIH Research Projects · FY 2025 · 2020-08

PROJECT SUMMARY: Overall The NIDA Center for Neural Circuits in Addiction at the University of Minnesota (UMN) develops and disseminates new technologies in the study of neural circuits to produce groundbreaking work in addiction neuroscience. The Center comprises four Research Cores: 1) The Viral Innovation Core (VIC) assists investigators in applying state-of-the-art viral manipulation approaches to their studies of the anatomical, molecular and neural circuit bases of addiction providing expertise for design of custom vectors; 2) The Structural Circuits Core (SCC) offers state-of-the-art anatomical mapping of neural circuits involved in addiction. Integrated with the University Imaging Center and UMN Informatics Institute, SCC provides automated use of brain clearing technology paired with meso- and micro-scale imaging of the CNS; 3) The Addiction Neural Dynamics Core (ANDC) offers a range of imaging and electrophysiology modalities to monitor brain activity in behaving animals across a range of spatial and temporal scales including: novel wide field-of-view optical imaging during behavior at both the mesoscopic and cellular levels, fiber photometry, Neuropixel probes, new optical sensors, and neuroengineering services for custom applications. 4) The Addiction Connectome Core (ACC) is collecting and sharing an “addiction connectome” based on structural and functional connectivity Magnetic Resonance Imaging (MRI) data in rodents and non-human primates over the addiction cycle and creating a computational platform to integrate functional and structural data to test relationships between drug exposure and neural connectivity. Our goal is for the Center to be a national resource for neural circuit research technologies that fuels high-impact, collaborative research to address critical knowledge gaps in our field. The renewal specific aims for the Center are: Aim 1. Maintain the framework and vitality of each Center Core. Provide: a) Education and training in new technologies, b) Access to tools, reagents and expertise for data collection and analysis, c) Further development and adoption of new technologies, d) Catalysis of new collaborations among users and e) Dissemination of resulting research and new technologies to the wider addiction research community. Aim 2. Expand innovation and service in our Research Cores. The Center's four Research Cores have each described additional innovative tools under development with Center resources. While Center productivity has been strong in our first funding period, the availability of new, state-of-the-art technologies to offer Center Investigators should continue to boost the productivity and impact of neural circuit research in addiction at UMN.

NIH Research Projects · FY 2024 · 2020-08

Project Summary/Abstract Human papillomaviruses (HPVs) are cancer-causing viruses. More than 250,000 people die each year from these cancers, particularly cervical, anal, and head and neck (H&N) cancers. Immune proteins known as antibodies can protect against these viruses and successful vaccines must induce such antibodies. Current vaccines can protect us against only two of the 15 HPV types found in cervical and H&N cancers. Better and more lasting control of HPV infections requires improved knowledge of how these antibodies protect and which are the “best” antibodies to provide this protection. Our studies are focused at understanding the exact interactions between HPV capsids and human cells during an infection. We will use cryo-electron microscopy (cryo-EM) and computer-driven high resolution techniques to define these interactions at atomic resolution, starting with a better more detailed examination of the capsids. For decades researchers have relied on the use of various virus like particles (VLPs) that are now known to have different characteristics, especially in the regions that illicit a host immune response. Part of this characterization is to map the location and incorporation of the minor structural protein (L2) that has important function during entry and is conserved across species. Understanding L2 function will reveal a significant target that has remained uncharacterized until now and may allow researchers to redirect the immune antibody response towards a more effective and long-lasting protective HPV vaccine. Finally, we are engaged in understanding the mechanisms that drive entry of HPV. We have begun to understand how the virus changes shape during entry into human cells. Targeting the conformational changing virus is an important new direction for creating new drugs to stop infection.

NIH Research Projects · FY 2026 · 2020-08

PROJECT SUMMARY/ABSTRACT Chronic tics affect 1-3% of youth in the US and are a disabling neuropsychiatric symptom associated with multiple childhood-onset mental disorders. Tic suppression using Comprehensive Behavioral Intervention for Tics (CBIT) is the current first-line, gold-standard therapy for tics. However, many patients do not fully benefit from CBIT, likely because they lack the fundamental tic suppression ability that CBIT aspires to enhance. Our preliminary data and the literature show that tic suppression ability can be enhanced with inhibitory repetitive transcranial magnetic stimulation (rTMS) of the supplementary motor area (SMA). SMA is a key node of cortico-striatal circuits and is known to be hyperactive and hyperconnected in tic disorders. We therefore anticipate that combining CBIT with inhibitory stimulation of SMA may facilitate higher CBIT response rates. This study will test whether augmenting CBIT with inhibitory, noninvasive stimulation of SMA normalizes activity in SMA-mediated circuits and enhances tic suppression ability in young people with tic disorder. The R61 phase will compare two rTMS regimens, 1 Hz rTMS and continuous theta burst stimulation (cTBS), against sham stimulation. R61 aims will test engagement of brain (SMA-mediated circuits) and behavior (tic suppression ability) targets and identify the optimal rTMS regimen. To this end, 60 youth ages 12-21 years with chronic tics will complete 10 daily sessions of CBIT plus randomly assigned rTMS regimen, with fMRI, behavioral, and clinical assessments before and after treatment. The R33 phase will investigate the effects of CBIT augmentation with the optimal rTMS regimen in a double blinded randomized control trial in a new sample of 60 youth with chronic tics. R33 aims test the link between target engagement and functional outcomes, examine the clinical trajectory of the dose-response relationship, and assess intervention durability at 1 month follow-up. TMS targeting in both phases will be informed by individualized electric field modeling. This project will establish CBIT+rTMS as a treatment for chronic tics and provide a model for mechanistically studying pediatric interventions combining behavior therapy with neurostimulation. Results from this line of research will inform TMS therapy augmentation strategies and improve our understanding of neural mechanisms underlying CBIT, TMS, and tics.