University Of Minnesota

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY/ABSTRACT During the aging process there is a loss of automaticity in balance and mobility, where the engagement of cortical resources for balance control may interfere with older adults’ ability to perform cognitive and balance behaviors simultaneously. Over the course of normal aging, there is a decline in cerebral blood flow that is linked to impaired cognitive function in older adults. However, it remains unknown whether age-related declines in cerebrovascular and nervous system function may interact to manifest as cognitive interference in balance control that precipitate falls and clinical dementia. Further, older adults who carry the Apolipoprotein E4 (APOE4) allele, the greatest known genetic risk factor for Alzheimer’s disease, show greater cerebrovascular dysfunction compared to age-matched noncarriers, and display worse balance performance under cognitive loading conditions, supporting the potential effect of individual genotype on the link between cerebrovascular health and balance control with aging. Using electroencephalography (EEG) to measure dynamic cortical activity during standing balance reactions, the candidate’s recent fellowship findings provide an individualized framework of cortical engagement strategies for balance control in older adults that is associated with distinct aspects of balance behavior and fall risk, including cognitive interference in balance performance. Currently, a major scientific barrier to the clinical translation of this research is the lack of understanding of the factors that influence individual-specific cortical strategies for balance control with aging. Emerging evidence suggests cognitive impairment with aging may be caused by dysfunctional cerebral blood flow, specifically characterized by impaired cerebrovascular regulation under conditions of physiologic stress. Blunted cerebral blood flow response to an acute bout aerobic exercise, an assessment method pioneered by Dr. Billinger (primary mentor) and her laboratory, appears to be an early indicator of dysfunctional cerebrovascular regulation in preclinical older adult populations. The proposed project will be the first to test the link between cerebrovascular regulation during an acute bout of aerobic exercise, measured as cerebral blood flow velocity using transcranial Doppler ultrasound, and cortical function during balance behavior with aging, measured with cognitive dual-task balance performance (Aim 1) and EEG measures of cortical activity during balance reactions (Aim 2). An Exploratory Aim will test whether genetic APOE4 carrier status alters the relationship between cerebrovascular regulation and balance control in older adults. The scientific knowledge gained from these studies would create an individualized framework for understanding cardiovascular-nervous system interactions that may contribute to balance disability in older adults. This framework would provide a foundation for the development of precision-medicine strategies for fall prevention, particularly in individuals at high risk for Alzheimer’s disease and subsequent falls.

NIH Research Projects · FY 2025 · 2024-03

PROJECT SUMMARY Huntington’s disease (HD) is a neurodegenerative disease that primarily affects the striatum, a brain region that controls movement and some forms of cognition. Patients manifest a myriad of motor, cognitive, and neuropsychiatric symptoms, the latter being the most burdensome. Apathy is the most prevalent neuropsychiatric symptom in HD and is strongly associated with cognitive dysfunction and suicide, which is the third most common cause of death in HD. The treatment of apathy should be a priority in the clinical care of HD patients, but the etiology or pathophysiology of apathy in HD is unknown. The goal of this proposal is to fill this gap in knowledge and provide insights into the cellular mechanisms that regulate apathy in HD. This is crucial to develop effective treatments to prevent unnecessary deaths and improve the quality of life of HD patients. Studies in the general population have shown that systemic inflammation and white matter (WM) lesions are risk factors for apathy. Increased inflammation and WM atrophy are found in the striatum of patients and mouse models of HD and we and others have shown that dysfunction of striatal astrocytes in HD plays a critical role in these processes. Astrocyte dysfunction has previously been associated with mood disorders, but whether striatal astrocytes regulate apathy in HD is unknown. We recently showed that a subpopulation of striatal reactive astrocytes expressing the glial fibrillary acidic protein (GFAP+), but not other known astrocyte markers, are clustered around a subset of axon bundles (WM fascicles) traversing the dorsomedial striatum (DMS) of a mouse model of HD (zQ175), a phenomenon that increased with disease severity. The DMS along with regions of the medial prefrontal cortex (mPFC) are interconnected and regulate motivation-related behaviors such as apathy. Based on this evidence we hypothesize that a specialized population of GFAP+ astrocytes accumulate on WM fascicles derived from the mPFC and traversing the DMS in HD, causing WM atrophy and apathy related behaviors. To test this hypothesis, we will conduct three complementary aims: Aim 1) we will identify the origin of WM fascicles associated with GFAP+ astrocytes in the DMS of HD mice using anterograde viral tracing analyses from injections conducted in different cortical regions and GFAP immunostaining analyses, Aim 2) we will characterize the astrocytes associated with WM in the DMS of HD mice using coupled spatial transcriptomics and proteomic analyses using the Nanostring nCounter system, and Aim 3) elucidate the effect of ablating WM associated striatal astrocytes in the regulation of WM atrophy and apathy by using an astrocyte selective viral expression of the diphtheria toxin fragment A in the DMS of HD mice. Successful completion of this proposal may reveal a new mechanistic connection between WM atrophy, striatal gliosis, and apathy in HD and will serve the basis for future functional characterization analyses of WM-associated astrocytes to start uncovering new ways to treat neuropsychiatric symptoms in HD.

NIH Research Projects · FY 2025 · 2024-03

PROJECT SUMMARY Abstract Animal survival is dependent on locomotion to successfully find shelter, locate a mate, capture prey, and avoid predators. Although it is well established that spinal locomotor circuits in vertebrates are activated by glutamatergic-mediated excitation, our understanding of glutamatergic signaling is incomplete. This is important to understand since glutamatergic excitation contributes to the generation of rhythmic activity and the amplitude of motor output. Dissecting the precise role that subtypes of ionotropic and metabotropic glutamate receptors play in spinal locomotor circuit function will provide mechanistic data critical for understanding locomotor circuit function. We will address this gap in knowledge by determining the roles of glutamate receptor subtypes in the larval zebrafish spinal locomotor network using a well-validated complement of tools that span from molecular to behavioral levels, including optogenetic activation of spinal locomotor networks, pharmacology, electrophysiology, high-speed videography, and calcium imaging. The goal of this proposal is to advance our mechanistic understanding of glutamatergic signaling responsible for regulating the properties of vertebrate spinal locomotor output and spinal motor neuron recruitment. The results of these experiments will set a foundation for investigations into the specific neuronal targets of glutamatergic actions, revealed here, in a future R01 proposal. Since many principles of CPG function are conserved across vertebrates, we expect these findings to translate to other animals, including humans.

NIH Research Projects · FY 2026 · 2024-03

SUMMARY The association between advanced age and impaired resistance to infections is well known, but poorly understood. The current COVID-19 pandemic is a clear example of the vulnerability of the elderly to SARS- CoV-2 infection as well as many other pathogens. Considerable research efforts have shown that components of both the innate and adaptive immune systems show signs of dysfunction as we age, with signs of both immunodeficiency, including reduced innate response and poor induction of adaptive immune memory, and immunopathology including an exaggerated “cytokine storm”. However, while aspects of age-related changes in immune cells have been explored in depth, the focus has been on defining the nature of dysfunction within cells of the immune system itself, rather than investigating the potential role of other cell populations in dominantly compromising immune homeostasis and immunological response to pathogens. Also, although the increase in immunosenescence with age, defined by cell surface markers for immune cell exhaustion, has been examined, the extent of cellular senescence in immune cell populations with age and pathogen exposure remains undefined. Our recent findings indicate that senescent cells (SnCs), including senescent immune cells, can exert a “bystander” effect on immune cells, provoking immunological dysfunction through secretion of inflammatory factors, including cytokines and chemokines, termed the “senescence-associated secretory phenotype” (SASP). We demonstrated that SASP factor production is increased when SnCs or mice containing SnCs are exposed to pathogens or microbial products that induce innate immune activation. Exposure of old mice to normal microbial experience (NME) housing resulted in 100% mortality compared to no mortality in young mice. However, reducing the senescent cell burden in aged mice before or following pathogen exposure reduced the spread of senescence, the cytokine storm and overall mortality. These results suggests that SnCs, acting at least in part through SASP factors, can increase peripheral senescence and immune dysfunction following pathogen exposure. Moreover, viral infection itself drives senescence, termed virus induced senescence, in mice and humans. Using mouse models in which cellular senescence is induced specifically in immune cells, we also demonstrated that senescent immune cells drive immunological dysfunction and secondary senescence and pathology in non-lymphoid tissues. Thus, our overarching hypothesis is that senescent cells, including senescent immune cell types, dominantly compromise innate and adaptive immune cell homeostasis in both lymphoid and non-lymphoid organs and reactivity to pathogens. Importantly, we also hypothesize that these adverse effects can be reversed by SnC elimination with senolytics, providing a new therapeutic strategy to restoring immune function in the aged. We propose to test these hypotheses in our PPG application entitled “The role of senescent cells in dysregulating immune responses and pathogen control”, consisting of three collaborative projects and three integrated cores.

NIH Research Projects · FY 2026 · 2024-03

Human communication crucially depends on the ability to maintain good speech intelligibility in dynamically varying acoustic backgrounds. This ability declines with age and age-related hearing loss. Understanding the mechanisms underlying this decline is key to finding successful interventions and potential treatments for this widespread problem of high public-health relevance. Recently, magneto- and electroencephalographic (M/EEG) measures have been increasingly used to investigate changes in subcortical and cortical neural processing due to age and hearing loss. Advances in measurement and data analysis methods enable characterization of neural tracking of acoustic, and higher-level (linguistic and semantic) speech features from M/EEG recordings obtained while study participants listen to continuous speech. These techniques provide a unique window into neural tracking of the target speech and to-be-ignored competing background. However, the interpretation of these measures is hampered by poor control for differences in peripheral (cochlear) auditory function, lack of direct experimental validation for the role of specific underlying mechanisms, and often small study samples. Non-speech stimuli have been used to gain a better understanding of specific mechanisms contributing to the age- and hearing-loss-related decline in speech perception but experimental evidence that individual or group differences in neurophysiological responses to these stimuli are reflected in perception is often lacking. The goal of this proposal is to provide the missing link between measures of cortical tracking of temporal envelope fluctuations in non-speech and speech stimuli and performance in perceptual tasks, using comparable stimuli. The studies will use young normal-hearing listeners, older normal- hearing listeners, and older hearing-impaired listeners. In Aim 1, we will investigate effects of age and hearing loss on perceptual measures of modulation-rate selectivity and discrimination using non-speech well-controlled stimuli with envelope modulation rates relevant for speech perception. In Aim 2, we will measure cortical responses to the non-speech stimuli used in these perceptual tasks to establish the sensitivity of EEG-based measures to changes in perception resulting from comparable experimental manipulations. In Aim 3, we will estimate cortical responses to speech envelope for natural (continuous) speech stimuli to investigate contributions from loss of cochlear nonlinearity, changes to modulation-rate selectivity and discriminability, and changes to cognitive function to neural processing and perception of masked speech. The outcomes from this project will provide the experimental basis for interpreting noninvasive neural (cortical) measures of temporal- envelope processing, thus advancing our understanding of mechanisms contributing to deficits in speech-in- noise perception experienced by older normal-hearing and hearing-impaired adults. The results from the project will have an impact on the development of potential future interventions and treatments for communication problems that are widespread among the growing population of older individuals.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY Relapse and craving in addiction are heavily controlled by environmental cues that evoke dynamic motivational states and reinforce actions. Both the basolateral amygdala (BLA) and dopamine (DA) signaling are critical for associative learning processes and cue-driven motivational states. The BLA receives dense dopaminergic projections and is enriched with D1 DA receptors (D1DRs), however BLA DA functions in addiction remain largely unexplored. Presentations of cocaine-predictive stimuli increase extracellular DA levels and activate neurons within the amygdala, while BLA D1DRs influence drug-seeking behaviors and their activation increases excitability of BLA principal neurons - a major target of DA inputs into the BLA. As there are extensive excitatory projections from the BLA to the nucleus accumbens (NAc), if BLA DA and D1-neurons are underlying facets of state dynamics-driven drug seeking behaviors, synaptic strength within this pathway may be uniquely potentiated following binge-like cocaine seeking. Understanding the role of BLA activity and DA signaling in drug seeking will reveal novel insight into the brain circuitry that drives emotional learning and addiction-related behaviors to provide a strong scientific framework for investigating mechanisms underlying affective diseases. This proposal will make use of new tools to record and manipulate DA and D1 neurons in the amygdala to investigate their contributions to dynamic cocaine seeking behaviors (Aim 1) and investigate how binge-like cocaine self-administration impacts the functional connectivity of glutamatergic BLA to NAc circuits (Aim 2). First, I will measure in vivo DA signaling and D1-neuron activity in the BLA during cocaine self-administration using fiber photometry to test the hypothesis that BLA DA transmission and D1-neuron activity will track the emergence of dynamic, sensory-guided drug seeking motivational states. I will also optogenetically inhibit BLA D1-neurons during the same paradigm to investigate if BLA D1-neurons play a necessary role in state-level control of binge-like drug seeking. Finally, in an ex vivo preparation, I will use optogenetics to stimulate the terminals of glutamatergic BLA projection neurons in an NAc slice while recording the resulting local field potentials after rats undergo cocaine self-administration. These studies will test the hypothesis that BLA-NAc excitatory synaptic strength will be modulated by the pattern of drug use history via drug state-intermittency information from the BLA. This proposal will establish fundamental principles by which dopaminergic and glutamatergic mechanisms interact within the amygdalostriatal system to influence the emergence and control of dynamic drug-seeking motivational states.

NIH Research Projects · FY 2026 · 2024-02

RESEARCH SUMMARY Alcohol use disorder (AUD) accounts for the largest percentage of active substance use disorders. One prominent trait of AUD is compulsive use despite adverse consequences. Previous work has found that animals who drink alcohol in excess display diminished lateral habenula (LHb) activity, a brain region widely acknowledged to participate in aversive behaviors, suggesting that LHb hypoactivity may be an integral factor in compulsive alcohol use. However, mechanisms that contribute to these reductions in LHb activity have not been fully explored. Comprehensive assessment of LHb plasticity in preclinical models of AUD through the measurement of afferent neurotransmission dynamics could offer potential insight into a neurobiological basis for the reduced LHb activity observed in aversion resistance. One afferent region of particular interest is the ventral pallidum (VP). Recent findings have shown that VP glutamate (VPGlu) neurons, which project extensively into the LHb, contribute to adaptive constraint of natural reward consumption and reduction of drug-seeking actions. Yet, there remains a significant knowledge gap concerning potential alterations of LHb-projecting VP neurons that arise in response to the development of aversion-resistant alcohol use. Clarifying the changes that occur in both multiregional and VP-specific afferent input is necessary to improve our understanding of physiological alterations preventing normative aversive behavior in aversion-resistant drinking. Thus, the broad goal of the proposed work is to elucidate neurobiological adaptations of LHb afferent projections during compulsive alcohol consumption. The primary objective of this proposal is twofold: first, to investigate the impact of alcohol use on afferent neurotransmission into the LHb during aversion resistant alcohol consumption, and second, to explore the significance of VP-to-LHb projections in this behavior. Given that afferent input from several distinct brain regions has been shown to influence aversive behavior and alcohol misuse, I hypothesize that LHb afferent neurotransmission is adaptably dysregulated in animals that exhibit aversion resistant alcohol use, which may be due in part to changes in activity of VP inputs. To test this hypothesis, I will use in vivo fiber photometry to record neurotransmitter activity in the LHb and optogenetics to manipulate VP-to-LHb projections during aversion-resistant alcohol consumption alongside histological techniques to quantify neurochemical content of LHb projections. Experiments proposed here will advance our understanding of the neural mechanisms underlying aversion-resistant alcohol use, establishing a foundation for future research examining LHb-associated neural circuitry in compulsive alcohol use. Throughout this proposal, I will gain valuable training in the execution of behavioral neuroscience experiments, in vivo neurotransmitter recording methods, neuronal manipulation techniques, histological processing, and advanced computational strategies. This project will allow me to build a firm foundation for a successful career as an independent investigator.

NIH Research Projects · FY 2025 · 2024-02

PROJECT SUMMARY Male contraception has remained a long-desired, but yet to be met goal. Critical to this goal is the identification of a suitable and druggable target, and the availability of adequate compounds. The voltage-gated ion channel CatSper is an exceptionally promising target for male contraception because it is exclusively expressed in sperm, is critical for sperm function, and is required for male fertility. Mice in which CatSper has been genetically deleted are completely infertile. Furthermore, naturally occurring CatSper mutations have been identified as the cause of male factor infertility in humans. Hits from a high throughput screening (HTS) campaign, blocked high potassium, high pH- and progesterone induced Ca2+ influx into human sperm. Moreover, these compounds inhibited cell hyperpolarization and hyperactivated motility (HAM) of human sperm. An ion channel selectivity screening indicated good selectivity of some hits for CatSper over other ion channels. Based on these data, we hypothesize that we can discover and develop orally bioavailable highly selective Catsper inhibitors. The inhibitors will be characterized for inhibition of calcium influx, sperm motility, ion channel selectivity, and in vitro ADMET assays. Promising compounds will be investigated for pharmacokinetic properties before examining their effectiveness on reduction of sperm motility and HAM, reversibility in mice and on mating trials in mice. We will also monitor off-target effects and determine preliminary maximum tolerated doses. The goal for this project is the development of a preclinical candidate for male contraception.

NIH Research Projects · FY 2026 · 2024-02

ABSTRACT The University of Minnesota (UMN) CTSI is ideally positioned to implement and train multidisciplinary teams of translational researchers from the 6 health science schools and colleges (Medicine, Public Health, Nursing, Pharmacy, Dentistry, Veterinary Medicine), the broader University, and 2 major Twin City Hub Partners: the Minneapolis VA Medical Center and Hennepin Healthcare. The UMN CTSI K12 Program will train highly promising and diverse research-oriented Assistant Professors in clinical and translational science (CTS) using multidisciplinary mentoring teams to advance their individual research projects and CTS skill sets. K12 Scholars will be trained for 3 years, including 2 years with NCATS K12 funding and 1 year of UMN support, with access to some career development activities and mentoring beyond 3 years. This grant will support 6 NCATS-funded Scholars at a time. The Program will 1) provide rigorous, competency-based training in the design and conduct of high-quality clinical and translational research with both required and individualized components (including Responsible Conduct of Research, Reproducibility and Rigor, and Human Subjects and Animal Protections); 2) ensure K12 Scholars acquire skills and experience in team science and community engagement; 3) promote scientific and career development, including training K12 Scholars to be excellent mentors, communicators, and leaders and offering experiential learning opportunities; and 4) support each K12 Scholar’s development of a productive translational research program, resulting in successful K and R01 grant applications and transition to independence. This program builds on the current KL2 program and our innovations in leadership and communications training, such as using personality assessments and optional coaching to aid Scholars’ personal development. Planned enhancements include required training in data health science with development of a new foundational course; augmented evaluation of mentoring effectiveness; increased interactions with community and stakeholders, including a Community Mentoring Program; increased education in dissemination and implementation science; and using Scholar portfolios to demonstrate acquisition of the characteristics of translational scientists. We will expand the diversity of our Community of Scholars through holistic review of K12 applicants and close interactions and near-peer mentoring with special programs (Pre-K Discovery Scholars and Medical School Early Research Career Awards). We will also augment our Scholars’ interactions with programs that introduce college and precollege students, mainly from disadvantaged and underrepresented communities, to the health sciences. With these innovations and activities in place and with robust institutional support, we expect our K12 Scholars to become highly talented leaders in their fields, contributing to multidisciplinary investigations, disseminating their research and expertise through multiple channels, and mentoring new generations of CTS researchers.

NIH Research Projects · FY 2025 · 2024-02

PROJECT SUMMARY Immune effector cell-associated neurotoxicity syndrome (ICANS) is a cluster of symptoms associated with immunotherapy that did not show up in pre-clinical studies but has been found in 40-90% of the people undergoing immunotherapy as part of cancer treatment. The purpose of ICANS detection and prompt treatment is to halt ICANS progression and minimize the risk of brain edema and herniation, the most feared sequelae of ICANS resulting in severe cognitive symptoms, coma, ICU stay, intubation, and potentially death. Current standard-of-care approaches to monitoring for ICANS consist of a brief neurocognitive assessment resulting in an immune effector cell-associated encephalopathy (ICE) score indicative of the severity of cognitive impairment. However, recent work shows that there is an opportunity to detect ICANS at an earlier stage than is currently possible with ICE by monitoring for subtle early changes in speech and language such as decreased fluency and coherence, word finding difficulties, and increased repetitiveness of speech. We have developed a Stress, Affect, Language and Speech Analysis (SALSA) system designed to administer and analyze speech-based neurocognitive tests over the telephone. SALSA conducts a conversation with the patient and scores the audio received from the patient for several markers of speech fluency, verbal fluency and working memory deficits. Our long-term goal is to develop and validate an end-to-end AI-based solution for high intensity but low patient and provider burden neurocognitive screening for early manifestations of ICANS based on the SALSA platform. The short-term objective of the proposed study is to examine the feasibility, safety and ability of SALSA to detect ICANS with specificity and sensitivity equal or better than standard of care in a prospective clinical study.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY High blood pressure (BP), particularly systolic BP (SBP), is the major modifiable risk factor for cardiovascular diseases (CVD) and related conditions such as chronic kidney disease and cognitive decline/dementia. In fact, ~60% of adults in the United States have above-normal SBP (≥120 mmHg). Above-normal SBP is associated with vascular endothelial dysfunction, a key antecedent for developing CVD. In addition, rates of BP control continue to worsen, predicting a new epidemic of disorders driven by above-normal SBP unless innovative therapies with clinical efficacy for lowering SBP can be adopted by and translated to the public. High-resistance inspiratory muscle strength training (IMST) is a novel, low-barrier, time-efficient, lifestyle intervention involving repeated inhalations against resistance with a hand-held device. In a randomized, double-blind, sham-controlled, parallel group design, pilot study in men and women (n=36) with initial SBP ≥120 mmHg, I showed that IMST (30 breaths/day [~5 min/day] at 75% maximal inspiratory pressure [PIMAX], 6 days/week for 6 weeks) had excellent adherence (94% of prescribed training sessions completed), increased inspiratory muscle strength (~20% increase in PIMAX), lowered SBP by 9 mmHg, and improved vascular endothelial function by ~45% compared to low-resistance sham training – thus establishing the clinical efficacy of high-resistance IMST. However, this trial was performed with frequent researcher supervision and feedback. Therefore, the next step in the overall translation of IMST for improving public health is to establish a vehicle for dissemination of IMST by utilizing digital health technologies. In this R03 application, I propose to pilot-test a smartphone app that independently guides users through an IMST intervention. I will directly compare the efficacy of 6 weeks (30 breaths/day, 6 days/week, 75% PIMAX) of at-home, app-guided IMST vs. an established clinic-based, investigator-supervised IMST program. I hypothesize that at-home IMST with a smartphone app will lower SBP, improve vascular endothelial function, promote adherence and increase inspiratory muscle strength to a similar extent as clinic-based IMST. I also will utilize an innovative follow-up period in which adherence to IMST and changes in home SBP are monitored for an additional 12 months after completing the randomized controlled trial, under free-living conditions, in all study participants; this will provide invaluable real-world data to inform future trial designs. Aim 1: To determine changes in home SBP after 6 weeks of at-home or clinic-based IMST in men and women with above-normal SBP at baseline. Safety and tolerability also will be assessed. Aim 2: To measure a) adherence; b) the change in PIMAX; and c) the change in vascular endothelial function after 6 weeks of at-home or clinic-based IMST. Aim 3: To monitor adherence to IMST and changes in home SBP during a 12-month free-living follow-up period in which all participants are given unrestricted access to the IMST smartphone app and training device.

NIH Research Projects · FY 2026 · 2024-01

ABSTRACT Although studied for decades, the physiological changes in the basal ganglia thalamocortical (BGTC) circuit that underlie the development of motor signs of Parkinson’s disease (PD) remain under debate. Excessive synchronization and coherence in neural activity has been demonstrated within the internal segment of the globus pallidus (GPi) and between GPi - motor cortex (M1). However, the relationship of coherence within and across subcortical-cortical regions to severity of motor signs of PD, specifically bradykinesia, is not well understood. Deep brain stimulation (DBS) targeting the posterolateral sensorimotor region of GPi has been shown to be an effective location for reducing clinical motor signs, however, there is debate around the optimal subregion (e.g. ventral vs. dorsal) within GPi for stimulation. There is evidence that stimulating the pallidothalamic pathway, specifically the lenticular fasciculus, is associated with improved motor severity. There is also evidence that GPi-M1 coherence reduces with DBS and is associated with improved bradykinesia. However, the relationship between pathways and neurophysiological activity, is unknown. This project will explore the spatial distribution of pathophysiological activity within the GPi and across the pallidothalamocortical network, how it modulates with movement and changes stimulation directed toward regions of GPi exhibited relatively high level of coherence with M1. This information will provide the rationale for the development of precise, patient-specific stimulation paradigms and lay the groundwork for novel closed-loop stimulation algorithms. The goals of this study are: 1) to describe the characteristics of low/high beta and high frequency oscillations that underlie bradykinesia. 2) describe the characteristics and dynamics of coherence in the beta band between GPi-M1 and their relationship to quantified measures of bradykinesia, and 3) describe the relationship between pallidothalamic pathway activation and measures of bradykinesia using real-time measure of GPi-M1 coherence to direction stimulation in GPi. This project will leverage access to recordings in the operating room during DBS lead implant surgery to record simultaneous local field potentials (LFP) from microelectrodes, segmented DBS leads and electrocorticography (ECoG) strips while the patient performs a self-initiated reach-to-target task in order to examine the modulation of GPi-M1 coherence during movement (SA1,2). We will use high field 7T imaging and biophysical computational models to correlate activated pallidothalamic pathways to changes in quantified measures of bradykinesia using real- time measures of GPi-M1 coherence to direct stimulation toward regions of GPi showing relatively high or low GPi-M1 coherence while the patients performs a self-initiated reach task (SA3). This study will provide the rationale for precise biomarkers and pathway-based stimulation targeting within the sensorimotor region of GPi, developing patient-specific closed-loop algorithms and incorporating spatially localized pathophysiological activity into model-based programming.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY (Overall) A lag between biomedical research discoveries and the implementation of findings in clinical care is widely recognized and primarily attributed to a disconnect between researchers and practitioners. One study found that over the course of 17 years, only 14% of clinical research findings led to direct patient benefit. A reason research findings are often do not implemented in clinical practice is because health services research takes place over extended timeframes and researchers place an emphasis on publishing their findings in scientific journals with less attention to application. Moreover, most researchers are typically external to healthcare systems, conducting their research in universities or research firms. Closing the gap in translating research findings to clinical care requires a new way of conducting research by embedding researchers in health care systems, allowing them to engage in rapid, iterative learning in which evidence informs practice, and practice informs evidence. The vision of the proposed Learning Health System Embedded Scientist Training and Research (LHS E-STaR) of the North (LEaRN) Center is to leverage and extend existing infrastructure and partnerships established at the University of Minnesota (UMN) under the Minnesota Learning Health System K12 Mentored Career Development Program (MN-LHS) and its Center for Learning Health System Sciences (MN-CLHSS). The LEaRN Center will accelerate the professional development and patient-centered outcomes and comparative effectiveness research (PCOR/CER) conducted by specially trained, embedded LHS researchers in the Minnesota health care system and beyond. The LEaRN Center represents a partnership between UMN and five hub partner sites with established traditions of academic excellence and collaboration between clinicians and embedded scientists with demonstrated success achieving the long-term goal to expand and diversify the LHS-research trained workforce. Led by MPIs Timothy Beebe and Genevieve Melton-Meaux, the LEaRN Center will leverage the unique strengths of five hub partners to provide diverse didactic and experiential research and training opportunities to LHS scientists to equip them with the LHS tools and expertise to make meaningful differences in health care settings serving children, the elderly, under-represented and rural populations, Veterans, and individuals with multiple disorders. The LEaRN Center will address five Aims: leverage and expand existing LHS infrastructure and partnerships to identify and nurture a new generation of embedded LHS scholars (Aim 1); enhance the diversity of LHS scientists, their science and their mentors (Aim 2); create a novel LHS infrastructure that supports the conduct, dissemination, implementation, and use of PCOR/CER in healthcare system (Aim 3); create learning communities and networks to convene, deliberate, and share knowledge (Aim 4); and implement a rigorous system for program evaluation and improvement (Aim 5). The LEaRN Center will cultivate the next generation of LHS scientists with the expertise, field experience, and community and professional partnerships to close the gap between researchers and clinicals and assume LHS leadership roles.

NIH Research Projects · FY 2026 · 2024-01

Project Summary Global change, including climate warming and human population increases and movement, has facilitated range-expansion of arthropod vectors of human pathogens, with mosquitoes, bugs, and ticks increasingly being reported outside their historic ranges. Concomitantly, there has been an explosive expansion of vector-borne disease agents, especially obligate intracellular bacteria transmitted by ticks including the recently described human anaplasmosis agent, Anaplasma phagoctophilum (Ap) that causes a severe and potentially life- threatening illness. Progress in our understanding of this and related organisms has been hindered by the inherent difficulties with manipulation of obligate intracellular bacteria in the order Rickettsiales. Moreover, over 30% of their encoded genes have no matches in the databases, and are thus of unknown function. While bioinformatics algorithms offer an approach to predict form and function, these predictions are unreliable. At the same time, uptake of existing genetic systems has been slow, in part due to their limitations. To alleviate this situation, we propose to employ a modified himar1 transposon-transposase system that enables efficient replacement of the transposon with another cassette containing a wild-type copy of the mutated gene using recombinase mediated cassette exchange (RMCE), a well-established molecular technique, to restore gene function. We will accomplish our planned projects following four specific aims: Aim 1: Generate a collection of Ap mutants recovered in tick vector and human host cell culture using the himar1 transposon system where the transposon is designed with flanking mis-matched lox sequences to allow subsequent replacement of the transposon using RMCE. Aim 2: Determine insertion sites using whole genome sequencing. This will be facilitated through the use of the Ap-HGE1 isolate for which the genome sequence is available. Aims 1 and 2 will be carried out during the Phase I (R61) component of the application, and set the stage/provide the mutants for the subsequent Aims 3 and 4, which will occupy the Phase II (R33) component of the award. Aim 3: Test infectivity of selected mutants and of genetically “restored” mutants in vitro using multiple tick and mammalian cell lines, and verify gene knock-out/knock-in using RT-PCR to demonstrate absence and restored presence of transcripts, and immune-assays to demonstrate absence/restored presence of gene products. Mutants of interest will be selected for RMCE to restore gene function, and successful RMCE will be verified using site-specific PCR and Sanger sequencing coupled with assessment of restored phenotype. Aim 4: Test infectivity of selected mutants and of genetically “restored” mutants in vivo in ticks and mice, including tick transmission studies.

NIH Research Projects · FY 2026 · 2024-01

Project Summary/Abstract: Atherosclerosis is a disease of the mid- and large-sized arteries that promotes plaque formation. Plaque development can lead to restricted blood flow, vessel rigidity, and in some cases thrombosis. Atherosclerosis is a major underlying condition that promotes the morbidity and mortality associated with cardiovascular disease, such as heart disease and stroke. Atherosclerosis is mediated by chronic exposure to elevated serum cholesterol which leads to deposition and accumulation of inflammatory cells in the intima-region of the vessel wall. Monocyte infiltration is a hallmark of disease progression where cells differentiate into lipid-laden macrophages, termed “foamy cells”. We interrogated single cell RNA-seq (scRNA-seq) gene expression data from atherosclerotic plaques which identified genes uniquely associated with foamy macrophages, including the myeloid lipid sensor Trem2. Additionally, an unbiased genome-wide Crispr-screen of in vitro derived foamy macrophages found Trem2 was required for oxidized LDL uptake. However, paradoxically, Trem2 was also required for efflux of cholesterol in foamy macrophages. Since Trem2 has been associated with enhanced lipid uptake in adipose macrophages and efflux in microglia, we sought to test its role in atherosclerosis. Using Trem2- knockout and conditional Trem2-deletion approaches, we found Trem2 mediates lipid accumulation in plaque macrophages and loss of Trem2 resulted in a dramatic reduction in atherosclerotic plaque size. Thus, based on our preliminary data, we hypothesize that Trem2 regulates foamy macrophage lipid uptake and survival in atherosclerosis. We have extensive experience studying myeloid cells in atherosclerosis and include newly developed monocyte fate-mapping model to track monocyte differentiation in plaque, and a viral atherosclerosis regression model, which places our lab in unique position to address the questions outlined in this application. In addition, we incorporate a Trem2 agonistic antibody as an approach to complement deletion experiments to determine the mechanisms of Trem2 in atherosclerotic disease. Together, we will address the role of Trem2 in atherosclerosis progression, examine in depth signaling mechanisms in foamy cells that are regulated by Trem2, and determine whether Trem2 is a therapeutic target for intervention. Findings from this study represent potentially highly impactful knowledge for translation of a novel candidate to drive plaque regression in atherosclerosis patients.

NIH Research Projects · FY 2026 · 2023-12

Project Summary The goals of this proposal are to help Sasha Prisco, MD, PhD, a cardiovascular physician-scientist, transition to independence and to further the understanding of mechanisms of right ventricular dysfunction in pulmonary arterial hypertension. Pulmonary arterial hypertension is a progressive vasculopathy which increases right ventricular afterload, leading to right ventricular failure. Right ventricular function is the greatest predictor of survival in pulmonary arterial hypertension. Unfortunately, there are no current pharmacologic therapies that directly target the failing right ventricle. Our recent preclinical data demonstrated pathological inflammation through activation of the cytokine receptor glycoprotein 130 induced deleterious microtubule remodeling, downregulation of junctophilin-2 (an essential protein that maintains t-tubule structure and function), and depressed right ventricular function in pulmonary arterial hypertension. Emerging data show alterations in gut microbiota disrupt the intestinal barrier, which permits bacterial translocation, and subsequently activates systemic inflammation, suggesting that modulating the microbiome may be an approach to mitigate inflammation. We recently identified that modifying the gut microbiome with intermittent fasting improved right ventricular function and postulate that increased abundance of Lactobacillus underlies these benefits. We will test the hypothesis that Lactobacillus supplementation combats pathological gut dysbiosis, which prevents immune cell activation, and subsequent glycoprotein 130-mediated microtubule remodeling in the following specific aims. In Aim 1, we will determine if Lactobacillus supplementation mitigates pathological microtubule remodeling and enhances right ventricular function in two rodent models of pulmonary arterial hypertension, monocrotaline and Sugen-hypoxia. In Aim 2, we will investigate the effects of Lactobacillus supplementation on gut dysbiosis and systemic inflammation. For this proposal, we will use a variety of approaches from metagenomics analysis of the gut microbiome, SomaScan proteomics, and single-cell RNA-sequencing to histological assessments, echocardiography, invasive hemodynamics, and treadmill exercise testing. This project has the potential to identify a novel therapeutic approach for pulmonary arterial hypertension.

NIH Research Projects · FY 2026 · 2023-12

Project Summary/Abstract Vaccination is a potent regulator of the immune system and much research is being conducted to understand how antigen-specific stimulation can be used to induce and redirect anti-tumor immunity. Our team develops a cancer immunotherapy program using novel AAV vectors to deliver antigens both directly and by cross- presentation to antigen presenting cells. Optimization of naturally occurring AAV serotypes and novel methods of AAV production are necessary to warrant wide use of these vectors for cancer immunotherapy. The main aims of this proposal is to determine the safety and efficacy of our novel AAV-based vaccines as part of preclinical studies by using companion dogs with oral melanoma. In recent years, we have undertaken studies to gain a better understanding of the underlying molecular mechanisms of AAV and host immune system interaction via the high efficiency transduction of DCs. We have made the following scientific achievements, which form the basis of the current proposal: • Identified and mutagenized critical surface-exposed serine and threonine residues on the AAV capsid that are involved in intracellular trafficking of virus in the host cells. • Demonstrated that rational modifications in the AAV expression cassette results in antigen processing by dendritic cells (DCs), leading to a stronger and prolonged antigen-specific immune response. • Developed the next generation of highly efficient AAV-vectors that expressed a tumor-associated antigens (premelanosome protein gp100 (also known as Pmel), tyrosinase (Tyr), tyrosinase-related protein 1(TRP1), and dopachrome tautomerase (TRP2). • Tested these novel AAV vectors for their ability to stimulate a specific T-cell clone proliferation and protective immune response in a small animal model. In this proposal, we will test ability of our recently developed optimized AAV capsid and expression cassette, whose unique properties enhance a cellular/humoral immune response toward vector encoded tumor antigens. Successful completion of the current proposal will result in: • Production of high titers of a therapeutic AAV-based vaccine. • Identification of an optimal AAV-based dose for vaccination that can be used to slow/eliminate the progression of melanoma cancer in a large animal model such as companion dog-patients with spontaneous cancer. • Mechanism of the novel cancer vaccine function in the most appropriate animal model. The optimized AAV vector can be potentially used as a vaccine platform for the treatment of cancers in canine and humans.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY Listening effort and fatigue have serious impacts on quality of life for individuals with hearing loss. As the clinical importance of listening effort becomes more widely acknowledged, there is an increased urgency to improve our understanding of effort and fatigue in contexts relevant to real-world communication. One factor that has the potential to alleviate effort and fatigue in everyday listening is the ability to see a conversation partner’s face. While visual speech cues are known to improve speech intelligibility — particularly for listeners with hearing loss — the link between visual speech and listening effort has not been established. Translating the perceptual benefits of seeing a talker’s face to real listening further hinges on moving beyond video-based, non-interactive contexts and investigating how listeners use visual speech cues during social communication. The goals of this project are twofold. First, we will determine how and when seeing a talker’s face alleviates effort and fatigue for listeners with cochlear implants (CIs), focusing on cognitively and perceptually demanding listening scenarios. Second, we will examine eye gaze behavior during live conversations: how social interaction changes where on the face listeners tend to look, how these patterns differ for listeners with CIs (who likely rely more on visual cues from the talker’s mouth), and how individual differences in gaze behavior relate to the effort of speech perception during conversation. Results will improve our understanding of audiovisual speech perception and effort during natural communication, laying the groundwork for future studies on how listeners with CIs use visual speech to improve the perception of prosody and track multi-talker conversations. This work will inform the development of diagnostic testing to assess multisensory speech perception, as well as rehabilitation strategies to maximize audiovisual benefits for individuals with hearing and/or vision loss.

NIH Research Projects · FY 2025 · 2023-12

Project Abstract The ability to efficiently defend one’s home territory from intruders is an essential behavioral adaptation. However, the neurobiology of this experience-dependent plasticity is unknown. Furthermore, the neural mechanisms in females and sex differences are also unknown; these are critical barriers of therapeutic interventions aimed at improving mental health. My graduate research suggests that females are more sensitive to the rewarding effects of aggressive experience and that oxytocin (OT) transmission may underlie these sex differences. My recent post-doctoral studies support synaptic plasticity in the prefrontal cortex (PFC) and nucleus accumbens (NAc) underlies the adaptive consequences of aggressive experience. Thus, the goal of this proposal is to synthesize my research by 1) acquiring training in state-of-the-art electrophysiological techniques and investigate aggression-induced synaptic plasticity of PFC input to medium spiny neurons (MSNs) in the NAc, and 2) then apply these new skills to assess the contribution of OT to synaptic plasticity of NAc MSNs. Both phases will advance our understanding of the causal role of two distinct circuits in driving aggression reward in both sexes, and provide the training and resources to establish my independent career. Under the collective mentorship of Drs. Patrick Rothwell (primary mentor), Robert Meisel (co-mentor), state-of-the-art research facilities, and expert research consultants, I will have access to a unique and custom set of resources. Dr. Rothwell will lead my training in slice electrophysiology, optogenetics and calcium imaging with fiber photometry. To elucidate specific components of neuronal physiology, I will learn how to measure the effects of aggressive experience on basal synaptic strength of NAc MSNs in male and female Syrian hamsters. I will then assess the effects of aggressive experience on calcium signaling of NAc MSNs in male and females. In combination, I will also utilize optogenetics to assess the involvement of PFC glutamate projections in driving physiological changes and aggression reward in males and females. I predict enhanced PFC synaptic transmission onto NAc MSN drives aggressive experience-dependent behavioral plasticity, e.g. aggression reward and motivation. For the R00 phase I will establish an independent research lab and then implement the skills acquired during the K99 to investigate the role of OT in NAc synaptic plasticity, as well as driving aggression reward and motivation in males and females. OT has been historically considered a monotonic love hormone. However, this proposal seeks to further revolutionize our understanding of the non-canonical and non-monotonic nature of OT and improve sex-specific therapeutic strategies to combat psychiatric disease. I predict OT is a mediator of the NAc MSN synaptic plasticity that drives the enhanced aggression reward and motivation in females compared to males. Collectively, this proposal will provide me skills and professional development for running a research lab that makes fundamental discoveries about brain function to combat mental illnesses.

NIH Research Projects · FY 2025 · 2023-11

Project Summary (Abstract): This project will employ a recent innovation that we made in peptide:MHCII (pMHCII) tetramer design. Fluorescently labeled pMHCII tetramers have been used to detect CD4+ T cells of known specificity, aiding the study of these populations. However, pMHCII tetramers do not detect CD4+ T cells with TCRs at the low end of the biologically relevant affinity spectrum. The affinity of CD4 for MHCII is below the limit of detection. We used directed evolution to strengthen the interaction between MHCII and CD4, thereby stabilizing TCR-pMHCII interactions while still retaining the cognate specificity. pMHCII tetramers engineered for enhanced CD4 binding outperformed conventional tetramers in detecting cognate T cells, including the ones with low affinity TCRs. The overall goal of this project is to exploit this enhanced binding by high affinity 4E reagents in immunotherapies. The premise underlying this project is that recruitment of all antigen-specific CD4 T cells including the ones with low affinity TCRs will improve responses generated by vaccines, whereas deletion of these T cells could treat autoimmunity. The goal here is to use the high affinity 4E reagents to activate or inactivate T cells based on the clinical need. In Aim 1 we will assess the efficacy of pMHCII-4E reagents to specifically deplete auto-reactive CD4 T cells in a murine model of multiple sclerosis, Experimental Autoimmune Encephalomyelitis (EAE). Both in-vitro and in-vivo depletion followed by EAE induction will be attempted. In Aim 2 we will assess the efficacy of pMHCII-4E reagents to induce better immune responses and aid in bacterial clearance in acute or chronic / persistent bacterial infections.

NIH Research Projects · FY 2025 · 2023-11

PROJECT SUMMARY Eukaryotic cells are home to a diversity of organelles, symbionts, and pathogens that are often co-inherited across cell lineages and from parent to progeny. Across humans, animal models, and arthropod vectors of pathogens, intracellular microbial community dynamics are associated with numerous effects on host physiology that ultimately result in disease. These include mitochondrial diseases, exacerbated clinical symptoms of co-acquired pathogens, altered transmission dynamics of vector-borne pathogens, interactive effects on host immunity and metabolism, and even dysbiosis of the host gut microbiome. There is great interest in defining the factors that promote or inhibit co-inheritance of intracellular bacteria due to the combination of their direct and indirect effects on animal health and for their potential use as anti-pathogen agents. We propose to use a suite of insect models to investigate the factors that regulate co-inheritance of intracellular microbes with a focus on Wolbachia: alpha-proteobacteria, related to the intracellular human pathogens Anaplasma, Rickettsia, and Ehrlichia. Unlike their close relatives, Wolbachia inhabit the cells of arthropods and nematodes and manipulate host biology to facilitate vertical transmission via the maternal germline. The consequences of Wolbachia infections are diverse and include reproductive isolation between host populations, matriline sweeps, protection against secondary infections with pathogens, and even host speciation. Furthermore, some arthropods harbor multiple, stably co-transmitted strains of Wolbachia that must compete for host resources and space in the germline. Importantly, these Wolbachia-mediated phenotypes are currently being applied to manage vector-borne pathogens, and, there is significant applied interest in leveraging coinfections of Wolbachia to fine-tune and expand management programs. Given the applied interest in Wolbachia and its broad success as an endosymbiont of ecdysozoans, they are an attractive model for understanding the mechanisms of coinfection. Our long-term goals are to define the mechanisms behind host-microbe and microbe-microbe interactions that ultimately determine inheritance and evolution of these associations. This proposal derives from our published work and preliminary data that has given us techniques to manipulate and track intracellular infections, our ability to perturb a naturally stable coinfection, and our discovery that intra-organismal niche partitioning plays a key role in coinfection stability. We propose to use a combination of techniques including high throughput analysis of transcriptomes, multiplexing spectral microscopy, and molecular and cell biology approaches to accomplish the following Specific Aims: (1) Define factors that facilitate co-establishment of intracellular microbes, (2) Identify features of stable coinfections that facilitate evolutionary stability. We anticipate this work will identify conserved mechanisms that regulate intracellular infections, as well as provide foundational knowledge to support the development of therapeutic strategies focused on intracellular microbes.

NIH Research Projects · FY 2026 · 2023-11

The first ever International Indigenous Dementia Research Network Annual Conference series addresses a critical need to advance knowledge, discovery, and scientific collaboration in Alzheimer’s Disease and Related Dementias (ADRD) in Indigenous populations. American Indian/Alaska Natives (AI/AN), Native Hawaiians and Pacific Islanders, First Nations in Canada, and Indigenous peoples in Australia all experience a significant health equity gap reflected in the rates of ADRD. Moreover, these racial disparities are expected to expand in all Indigenous populations; for example, the prevalence of ADRD in AI/AN populations is projected to increase almost 6-fold by 2060. Indigenous ADRD research is an emerging field, and the number of studies is increasing. In the US, Indigenous people have been referred to as an invisible minority in relation to ADRD research, but there is a core group of researchers working with Indigenous populations on dementia all over the world. These scientists utilize community-based and Indigenous research methods to address dementia specific topics such as caregiving, screening and diagnosis, and culturally safe care. Unfortunately, little attention is given to these studies in mainstream conferences and knowledge exchange has been limited. There is currently no equitable venue for academics and communities studying dementia in Indigenous populations to come together and share scientific and Indigenous knowledge in a way that is comparable to other disciplines or disease focused research areas. The consequence of this structural inequity is slow progression of the field and researchers working in isolation, which leads to inadequately informed health care and poor policy preparation for the growing prevalence of dementia in Indigenous communities. To remedy this situation, we will implement a 5-year conference series focused on ADRD in Indigenous populations by bringing together current members of the International Indigenous Dementia Research Network (IIDRN) along with other leading scientists, policy makers, Indigenous Elders, Indigenous communities and organizations, people living with dementia, and trainees to exchange information on current research and advancements concerning ADRD in the context of health equity. The IIDRN is a network of over 100 members from seven countries. Recognizing that ADRD in Indigenous populations is still a developing field of research, these annual conferences will build and support research capacity, facilitate the development of national and international research collaborations, and sustain scientific advancement in Indigenous dementia research. Key components will include featured research sessions, keynote speakers, Elder involvement, mentorship, and volunteered papers and posters. Our long-term goal is to create an expanded, sustainable, supportive, worldwide network of scholars committed to knowledge exchange and collaboration to advance research, knowledge, and mentorship in community-based, culturally appropriate ADRD research with Indigenous populations.

NIH Research Projects · FY 2024 · 2023-09

Project Summary The prevailing neuroscientific characterization of addiction is that of evolving neuro-behavioral responses to chronic drug use that are initially motivated by increasing pleasure (impulsive drug use) that over time causes neuro-adaptations such that drug use is increasingly motivated by relief from negative affect (compulsive use). The compulsive stage of addiction can be seen as a “vicious cycle” since the short-term relief from negative affect through drug use ultimately exacerbates negative affect through neuroadaptations to chronic use. Our early work demonstrated that the vicious cycle was a primary factor in maintaining comorbidity between alcohol use disorder (AUD) and internalizing disorders (anxiety and depression). This provided the ground work for the development and validation of a cognitive-behavioral therapy program for AUD comorbidity that directly targeted the vicious cycle of addiction (VC-CBT). Further, we developed a fully autonomous and easily scaled digital platform to deliver VC-CBT that has proved to be as effective as the therapist-delivered version. The intervention is premised on educating individuals about the reversibility of the vicious cycle, and training them to use proven coping skills to manage negative affect without drugs can significantly aid them in achieving desired treatment goals. In this project, we leverage the trans-addiction status of the neuroscientific underpinnings of the VC-CBT intervention and its flexibility as a digital therapeutic to develop and test a digital treatment for comorbidity in opioid use disorder (OUD). Relative to other drugs of abuse, the progression from initial impulsive use to negatively reinforced compulsive use is known to be truncated and nearly universal among those who routinely use opioids, and those with co-occurring internalizing disorders are especially susceptible. This, along with the relatively high lethality of OUD, makes it an ideal near-term target for this trans-addiction therapy. To achieve this, we propose to test the clinical efficacy of digitally-delivered VC-CBT for OUD-INTD comorbidity in a UG3/UH3 program consisting of two phases. The overarching aim of Phase 1 is the modification and pilot testing of the established digitally-delivered negative affect VC-CBT for application in OUD. The overarching aim of Phase 2 is to conduct a scientifically rigorous clinical trial of the modified VC- CBT for OUD. The impact of this work would be to provide a scalable and inexpensive means of improving the otherwise poor OUD treatment outcomes among those with co-occurring anxiety or depression. Moreover, the project would support the viability of trans-addiction interventions that target processes common to multiple addiction types.

NIH Research Projects · FY 2025 · 2023-09

Enhancing American Indian Caregiver Mastery through a Savvy Caregiver Program-Peer addresses the growing number of American Indian caregivers with limited knowledge of dementia. The high level of burden associated with providing care for those with dementia, along with uncertainty about managing disease conditions, problems with different psychosocial aspects of care, lack of culturally responsive training and education materials results in caregivers reporting feelings of isolation and depression. Despite the unique needs of American Indian caregivers, few resources support this group in a culturally appropriate way. The Savvy Caregiver Program is a multi-component, psychoeducational program consisting of 6 weekly 2-hour sessions for family caregivers of people living with dementia at home. Informed by Stress Mediation and Social Cognitive Theories, the Savvy Caregiver Program was developed to alleviate caregiving strains and strengthen knowledge, skills, and outlook through classes, interactive exercises, and home assignments. This study will use a community-based participatory research framework to enhance the Savvy Caregiver Program by adding a peer-based educational and support component, referred to as the Savvy Caregiver Peer Program, that incorporates Stress Mediation and Generativity Theories. Six sequential talking circles will be held with 5-8 previous American Indian dementia caregivers who are enrolled members of White Earth Nation (Aim 1) to develop the Savvy Caregiver Peer Program prototype. Participants will review the Savvy Caregiver Program curriculum and discuss the roles and expectations of peer mentors in the program, including peer selection, training, and a management structure to oversee peer mentors and caregiver engagement. The 6 planning and design talking circles will gather strategic, culturally appropriate information to (1) provide the peer mentors with an opportunity to directly define their role and expectations as part of the Savvy Caregiver Peer Program; (2) educate peers on the Savvy Caregiver Program core elements and their role in supporting the materials; and (3) gather insights about the peer mentor material to be provided to the caregiver. Upon completion of the sequential talking circles and development of the Savvy Caregiver Program-Peer training materials and infrastructure, a parallel arm randomized clinical trial of 30 caregivers (20 to intervention, 10 to control group) will be conducted for 12 weeks (6 biweekly sessions) (Aim 2). Qualitative and quantitative data from peer mentors and caregivers will be collected to assess the feasibility and acceptability of recruitment, randomization, intervention adherence, and administration of caregiver measures. During Year 4 (Aim 3), we will host talking circles to engage caregivers and peer mentors in the refinement and improvement of the Savvy Caregiver Program-Peer in preparation for testing in a larger, subsequent randomized clinical trial. This study will contribute cultural and contextual knowledge to inform the eventual development of caregiver interventions grounded in cultural values to improve the quality of life and outcomes for American Indian dementia caregivers.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Phantom limb pain is common after amputation, but the mechanisms and associated factors contributing to this pain remain unclear. Without an understanding of associated factors, it is difficult for clinicians to recommend effective pain treatments. The long-term goal of this research is to better understand contributing factors to phantom limb pain on an individual level to guide effective, personalized treatment approaches in the future. The overall objective of this project is to establish the feasibility and acceptability of the ecological momentary assessment (EMA) method in measuring person-centered factors contributing to phantom limb pain. EMA is a systematic survey methodology to evaluate real-time personal and environmental factors in an individual’s natural environment. The hypothesis is that EMA surveys will achieve at least 80% retention rate and 75% response rate in the amputation population. This hypothesis will be tested through two specific aims. Aim 1: Investigate factors contributing to phantom limb pain among individuals with amputations. The approach for this aim will be to conduct focus group sessions with individuals with amputations to discuss their experiences with phantom limb pain and any aggravating or relieving factors. Data from the focus groups will be used to refine a list of EMA questions on phantom limb pain contributing factors. Aim 2: Determine the feasibility and acceptability of EMA to identify phantom limb pain factors. The approach for this aim will be to use repeated EMA surveys to measure phantom limb pain and its contributing factors in individuals with amputations in real time and in their natural environment. Responses to EMA questions will be analyzed to explore factors that contribute to phantom limb pain in each participant. The feasibility and acceptability of this method in this population will be determined using recruitment rate, retention rate, response rate, and semi- structured interviews with participants. This proposed research will contribute to science through an improved understanding of contributing factors to phantom limb pain after amputation and the establishment of feasibility and acceptability of the EMA method in measuring these factors. These contributions are expected to be significant because the systematic identification of patient-specific factors will guide informed future treatment recommendations for effective, personalized medicine for phantom limb pain, addressing a critical public health need. This research is part of a comprehensive training plan that includes advanced coursework on qualitative research and causal discovery data analysis, professional development through seminars, networking, and research dissemination, and mentored training in the research skills needed to continue the applicant’s trajectory to becoming an independent researcher. The University of Minnesota’s expansive research infrastructure, the multidisciplinary doctoral program in Rehabilitation Science, and the Minneapolis Adaptive Design and Engineering laboratory create an ideal environment for completing this research and training.