University Of Minnesota

NIH Research Projects · FY 2026 · 2024-11

Polycystic kidney disease (PKD), both autosomal dominant (AD) and autosomal recessive (AR) forms, remains the leading cause of inheritable kidney disease in adults and children throughout the US as well as worldwide. Though the pathogenesis of renal cyst formation is understood to be driven primarily by a loss-of-function mutation in the polycystin in ADPKD and fibrocystin gene in ARPKD, there remains no cure for these diseases beyond kidney transplantation. Vasopressin (AVP) signaling blockade has been demonstrated to blunt cyst formation, specifically through pharmacological targeting of AVP receptor type 2 (V2R) with Tolvaptan. While V2R antagonism may benefit the patient by delaying cyst and renal disease progression, chronic V2R blockade often leads to a decrease in quality of life due to symptoms such as polydipsia and polyuria. An understudied contributor to hypothalamic regulation of AVP is from the kidney itself, through the renal afferent nerves. With the emergence of catheter-based renal denervation to treat cardiovascular disease, alternative applications of this technique may benefit patient populations with potential aberrant renal nerve signaling. We have recently reported that afferent renal nerve activity (ARNA) is increased over two-fold in an ARPKD model compared to non-cystic controls, and total renal denervation (TRDNx), which disrupts both renal afferent and sympathetic nerve activity, mitigates the cystogenesis and lowers arterial pressure. In addition, targeted ablation of only renal sensory (i.e. afferent) nerves (ARDNx) had a similar abrogating effect on cystogenesis, which highlights the intriguing and novel role of renal nerves in the pathogenesis of this this model. While these data are promising, the mechanisms mediating these responses remain unclear and require further investigation. Critically, we aim to elucidate the role and mechanisms by which renal nerves contribute to AR- and ADPKD. The following aims form the experimental basis of this research proposal: (1) Determine the role of renal nerves in the progression of renal cystogenesis and neurohumoral axis in ARPKD. We will perform either complete bilateral or unilateral renal denervations in PCK rats to test the hypothesis that renal nerves contribute to all phases of renal cystogenesis, function, and proliferative signaling in both the early, mid, and late phases of ARPKD. (2) Elucidate the molecular mechanism and consequences of elevated afferent renal nerve activity in ARPKD. We will quantify the excitatory effects of renal inflammatory cytokines to isolate the causes for elevated afferent renal nerve activity in the PCK rat. We will pair these studies with histochemical tracings of neural activation following renal inflammatory stimuli. (3) Investigate the role for renal nerves and interaction with Tolvaptan in ADPKD progression. We will determine the role for renal innervation and interaction with V2R antagonist Tolvaptan (FDA- approved) in the cystogenesis and renal dysfunction in mouse models of rapid (PKD1-/-) and progressive onset (PKD1rc/rc) of ADPKD. These studies are poised to bring a robust and innovative experimental approach to dissecting the novel role of renal nerves in PKD pathogenesis, potentially identifying a novel therapeutic modality.

NIH Research Projects · FY 2025 · 2024-09

Project Summary This R01 proposal is submitted in response to NOT-DA-22-003, Public Health Research on Cannabis. The overarching aim is to assess cognition, neural function, and SUD risk in a sample of patients treated with medical cannabis products in Minnesota (n=120) as compared to non-cannabis using controls (n=60) and to differentiate outcomes based on prescribed doses and blood concentrations of THC versus CBD as an objective measure of drug exposure. Patients will be aged 35-65 and qualified for medicinal cannabis treatment in Minnesota due to diagnoses of chronic pain. While deficits in learning, memory and executive functions are reliably observed in young adult recreational cannabis users, it is unclear whether similar impairments characterize individuals who use cannabis for medical reasons, whether adults may be uniquely vulnerable to cannabis-related impairments or if, in fact, use in this age group might be neuroprotective. There are very few published studies of medical cannabis users that comprehensively focus on neurobehavioral outcomes even though at least 5 million people are registered for medical cannabis treatment in the United States. The current study will address this gap through a pre-post assessment of users as compared to matched controls (pain patients who do not use cannabis). Participants will be recruited through posted advertisements and through dispensaries via a collaboration with the primary local supplier of medical cannabis. They will complete a comprehensive pre- treatment behavioral assessment as well as multimodal MRI assessments. Sequences from the HCP-Aging battery will be utilized. All measures will be repeated after four months of treatment. Participants will be interviewed monthly by phone in the interval between visits. Behavioral outcomes, including substance misuse, will be measured. Blood cannabinoid levels will be quantified and correlated with behavioral and neural outcomes. Our three aims are (1) To assess impacts of medical cannabis compounds on cognition and behavior in otherwise cannabis-naive adults to determine whether impairments that characterize younger users are evident after the onset of medical cannabis use; we will also measure treatment-related changes in pain using well-validated measures. (2) To similarly assess the impacts of medical cannabis compounds on white matter microstructure, functional brain activity and functional connectivity using diffusion-weighted scans, task-based fMRI, and measures of resting state connectivity; (3) To differential change over time in these outcomes as a function of (a) exposure to distinct cannabinoids (THC vs. CBD) as assessed through blood concentrations and (b) age. Sex as a biological variable will be assessed as a covariate of interest. Thus, this proposal will yield a rich dataset through which medical cannabis effects on adults’ neurobehavioral function can be assessed and contrasted with the literature on non-medical users.

NIH Research Projects · FY 2025 · 2024-09

SUMMARY The primary goals of the University of Minnesota Prevention Research Center (UMN PRC) are to develop and disseminate actionable knowledge, enhance community and cross-sector collaboration, build infrastructure and expand training for healthy weight promotion in youth and their families. This proposal builds on a long and rich history of weight-related research and public health advancement by UMN School of Public Health faculty and colleagues across UMN. This PRC will focus on the CDC’s priority area of improving nutrition, physical activity, health and wellness among children with overweight and obesity from households with lower incomes. Given the well-documented systemic drivers of health inequity and powerful social determinants of health and weight, the center’s work will focus on youth and families from historically underserved communities, including those of lower income and those identifying as BIPOC (Black, Indigenous and People of Color). The Center’s work is grounded in best practices for dissemination and implementation research and leverages deep and long-standing partnerships with community leaders, public health agencies, health organizations and other key stakeholder networks with shared commitments to healthy weight promotion. Our proposed core dissemination and implementation research project is a Hybrid Type 2 Effectiveness Implementation Trial focused on the evidence-based NET-Works intervention designed to promote healthy eating, activity and weight among preschool age children with overweight or obesity from lower income and BIPOC communities. We will partner with Federally Qualified Health Centers (FQHCs), UMN-Extension and local public health to understand how to effectively adapt and sustainably implement NET-Works in across clinical (FQHCs) and community settings (i.e., UMN-Extension Regions) and develop an implementation science informed and setting-specific strategy for enhancing future implementation processes. Study results will be integrated into an intervention toolkit to be disseminated through local and national channels to facilitate implementation of the evidence-based NET-Works intervention into public health practice. The PRC’s overall 5-year goals for research, translation, dissemination, training, technical assistance, communication and evaluation are to 1) implement an applied research and translation agenda to develop and disseminate knowledge and practices for evidence-based innovations in applied public health supporting healthy weight promotion; 2) create and support infrastructure, resources, and local, regional and national partnerships that fortify the PRC’s ability to advance public health practice for scalable healthy weight promotion efforts; 3) prepare future leaders in weight-related dissemination and implementation-oriented research and practice to effectively and respectfully engage in community-rooted efforts to enhance health in scalable ways; 4) enhance public health workforce capacity to leverage evidence for practice innovations; and 5) collaborate with national PRC network partners to enhance the network and its impact.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Brain function is critically dependent on the proper relationship of cerebral blood flow (CBF) and neuronal metabolic demands, a phenomenon referred to as neurovascular coupling. Pathological reductions in CBF are commonly observed in presence of loss of brain function, but paradoxically there is often sufficient oxygen supply to support function. Answering this paradox not only would help understand the loss of brain function, but would also provide important new insights into how to interpret fMRI, which essentially measures neurovascular coupling, at the network down to the microscopic level of brain function. I propose to answer these longstanding questions, via a new approach. Rather than following the decades old path of focusing almost exclusively on oxygen delivery and its coupling to neuronal activity, I will develop and validate imaging methods and mathematical models for studying how neurovascular coupling maintains homeostasis of all of the substrates and products of functional brain metabolism. The importance of maintaining tight regulation of the levels of the metabolic products CO:i and protons, have long been recognized via EEG/MEG studies of respiratory hyper and hypocarbia; yet CO2 and protons homeostasis are mosUy disregarded, likely because non-invasive methodologies that allow their assessments are lacking. My goal is to fulfill this unmet need, and establish a transformative neuroimaging approach that quantifies non-invasively oxygen availability, pH and carbon dioxide accumulation in brain tissue. Achieving this goal requires comprehensive studies and theoretical understanding ranging from microscopic capillary transport to the regulation of systemic physiology, at the center of this project. Here my efforts will pivot to a new direction of unprecedented studies that will combine positron emission tomography (PET), optical imaging, MRI, implanted biosensors, and theoretical modeling. My colleagues and I have already conceptualized the highly innovative framework that grounds the studies of this proposal. In particular, by connecting for the first time the properties of neurovascular coupling to the needs of waste removal originating from the metabolic processes linked to neurotransmission, we paved the way towards accurate calculations of oxygen availability, pH and carbon dioxide accumulation from routine MRI measurements. Such a methodology has a tremendous potential to transform the scope and breadth of basic and clinical investigations of the brain (and beyond}, however rigorous validations are sorely needed in order to realize its potential. By capitalizing on recent advances in imaging platforms available at the CMRR and in partner institutions which I have been collaborating with for years, the time is mature to conduct the proposed high-risk, high-impact studies that can only be executed within the flexible scheme of a Pioneer award. Focusing on pathological mechanisms linking loss of brain function to abnormal accumulations of metabolic waste products, and on non-MRI techniques for validation studies, requires a major research shift for me, but is essential for building the foundation of a much broader agenda that will benefit the basic and translational neuroscience community and ultimately patient care.

NIH Research Projects · FY 2025 · 2024-09

Project Abstract Accumulation of senescent cells in adipose tissue, particularly visceral depots, is increasingly becoming more appreciated as a causal factor in age- and obesity-associated metabolic dysfunction, conditions that impart a heavy burden in terms of suffering and mortality on public health. Concomitant creation of an inflammatory milieu is thought to facilitate the development of systemic insulin resistance. As lipid peroxidation and pertinent drivers are shown to be associated with lifespan and age-related pathologies, I posit that resulting electrophilic lipid byproducts can incite or potentiate senescence in adipose. Produced abundantly in adipocytes by peroxidation of mitochondrial phospholipids, lipid aldehydes such as 4-hydroxynonenal (HNE) and 4-oxo-2-nonenal (ONE) covalently modify nucleophilic protein residues and herein I hypothesize that carbonyl stress exerts oxidative stress and mitochondrial dysfunction to induce the senescence program in adipose progenitor cells. Proposed studies would represent the first efforts to thoroughly and systematically characterize the biochemistry and cellular signaling underpinning cellular senescence brought on by lipid aldehydes. IMR90 fibroblasts continuously exposed to lipid aldehydes for seven days exhibit initiation of the senescence program, characterized by induction of SA-β-gal activity and enhanced expression of CDKN1A (p21Cip1), among other senescence markers. I’ve termed this type of senescence Biogenic Lipid Induced Senescence, BLIS. Associated with BLIS is the upregulation of an NFκB-independent subset of the putative human SASP. Furthermore, I demonstrated that permeabilization of mitochondrial membranes by BAK/BAX channels mediate the BLIS phenotype. The overall mechanism of lipid aldehyde associated senescence is multifaceted and likely to involve mitochondrial protein modification, as I observed hallmarks of aberrant mitochondrial function concomitant with development of BLIS markers and alkylation of mitochondrial proteins. Indeed, 4-HNE exposure effects reduced mitochondrial spare capacity and increased ADP:ATP ratios. Taken together, preliminary data suggest that reactive lipid aldehydes can induce cellular senescence and that adipose senescence may be linked to lipid-mediated senescence induction in fat tissue. Proposed work can be broken down into two aims: in my first aim, I will use a proteomics-based approach to define targets of mitochondrial carbonylation during obesity and aging and in my second aim, I will investigate the role of mitochondrial stress and signaling on adipose senescence. During proposed experiments, I will build vital skills as a researcher, most importantly in proteomics data analysis and hands-on in vivo work with mouse models. Backed by a mentoring committed composed of faculty active in the field of aging research and spanning multiple departments at the University of Minnesota, I am confident an F32 fellowship will facilitate both my development as a researcher and novel, impactful research.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Cancer survivors, even when cured from their cancer, are at an increased risk of excess mortality, attributable to higher rates of treatment-related health conditions, most notably secondary malignancies, cardiovascular disease, stroke and late health complications. Growing recognition of these health conditions and their resultant morbidity and mortality has led to the development of standardized, cancer survivor-specific screening and surveillance recommendations, with the goals of risk reduction, early detection, reduced mortality, and improved quality of life. Cancer survivorship care plans (SCPs), which outline prior cancer treatments, provide a comprehensive plan to address potential long-term effects. Despite the widespread implementation of SCPs into general practice, controversy exists on whether SCPs improve screening and surveillance practices, or reduce mortality. Given the resource burden the creation of SCPs places on the healthcare system and the lack of available efficacy data for their use, it is critical that key measurable outcomes, specifically mortality, be investigated to support their ongoing use. The proposal’s objective is to investigate the impact of SCPs on reducing cancer mortality among adult cancer survivors. The long-term goal is to optimize survivors’ health, minimizing chronic health conditions and improving overall mortality in cancer survivors. Based on our preliminary data, our central hypothesis is that SCPs when applied to the general population will not improve mortality. However, enhanced SCPs (SCP+) when applied to high risk populations will improve outcomes and mortality. We will test our central hypothesis and attain our objective via the following specific aims: Specific aim 1a: Quantify the effectiveness of receiving a SCP (versus no SCP) in reducing cancer mortality using institutional 2018-2023 data. Specific aim 1b: Quantify the effectiveness of SCP+ and its contribution to mortality in AYA patients, aged 15-39 years (versus no SCP+), using institutional data 2011-2023. Specific aim 2: Using tree-based and random forest causal survival machine learning (ML) methods, identify heterogeneous treatment effects of SCP and SCP+ and characterize those that receive maximum survival benefit relative to all others. The proposed work is innovative in that it compares SCP and SCP+ to examine the role of SCPs on mortality, integrates multiple data sources, and uses a novel machine learning technology to identify heterogeneity in group differences in survival. Our research is poised to make a significant impact by delving into crucial socioeconomic and geographic disparities in care delivery, optimizing the effectiveness of SCPs in minimizing mortality rates.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY There are more than 250,000 ovarian cancer survivors in the US and this number is growing. Throughout treatment for this disease, many patients encounter serious effects, including physical issues like nausea, vomiting, fatigue, sleep disruptions, peripheral neuropathy, hair loss, and sexual dysfunction, as well as psychological challenges such as cognitive dysfunction, fear of recurrence, anxiety, and depression. Comprehensively understanding how the prevalence and severity of side effects, unmet needs, and barriers to supportive care affect quality of life (QOL) in diverse ovarian cancer survivors remains a research gap and priority. Our long-term goal is to improve the survivorship experience of individuals with ovarian cancer. Our overall objective is to document 1) physical and psychosocial concerns, 2) barriers and facilitators to supportive care, and 3) factors associated with unmet needs among ovarian cancer survivors. Our central hypothesis is that ovarian cancer survivors face significant challenges, with differences in the frequency and type of concerns by patient characteristics, e.g., time since diagnosis, age, race/ethnicity, sexual identity, education, income, geographic location, and social support network. We will pursue the following specific aims: (1) describe the physical and mental health conditions of ovarian cancer survivors that impact quality of life and detail pharmacologic and non-pharmacologic interventions utilized to manage these conditions; (2) identify barriers and facilitators to accessing and receiving supportive care among ovarian cancer survivors; and (3) describe the unmet needs of ovarian cancer survivors and identify associated risk and protective factors related to the number and types of unmet needs. We will use a mixed-methods approach. We will recruit a diverse national sample of 2,000 ovarian cancer survivors in collaboration with the California Cancer Registry along with regional and national ovarian cancer advocacy groups to complete a cross-sectional survey. Among a subset, we will conduct follow-up interviews to gather additional information. The expected outcome of this study is a comprehensive description of survivorship experiences among diverse ovarian cancer survivors. This detailed information regarding their unmet needs and care gaps will serve as a call-to-action to develop and implement targeted interventions to improve QOL of individuals with ovarian cancer. The proposed research is innovative because we will assess outcomes in diverse ovarian cancer survivors, allowing for subgroup analyses and we will identify care elements that contributed either negatively or positively to survivors’ experiences. We expect our study will have a significant impact on informing effective strategies that can be readily implemented and expanded to improve the QOL of cancer survivors, an explicit goal of Healthy People 2030.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract The goals of this proposal are to further train Jenna Mendelson as a scientist conducting cardiovascular basic science research to combat cardiovascular disease and to advance the understanding of the mechanisms of right ventricular dysfunction (RVD) in a large animal model. RVD is a significant risk factor for death in cardiovascular disease. Yet, there are currently no therapies that directly target the right ventricle. Although small animal studies reveal important mechanisms, these findings are difficult to translate to humans. Porcine models may be a better bridge to humans because the anatomical size, structure, and physiology of porcine hearts are more similar to humans. Furthermore, we recently showed that in RVD, pigs have a metabolic molecular signature that more closely recapitulates human disease compared to rodents. Mitochondria are energy producing organelles that maintain cellular metabolism. Patients and animal models of RVD have mitochondrial metabolic dysfunction and reduced fatty acid metabolism, leading to insufficient ATP to meet cardiac energy demands. Glycoprotein 130 (GP130) is the ubiquitously expressed master membrane receptor for interleukin-6 superfamily of inflammatory cytokines. Downstream GP130 activation alters mitochondrial function, and in a rat model of pulmonary hypertension, we showed that inhibition of GP130 with the small molecule SC144 improved mitochondrial morphology, increased fatty acid oxidation, and improved RV function. Therefore, this research project will investigate the hypothesis that in a large animal model of RV pressure overload induced RVD, GP130 antagonism with SC144 will improve RV function by improving mitochondrial fatty acid metabolism. Aim 1 investigates the hypothesis that GP130 antagonism will improve RV function in a porcine model of pulmonary artery banding. Aim 2 will determine if GP130 antagonism with SC144 improves fatty acid metabolism. In both aims, we will utilize in-depth physiological assessments (cardiac MRI and pressure-volume loop analysis), super resolution confocal microscopy, electron microscopy analysis, proteomics, metabolomics, lipidomics, and molecular biology approaches to determine the effects of GP130 antagonism with SC144 on RV function and mitochondrial metabolic function. This project has the potential to link mitochondrial dysfunction to cardiac MRI and hemodynamic measurements of RV function in large animals, and identify GP130 signaling as a pharmacological target for RVD. Furthermore, the training of Ms. Mendelson through this translational proposal will advance the mission of the NIH by helping support the training of a scientist who will conduct clinically relevant research.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Human retroviral infections (i.e., human immunodeficiency virus type 1, HIV-1; and HIV type 2, HIV-2) impact a combined 38 million people worldwide and result in at least 680,000 deaths per year. Despite advancements in antiretroviral therapies (ART), there presently is no cure for these infections. Given the continued development of antiviral drug resistance, there remains a need for basic science investigations in addressing crucial knowledge gaps in the field, such studies can inform antiretroviral target identification, and have broad applications towards therapy and cure. One of the key aspects of HIV-1 replication that has remained underexplored has been virus particle assembly. Here in this proposal, the overarching hypothesis being tested is that differences in human retroviral capsid (CA) protein structure and CA-CA interactions can provide new insights into particle assembly and help identify conserved features that may be promising antiretroviral targets. There are three lines of investigation being pursued. First, the differential CA interfaces among HIV-2 will be investigated to examine whether differences in Gag lattice morphologies can be attributed to differences in CA interfaces. Second, comparative analysis between the HIV-1 and HIV-2 capsid core structure will be determined to assess whether a novel helix in the HIV-2 mature CA is present and responsible for morphogenesis of the mature CA lattice. Finally, the molecular and structural basis for differences in HIV particle assembly and viral infectivity will be investigated using site-directed mutagenesis studies. The proposed studies will provide new insights into the structure-function relationships among CA proteins and enable new insights in human retroviral replication.

NIH Research Projects · FY 2025 · 2024-09

Abstract This project aims to advance transcranial magnetic stimulation (TMS) technologies for psychiatric disorders. TMS outcomes vary among participants, likely due to a lack of adaptation to individual brain states. We thus propose a closed-loop approach where real-time electroencephalographic (EEG) recordings of brain oscillations can inform the timing of TMS at the prefrontal cortex. However, closed-loop TMS applications are currently not implemented in clinical practice due to a lack of validated methods for targeting prefrontal brain oscillations and identifying markers of TMS target engagement. Invasive electrophysiological recordings in nonhuman primates (NHPs) offer a high signal-to-noise ratio and improved localization of brain responses. Simultaneous scalp EEG recordings will inform translational efforts in humans. We aim to identify markers of TMS engagement in the prefrontal cortex from invasive electrophysiological recordings in NHPs and differentiate direct neural responses from indirect stimulation effects. We will further characterize the effects of closed-loop TMS on invasive electrophysiological responses and determine optimal stimulation parameters. By delivering TMS at different phases and power states, we will measure TMS evoked potentials (TEPs) to identify the most effective stimulation parameters for prefrontal closed-loop TMS. Finally, we will evaluate the effects of closed-loop theta burst stimulation (TBS) on neural plasticity. By tracking prefrontal theta rhythms in real-time, we will deliver TMS pulse bursts at specific phases to enhance the effectiveness of TBS protocols. We will assess induced neural plasticity through the measurement of TEPs and local functional connectivity. Successful completion of this research could lead to the development of improved closed-loop TMS protocols for the prefrontal cortex, with direct implications for the treatment of psychiatric disorders in humans.

NIH Research Projects · FY 2025 · 2024-09

Project Abstract - Overall The burden of climate change is of particular concern to American Indian, rural, and agricultural populations. While a considerable amount of research has evaluated climate effects in urban and coastal populations, largely due to more abundant data, less is available for rural populations, where there are persistent healthcare inequities and deficient health infrastructure. Additionally, the lack of comprehensive health outcomes data at a population level has limited the evaluation of climate factors such as extreme weather, air pollution, and drought in specific vulnerable groups that are difficult to identify. The burden of climate change is of particular concern to American Indian persons. The historical systematic destruction of their communities and cultural connection to natural systems creating a condition of ecological grief, i.e., grief due to loss or deterioration of land, is believed to be linked to mental health conditions, substance use, obesity, and chronic health conditions. This project will establish the Mni Sota Center for Climate Change and Health (M3CH). Mni Sota is the Dakota word for ‘where the waters reflect the sky’, which well describes the Upper Midwest. The long-term objective of the Mni Sota Center for Climate Change and Health is to be a leading research enterprise to characterize health impacts related to climate change and translate findings to create practical and actionable measures for climate change adaptation with a specific focus on American Indian and rural communities. The objective of this proposal is to develop regional climate and health research capacity through the M3CH by leveraging the multidisciplinary assets of the University of Minnesota, partner institutions, and communities to create actionable knowledge for addressing the health impacts of a changing climate in the Upper Midwest. The primary focus of the proposed center is to develop capacity to address the impacts of climate change experienced by American Indian persons and people living in rural areas with an emphasis on populations in the Mni Sota region. The Specific Aims of the proposed center are to; 1) Leverage multidisciplinary expertise and partnerships to build regional capacity for research on climate change and health that aligns with the priorities of target communities. 2)Establish a Community Engagement Core to co-develop a research agenda with American Indian and rural communities that will guide future research using novel and existing data while following culturally safe research practices. 3)Support a research project that will develop climate change and health research capacity using a novel data resource based on a multi-system electronic health records consortium to evaluate the effects of extreme weather events in at risk communities and specifically American Indian and rural populations. 4)Establish a Pilot Project and Emerging Issues program that identifies and responds to stakeholder priorities in the co-developed research agenda and creates partnerships that will rapidly progress toward substantial research projects.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Chronic Temporomandibular Disorder (TMD) is associated debilitating pain and dysfunction of the muscles of the jaw, the temporomandibular joints, and related structures. TMD pain is highly prevalent, impacting ~5-12% of the general population and over 20% of individuals seeking treatment for alcohol use disorder. Moreover, treatments for chronic pain conditions like TMD, such as opioid analgesics, are relatively ineffective, rarely meet patients’ own criteria for successful treatment, and are associated with significant risk. Therefore, many patients seek alternative, maladaptive methods for pain relief, including self-medication with alcohol. Twenty- five percent of treatment seeking people with alcohol use disorder (AUD) report past-month pain, and 25% of chronic pain patients report heavy drinking. However, the effects of pain on alcohol consumption behavior in heavy drinkers with chronic TMD pain are poorly understood. Despite the need for empirical investigations of the effect of pain on naturalistic drinking behavior, previous work has not directly addressed this question. We address this gap in knowledge by assessing the effect of pain on the microstructure of individual drinking bouts, known as drinking topography (DT). The primary objective of this study is to determine the impact of pain on DT in community-dwelling heavy drinkers with and without chronic TMD pain both in the laboratory and in daily life using ecological momentary assessment (EMA). In the laboratory, we will use the Integrated Topography and Consumption Tracking in Virtual Reality (INTACT VR) platform to provide a highly-controlled drinking environment, increasing study rigor and reproducibility. In contrast, EMA provides high ecological validity and the ability to ascertain whether pain-related DT patterns in the laboratory are also observed in the real world. Importantly, our approach is informed by the Catastrophizing, Anxiety, Negative Urgency, and Expectancy (CANUE) model, a theoretical moderated-mediation model regarding modifiable psychosocial factors underlying pain as an antecedent for substance use. The results of this study will provide mechanistic information regarding the effect of pain on alcohol consumption in heavy drinking individuals with chronic TMD pain, as well as actionable information regarding modifiable and non-modifiable risk factors for potentially hazardous alcohol use associated with pain self-management. This knowledge will facilitate optimization of interventions to reduce alcohol-related consequences in people with chronic TMD pain. Such interventions can potentially also have indirect benefits on chronic pain given evidence that hangover and alcohol withdrawal are associated with increased pain severity.

NIH Research Projects · FY 2025 · 2024-09

While American Indian (AI) persons have historically used wild or homegrown tobacco for spiritual purposes, the use of commercially produced tobacco has risen dramatically. Today, smoking-related cancers are as much as three fold higher among AI persons than White persons. Our preliminary data show that the odds of quitting smoking among AI persons are 40% lower than White persons. Low engagement with smoking cessation interventions is considered a major contributor to the disparity in cessation. NCI’s Smokefree program provides a suite of evidence-based digital resources for smoking cessation, including a website (Smokefree.gov), text program (Smokefree TXT), smartphone app (QuitGuide), and social media (Smokefree Facebook). These resources facilitate interaction with one another, have wide reach, and have been shown to increase cessation in the general population. However, we posit that Smokefree does not meet the needs and cultures of AI persons and is unlikely to engage and maximize cessation in AI persons. For this reason, through engagement with tribes and AI-serving clinics and nationally drawn community advisory boards, our team has conducted preliminary studies to develop Smokefree TXT for Natives and QuitGuide for Natives. Our team also maintains a social media page, Quit Connections, to provide a community for AI persons during their quit journey. These culturally aligned resources incorporate Indigenous worldviews and strengths, respect tobacco for spiritual purposes, integrate smoking triggers such as grief that are common to AI persons, and promote healing through culture and community connectedness as part of the quit journey. Our next step is to determine to what extent these culturally aligned resources, when packaged as Smokefree for Natives and supplemented with a culturally aligned Smokefree.gov, increase smoking cessation among AI persons. Our central hypothesis is that in AI persons who smoke (PWS) Smokefree for Natives will yield greater smoking abstinence versus the non-tailored Smokefree. This proposal builds on longstanding collaborations and employs mixed methodologies including Indigenous practices in engagement, a rigorous clinical trial, and qualitative interviews. The aims are: Aim 1: To co-create a website, Smokefree.gov for Natives, which will serve as the landing page for AI-aligned online cessation treatment content and facilitate access to a suite of culturally aligned digital cessation resources for AI persons; Aim 2: To test the efficacy of Smokefree for Natives via a remotely conducted randomized controlled trial among American Indian PWS (n=416); Aim 3: To qualitatively assess perceptions of Smokefree for Natives among AI PWS (n=40) and thematic differences in response based on demographics and geography. This proposal represents the braiding together of Indigenous and Western research approaches and represents a logical progression of our engagement efforts to date. Given that AI persons experience one of the most extreme smoking disparities, a scalable and culturally aligned smoking cessation intervention for AI persons could have considerable public health impact.

NIH Research Projects · FY 2024 · 2024-09

Abstract In the United States, 8.2 million women and 2.0 million men age 50 and above have osteoporosis. Moreover, half of all women and one quarter of men are projected to suffer an age-related low bone mass fracture within these populations. Importantly, an estimated 25% of individuals die within one year of a hip fracture. Cortical bone comprises the majority of skeletal bone mass (80%) and diminished cortical bone mass accounts for 70% of all bone lost with age. Although bone anabolic agents enhance vertebral cortical bone mass, efficacy of these agents is lower at the hip as compared to the spine (+12.3% spine, +3.9% hip); therefore, additional therapeutics improving cortical bone mass are desperately needed. Recent evidence shows that EMP-derived osteoclasts support balanced bone remodeling. In contrast, HSC-derived osteoclasts facilitate bone resorption in perturbed states. These observations suggest that osteoclasts of alternate developmental origins impact bone remodeling differentially, but we lack an understanding of how bone remodeling may differ within specific bone compartments (e.g., cortical versus trabecular bone). The two-year deliverables of the proposed study are: 1) identification of myeloid progenitors that aid in maintenance of cortical bone with age and 2) characterization of putative cells/molecules that promote coupling within cortical bone. If successful, this work could spur the development of new therapeutics that specifically limit age-associated cortical bone loss.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT Juvenile idiopathic arthritis (JIA) is an autoimmune disease characterized by chronic inflammatory arthritis affecting children. It is the most common chronic pediatric rheumatic disease. Children with JIA are typically treated with long-term immunosuppressive medications. Although there are many good treatments available to treat JIA, disease flares are common, affecting approximately 40% of patients even after disease control is achieved. Yet, the etiology of disease flares has not been well-studied. Pediatric rheumatologists commonly blame viral infection as the causes of JIA flares, and although this is a reasonable assumption, there is little evidence to support this claim. JIA shares common pathophysiology with adult rheumatoid arthritis (RA). RA studies have led to the mucosal origin hypothesis, which theorizes that immune responses against mucosal organisms drives the development of autoantibodies in pre-clinical RA, prior to evidence of joint inflammation. More recently, studies have linked viral upper respiratory infections (URIs) as a ‘second hit’ that leads to onset of arthritis in RA. If URIs have been linked to arthritis in adults, it is highly plausible that URIs are associated with JIA onset and flares in children, particularly since young children have far more frequent URIs compared to adults. There is only one prospective study of viral URIs in patients with JIA, and the study found that in 20% of patients who had disease worsening, there was a temporal association with a symptomatic infection. This proposed study hypothesizes that children with JIA have increased susceptibility to viral URIs, prolonged viral carriage, and prolonged dysbiosis of the nasopharyngeal microbiome following URIs. It also hypothesizes that JIA disease flares are temporally associated with URIs, regardless of the severity of the URI symptoms. The hypotheses will be tested by enrolling a cohort of 35 young children with JIA and 35 healthy siblings to serve as controls. The children will undergo weekly nasal swabs for 26 weeks over the respiratory viral season (November-April). Symptoms, hospitalizations and antibiotic use will be collected weekly using electronic surveys. The study will also assess for incident symptomatic and asymptomatic respiratory viral infections using an amplicon-based next-generation sequencing technique and quantify microbiome alpha and beta diversity and composition by 16S rRNA sequencing. The study will also assess for associations between viral URI, microbiome changes, and JIA disease activity with a self-reported JIA disease flare survey, also collected weekly. The results of this study may provide guidance to children with JIA about risk for URIs, period of infectivity and associations between viral infection and disease flare. Importantly, if the study identifies a relationship between the nasopharyngeal virome and microbiome and how it affects JIA disease activity, it may lead to the identification of novel pathways for JIA and RA treatments.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT SCA1 is a dominantly inherited neurodegenerative disease caused by expansion of CAG repeats in the ATAXIN-1 (ATXN1) gene. Patients with SCA1 suffer from progressive gait and balance deficits, and severe degeneration of Purkinje cells (PCs) in the cerebellar cortex and neurons in the cerebellar nuclei (CbN). There are no effective disease modifying therapies currently available for SCA1, indicating a critical need for better understanding of disease pathogenesis. Cerebellar nuclei are a key part of the cerebellar network and the main information output from the cerebellum. As a consequence, CbN are relevant to motor behaviors regulated by the cerebellum. Remarkably, very little is known about the dysfunction of CbN in any of the spinocerebellar ataxias (SCAs), including SCA1. The research described in this proposal will determine how CbN function is altered throughout SCA1 progression, how mutant ATXN1 (mATXN1) impacts the CbN, and how changes in CbN contribute to SCA1-like motor deficits. An additional impact of this study will be to expand the concept of SCA1 as a cerebellar circuit dysfunction disease, stimulating future studies into interactions of the cerebellar cortex and CbN, not only in SCA1, but in other ataxias as well.

NIH Research Projects · FY 2024 · 2024-09

ABSTRACT The Src-family kinase Lyn is critical for maintaining immune homeostasis and protecting against autoimmunity, and deficits in Lyn function are linked to systemic lupus erythematosus (SLE). However, cell studies report con- flicting (paradoxical) inflammatory and immunosuppressive functions, varying by cell and perturbation. We dis- covered that the two Lyn splice forms (A, B) are differentially regulated, suggesting non-overlapping interactions and roles, suggesting that the apparently paradoxical positive and negative effects might be explained by iso- form-specific functions that vary with expression, immune compartment, and environment. We generated single- isoform LynAKO and LynBKO mice and discovered (1) a dominant role for LynB in protecting against autoimmunity and (2) a female-specific role for LynA in immune regulation. Our preliminary data point to overlapping roles of LynA and LynB in steady-state ITIM signaling but a specific role for LynB in inducing antimicrobial hemi-ITAM signaling. To this toolkit we add a reagent that biases splicing toward increased LYNB production in human cells. We hypothesize that LynB forms unique interactions in ITAM and TLR complexes, while LynA uniquely sup- presses ER (estrogen-receptor) signaling, accounting for the sexual dimorphism. Alterations in LynA and LynB expression will explain the apparently paradoxical observations of net positive and negative functions and sug- gest a path forward for therapeutic development. 1: Define roles of Lyn isoforms in ITAM, TLR, and ER signaling in human and murine myeloid cells. As myeloid cells drive autoimmunity and have been targets of immunomodulatory therapies, they will be the focus of signaling studies. Candidate and unbiased kinase-sub- strate mapping and interactomics in macrophages and DCs will provide a comprehensive profile of LynA and LynB substrates and functions in receptor activation. Predictions: LynB will interact stably with ITAM and TLR signaling complexes and downstream mediators, whereas LynA will uniquely suppress ER signaling. LynA and LynB will be found to localize differently at the cell membrane, explaining why upregulation of the other isoform fails to rescue signaling. 2: Define isoform- sex-, and cell-specific functions of LynA and LynB in lupus progression. We will assess progression of lupus in spontaneous and inducible models in male and female mice from our Lyn knockout series. WT and LynKO experiments will be repeated mice with ovariectomy and with pharmacological antagonism/agonism of estrogen, progesterone, and TLRs to pinpoint contributors to sexual dimorphism. We will assess cell-specific contributions to disease. Finally, we will test the ability of a splice- altering reagent to suppress disease. Predictions: Upregulation of a single isoform will only partially suppress lupus, cell-specificity will follow LynA/B expression patterns, sex hormones will drive lupus in females, and alter- ing LynA/B balance will modulate disease. With our Lyn knockout series, we are poised to resolve longstanding paradoxes in Lyn signaling. Our Lyn splice reagent adds translational value, testing a new therapeutic avenue.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Research Challenge: More than 582,000 people in the US experience homelessness each night, and a staggering 1.25 million people enter the shelter system each year. People experiencing homelessness endure extreme adversity, drastically increasing their risk of dying young. Although the response to the homelessness crisis primarily occurs at the local level, local data on homeless mortality is largely unavailable. The limited existing data show substantial variation in homeless mortality rates by place, suggesting that place-based factors may impact mortality risk. However, methodological differences in how existing data are collected and compiled make valid cross-location comparisons difficult. As a result, at present there is no way to rigorously test how local place-based factors—such as policies, service availability, and economic conditions—relate to homeless mortality, which impedes the ability to identify promising local policy solutions or interventions. Objective & Specific Aims: The overall objective of the proposed research is to identify policy-sensitive drivers of homeless mortality. This objective will be achieved through the following specific aims: (1) calculate homeless mortality rates for each US state and Continuum of Care (local planning bodies that coordinate homeless services for a specific city, county, or small group of counties), (2) document frontline providers’ perceived place-based risk and protective factors of homeless mortality, and (3) investigate the association of place-based factors with homeless mortality. Approach: The proposed study will use a sequential mixed methods design to provide insight about homeless mortality and its place-based predictors. In Aim 1, restricted-access US Census Bureau data on people experiencing homelessness will be linked to Social Security Administration mortality records to estimate area- level homeless mortality rates. In Aim 2, 48 key informant interviews will be conducted with frontline providers of homeless and health care services to identify perceived place-based predictors of homeless mortality. In Aim 3, using homeless mortality estimates from Aim 1 and potential predictors identified in Aim 2, multi-level modeling will be used to test the association between place-based factors and homeless mortality. Impact: This project will yield the first comparable state-level and Continuum of Care-level estimates of homeless mortality as well as identify place-based correlates of mortality. This proposal, which crosscuts the missions of NIA, NICHD, and NIMHD, would have positive impact by identifying potential policy avenues that could bring to bear improved health and reduced mortality among people experiencing homelessness.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY / ABSTRACT Low back pain (LBP) is a leading cause of disability worldwide with an estimated 40% of LBP attributed to degenerating intervertebral discs (IVD), frequently referred to as discogenic LBP. Many of the current preclinical models of discogenic LBP impose focal injury with rapid onset and are typically limited to 1 or 2 IVDs. In contrast, in clinical discogenic LBP, IVDs degenerate over a long period of time creating pain- generating tissue states during this progressive process. The overall objective for this application is to develop a clinically representative preclinical model of discogenic LBP that recapitulates the human discogenic LBP biological processes, making it more likely to aid in the development of novel therapies to reduce or stop the pain. In our prior work with a mouse lacking the SPARC gene (a structural protein in IVDs and other tissues), we demonstrated that this preclinical model leads to IVD degeneration replicating human discogenic LBP. While these mice demonstrate healthy behavior, removing the SPARC gene from the entire body leads to off- target effects. As an example, the eyes and brains have atypical features. We therefore propose to develop and validate an inducible, disc-specific SPARC deletion model using Cre/LoxP which would retain the clinical discogenic LBP phenotype while also ensuring normal development of all of the other tissues in the body. Aim 1 (R61, Year 1&2): Optimize the crossbreeding protocol(s) and induction timing to reproduce the behavioral, radiographic, and cellular/molecular facets of clinical discogenic LBP. Our working hypothesis is that crossing SPARC-floxed mice with tamoxifen‐inducible cytokeratin 19 mice (Krt19-CreERT; targets nucleus pulposus (NP) cells) and/or with tamoxifen-inducible aggrecan mice (Agc1-CreERT2; targets all components of IVDs) will lead to a clinically representative discogenic LBP model. We will induce recombination in utero and at skeletal maturity to initiate IVD degeneration and test for signs of low back pain. Milestones: Demonstration of IVD degeneration and pain phenotype. If multiple models meet the criteria, the model with the latest induction time and the most favorable off-site recombination profile will be selected. Aim 2 (R33, Year 3): Validate the behavioral phenotype and determine responsiveness to pharmacological intervention. Our working hypothesis is that axial pain will be sensitive to morphine, pregabalin and ibuprofen while radiating pain will only respond to pregabalin. Aim 3 (R33, Year 3): Independent replication. Concurrent to Aim 2, an independent lab at University of New England will perform the same procedures as described in Aim 2. These results will have an important positive impact because there is a need for a clinically representative discogenic LBP preclinical model for the discovery and validation of novel non-addictive therapeutics.

NIH Research Projects · FY 2025 · 2024-09

Project Summary I am an Assistant Professor in the Division of Infectious Diseases & International Medicine at the University of Minnesota. My long-term goal is to become an independent investigator with expertise in conducting clinical trials with nested translational immunology research to further the management of AIDS-related opportunistic infections of the central nervous system. I am particularly interested in developing the skillset, competence, and cultural rapport to conduct ethically-sound trials in resource-limited settings in Africa, where the burden of HIV/AIDS-related CNS infections disproportionately impacts the population. Training: This K23 award will provide the mentoring, didactics, and hands-on training to establish an independent research career. With the mentorship of an interdisciplinary team with expertise in international clinical trials and immunology involving HIV-related opportunistic neuroinfections, I will: 1) Improve my knowledge of biostatistical design and analysis, 2) Acquire experience on human immunology principles and data interpretation to facilitate effective translational research collaborations, and 3) Gain robust education and mentorship in clinical trial design and execution, particularly as it pertains to infectious diseases in Africa. Research: CMV viremia is independently associated with mortality in persons with advanced HIV disease; however, no recommendations exist for the treatment or prevention of CMV viremia alone. My published data demonstrated CMV viremia increased the mortality hazard by 3-fold in a cohort with first-episode cryptococcal meningitis. I hypothesize that CMV viremia exerts a mortality risk that is (1) time-dependent, and (2) associated with impairment of the host Th1 immune response (e.g. interferon-gamma [IFN-] response). My K23 objective is to build the skills and preliminary data necessary to design a future randomized clinical trial to test if anti- CMV therapy might mitigate excess mortality. My K23 Specific Aims are: 1) Determine if CMV viremia is a time-dependent risk factor for 18-week mortality among Ugandans with advanced HIV disease and concomitant cryptococcal meningitis; and 2) Determine if host Th1 responses are impaired in persons with active CMV viremia compared to CMV non- viremic persons among those with HIV-related cryptococcal meningitis. Deliverables: This study will provide key missing clinical trial design parameters, such as the optimal duration of an anti-CMV intervention (i.e. informed by CMV viremia duration/persistence and time-dependent mortality risk) and the appropriate risk criteria for enrollment (i.e. any baseline CMV viremia vs CD4-predicted cumulative exposure). Further, identifying a plausible immune mechanism (e.g. impaired Th1 responses) opens the door for improved risk stratification and for future targeted immunomodulatory clinical trials (e.g. subcutaneous IFN-). A future randomized trial best determines if CMV viremia is a cause of excess mortality.

NIH Research Projects · FY 2025 · 2024-09

Project Summary The ultimate objective of this R03 proposal is to enable Dr. Ida Fonkoue to launch her independent research career by 1) expanding her current K01 research objectives; 2) providing additional support in her transition to a future NIH R01 grant; and 3) generating sufficient preliminary results to support that R01 application. The candidate’s long-term goal is to build an NIH-funded research program in clinical and translational research in women’s health, studying longitudinal derangements of vascular, neural and hormonal control, that contribute to the high rates of hypertension and cardiovascular disease (CVD) in women living with chronic stress exposure such as those with post-traumatic stress disorder (PTSD), generalized anxiety disorder or panic disorder. Over 7 million U.S. adults have PTSD, a disorder associated with a greater risk for hypertension and CVD. While healthy premenopausal women are relatively protected from CVD compared to men, a diagnosis of PTSD increases CVD risk in women by up to 3-fold. According to the Centers for Disease Control and Prevention, over 60 million women in the United States are living with some form of heart disease. Understanding the mechanisms underlying long-term CVD risk in women with PTSD is of paramount importance to develop intervention strategies aiming at protecting the future health of this vulnerable population. Based on our preliminary data, the working hypothesis of this project is that: Over time, PTSD significantly inhibits nitric oxide bioavailability, resulting in accelerated autonomic and vascular dysfunctions in premenopausal women; and that these changes are exacerbated by low estradiol (E2) levels and sleep disturbances. Aim 1 will measure longitudinal alterations in sympathetic nervous system (SNS) activity in premenopausal women with PTSD and determine the extent to which these alterations are a function of low E2 levels and low sleep efficiency at two years follow-up. Aim 2 will measure longitudinal alterations in vascular function in premenopausal women with PTSD and determine the extent to which these alterations are a function of low E2 levels and low sleep efficiency at two years follow-up. We will use gold-standard in vivo measures of sympathetic nerve activity (microneurography), endothelial (FMD) and vascular (applanation tonometry) function to study young, traumatized women with and without PTSD. The university of Minnesota University, where the project will be completed, boasts an intellectually rich research environment whose resources will be used to carry out the proposed research, including an NIH-funded Clinical and Translational Science Institute (CTSI). During this R03 award, the PI will devote 75% effort to this project and her current K01 project. She recently achieved an important career-development milestone for her transition to full independence by completing her Master of Science in Clinical Research. This research project, combined with findings from her K01 and ongoing multidisciplinary mentorship, will help Dr. Fonkoue launch and sustain a meritorious R01-funded independent research program.

NIH Research Projects · FY 2024 · 2024-09

SUMMARY A fundamental question in developmental biology is how migratory cells initiate migration, move in a directed fashion towards their target, terminate migration and differentiate. Neural crest cells (NCCs) are an excellent example of these developmental processes, initially forming at the neural plate border/dorsal neural tube, undergoing an epithelial to mesenchymal transition, and migrating before differentiating. This represents an important problem, because defects in neural crest development underlie many human congenital birth defects including Treacher-Collins syndrome, DiGeorge syndrome, and Hirschsprungs disease. We have determined that NCCs extend cell projections that are enriched in specific RNAs. From these data, we hypothesize that localization of specific migratory mRNAs to NCC protrusions by zipcodes are required for directed migration. The rationale for the proposed studies is that an in-depth understanding of the cellular mechanisms of normal NCC migration will provide insights into the etiology of both neural crest- associated birth defects, including numerous syndromes, and cancer cell metastasis. We will test this hypothesis in the following specific aims: 1) Test the hypothesis that specific mRNAs are enriched in NCC protrusions and are required for NCC migratory behavior. In Aim 1, we will determine the transcriptome and proteome of NCC projections and test their function. 2) Test the hypothesis that zipcode sequences in NCC protrusion localized mRNAs are required for localization and NCC migration. In Aim 2, we will examine the localization and function of UTR regulatory sequences. Together, these studies will reveal the cellular and molecular mechanisms by which specific RNAs and proteins enriched in NCC projections promote NCC migration. The results of this proposal have the potential to reveal important new insights into NCC migration in normal development and disease and will provide a foundation for the design of therapeutic strategies for neural crest associated birth defects.

NIH Research Projects · FY 2026 · 2024-09

Abstract: 40 years into the pandemic, stigma remains the most challenging barrier for HIV prevention. A quarter of people living with HIV remain untested, depriving them of opportunities to enter the HIV prevention continuum and access evidence based prevention tools. Testing is particularly low in gay and bisexual men who have sex with men (MSM) who face additional discrimination on account of their same sex behaviors. Stigma can be internalized or anticipated but it is most pernicious when it is enacted in healthcare settings, as this directly bars care access while also discouraging future care seeking. Enacted healthcare stigma is notoriously difficult to measure, as few providers willingly report discriminatory behavior and patients lack the medical knowledge to assess the appropriateness of care. Our solution is to conduct unannounced standardized patient (SP) visits to measure and address enacted healthcare stigma. SPs are actors hired from the local community and trained to present standardized, unannounced disease cases in area clinics for the purposes of evaluation and feedback. Their ability to objectively document provider behaviors through unannounced visits presents an elegant solution to the common tendency of providers to alter behaviors under observation. By randomly varying the sexual orientation and HIV status of presented cases, our technique obtains discrete measures of HIV, sexual, and intersectional stigma. Results of an initial round of SP visits are shared with advisory boards of providers and MSM to solicit their views on stigma drivers which inform a tailored stigma reduction training for study providers which is then evaluated in a second round of visits. Our team has conducted an NIH-funded pilot randomized control trial (RCT) that demonstrated high feasibility and acceptability of the SP approach for measuring and reducing stigma (R34MH121251). This R01 application follows on the success of the R34 to propose a fully powered cluster RCT using tools, lessons, and experience gained from our pilot. This trial will newly include rural clinics to expand generalizability and will also explore future implementation potential of our intervention with regional policy makers. Our interdisciplinary team combines expertise in HIV prevention, stigma, LGBT health, standardized patient research, and medical education to investigate the following aims: 1) Conduct a baseline round of SP visits to inform the design of a SP-informed stigma reduction intervention with support from MSM and provider community advisory boards; 2) implement the intervention in treatment arm clinics and evaluate its impact on enacted stigma and clinic-level HIV testing volume and 3) conduct qualitative interviews with stakeholders (providers, MSM, health officials) to help inform the design of a Implementation Blueprint to guide potential future adopters in assessing its suitability and their team readiness to implement a SP-informed stigma intervention in their setting.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract-Overall Coordinated and integrated care programs for individuals with Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD) and their family caregivers are growing. These models of care integrate disease care management, provide multidisciplinary care planning, and navigate healthcare and social service systems for persons living with dementia and their caregivers. However, knowledge of these services’ effectiveness is limited due to the lack of high-quality data at the state and sub-state levels, which hampers evaluation of policies that support integrated/coordinated dementia care services. Lack of data also inhibits opportunities to adapt and scale integrated/coordinated dementia care services within and across states. The State Alzheimer’s Research Support Center (StARS) will guide states through partnership, engagement, and 1-year pilot projects to build collaborations and create a shared data infrastructure to advance the accessibility, affordability, and effectiveness of dementia care services across the United States. Guided by the National Institute on Aging Health Disparities Research Framework, the specific aims are as follows: 1) to establish partnerships to identify existing coordinated/integrated dementia care services and available data sources within states; 2) to support up to 16 dementia care pilot projects; 3) to build a within- and across state data infrastructure to evaluate dementia care services and policies; and 4) to implement a multifaceted dissemination strategy to promote best practices in the identification, linking, and sharing of dementia care data. The State Alzheimer’s Research Support Center will create a national data infrastructure that enables states and all communities to better understand dementia care services’ effects on key care transitions, such as hospitalization readmissions, nursing home admission, home health care, as well as the health and well-being of people living with dementia and their caregivers. This infrastructure will also facilitate the examination of policy variations and changes on dementia care services within and across states. The partnership building, pilot project support, and data sharing infrastructure of StARS will ultimately result in greater dissemination of integrated/coordinated dementia care services that yield positive outcomes for people with dementia and care partners.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Female genital mutilation/cutting (FGM/C) affects girls and women throughout the world, with 3 million girls cut each year. The highest rates of FGM/C are in East Africa. There are significant reproductive, sexual, and mental health consequences for girls and women impacted by FGM/C. Healthcare providers (HCPs) require training to meet these needs, yet globally there is a dearth of training programs. Effectiveness studies of FGM/C training are even rarer. Tanzania has a high FGM/C rate, yet we found in preliminary studies that healthcare students were unprepared to meet the need of these patients. The goal of the proposed study is to develop training materials specific to the needs of HCPs within Tanzania, deliver a pilot intervention/training program, and study the effectiveness of the program at Muhimbili University of Health and Allied Sciences (MUHAS). In order to meet that goal, it is critical that training materials are developed carefully, with attention to both cultural and ethical concerns facing healthcare providers within the country. There are three specific aims. In Aim 1 we will conduct a social ecological needs assessment of the healthcare needs of women in Tanzania who have experienced FGM/C. The results of Aim 1 will be used to adapt a promising training program to accomplish our second aim. In Aim 2 we will develop a FGM/C training tailored to the Tanzanian context. A core component of Aim 2 will be to use a train the trainer program. In Aim 3 we will evaluate the effectiveness of the training through a randomized, controlled, single blinded trial of the training (intervention) against a waitlist control arm (n=200 students per arm; 400 in total). In Aim 3 we will assess medical, nursing, and midwifery students’ improvements in knowledge, attitudes, and clinical skills. Development and testing of a tailored training course about FGM/C for students in health care, if effective, has high potential to be integrated into existing curriculum; and be widely adopted as a new standard of training for health professionals across both low prevalence and high prevalence FGM/C areas.