University Of Minnesota

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Diabetes is a heterogeneous disease characterized by chronic poor glycemic control, resulting in pathological changes in tissues throughout the body. Chronic hyperglycemia causes the cardiovascular system to undergo growth and remodeling (G&R) that is captured hypertension and increased arterial stiffness, both significant risk factors for cardiovascular disease. Diabetes results in both cellular and matrix changes in arterial health, and then each of these components further drive the pathological G&R by responding to the direct effects of the disease. Fortunately, there exist medical and lifestyle interventions to help mitigate the diabetic disease state and restore glycemic control. Large elastic arteries like the aorta serve as capacitors to absorb changes in blood volume due to pulsatile pumping and protect the more fragile downstream microvasculature. Overall health and stiffness of these large vessels is captured in the clinic via pulse wave velocity which is elevated in diabetic patients, and there is evidence that the pulse wave velocity decreases back towards baseline following restoration of glycemic control. The overarching objective of this project is to determine how hyperglycemia affects aortic biomechanics and mechanobiology and whether restoration of normoglycemia is sufficient to reverse these changes. To establish how arterial biomechanics are affected by hyperglycemia, I first employed a diabetic mouse model to ascertain changes in active and passive wall mechanics, and these preliminary results demonstrate that chronic hyperglycemia results in stiffer and hypercontractile murine aortas. The central hypothesis of this proposal is that chronic hyperglycemia results in cellular and matrix aortic G&R, and glycemic recovery results in reversal of the cellular, but not matrix, phenotype, leading to partial rescue of aortic health. To test this hypothesis, I will utilize an inducible mouse model of chronic hyperglycemia that can subsequently be rescued by administration of Phloridzin. Experiments proposed in Aim 1 will determine the in vivo and ex vivo biomechanical changes in aortic health due to hyperglycemia and following treatment. Aim 2 will then explore how the tissue-scale mechanical changes arise by investigating how the matrix composition and cellular phenotype are affected by the disease and treatment. The experimental work of the first two Aims will be coupled with a multiscale, bio-chemo-mechanical computational model of aortic G&R in Aim 3. The computational model will provide mechanistic insight into the roles of cells and matrix in disease progression and possible regression, resolving information that is inextricable experimentally. Collectively, these data will elucidate aortic G&R due to chronic hyperglycemia, whether these changes can be reversed by restoration of glycemic control, and the mechanisms behind these processes. This proposed work will have broad implications in the conceptual understanding of the cellular and matrix roles in diabetes-related cardiovascular pathologies and the development of methodologies to explore biomechanical and mechanobiological changes in vascular health due to disease and treatment.

NIH Research Projects · FY 2026 · 2024-09

Summary Approximately 1 in 3 children in the US experience neglect and/or abuse (“maltreatment”) before they turn 18 years old, with marginalized racial and ethnic communities and young children facing the greatest risks. For the past century, research has treated maltreatment largely as a failing of individual parents, despite robust evidence that maltreatment risk, particularly for neglect and physical abuse, is powerfully shaped by structural determinants such as poverty and stress. Population-level maltreatment prevention could have major public health impacts, but it is not yet clear how to prevent maltreatment at scale. Emerging research suggests that economic and social welfare policies that alleviate financial hardship and reduce stressors for families could potentially serve as population-level prevention interventions. However, two major gaps limit the utility of the existing evidence base for identifying policies with the potential to prevent maltreatment. First, prior research has evaluated individual policies one at a time without accounting for the ways that changes in one safety net policy may affect the eligibility for and benefits from others. This failure to account for policy interactions may result in mis-estimation of overall safety net benefits and mis-attribution of effects of one policy to another. Second, prior research has almost exclusively assessed maltreatment through Child Protective Services (CPS) involvement (e.g., reports of maltreatment to CPS), and thus impacts on other critical public health outcomes such as maltreatment-related injuries remain unknown. The overarching goal of this research is to identify the impact of social safety net policies on CPS reports and injuries related to neglect and physical abuse in young children. Two key innovations will directly address current knowledge gaps. First, to estimate benefits from each major social safety net program (EITC, CTC, SSI, TANF, SNAP/WIC, and Medicaid/CHIP), accounting for other programs, we will use and expand a safety net benefits calculator. This calculator sequentially applies program rules for each state and year, allowing benefits from one program (e.g., TANF) to be incorporated into eligibility and benefits estimates for others (e.g., SNAP), as dictated by program rules. Second, we will combine and harmonize over 300 state-years of data on ED and inpatient visits for pediatric injuries that are highly correlated with maltreatment. We will estimate the impact of social safety net policies on these maltreatment-related injuries in addition to CPS reports. We will focus on young children (aged <5 years) as they are at greatest risk of maltreatment. We will also examine these outcomes by race and ethnicity to determine impacts on equity. The aims of our research are to: (1) Estimate the effect of major social safety net policies (EITC, CTC, SSI, TANF, SNAP/WIC, Medicaid/CHIP) on CPS reports of neglect and physical abuse in young children (age <5 years), overall and by race and ethnicity; and (2) Estimate the effect of major social safety net policies (EITC, CTC, SSI, TANF, SNAP/WIC, Medicaid/CHIP) on neglect- and physical abuse- related hospitalizations in young children (age <5 years), overall and by race and ethnicity.

NIH Research Projects · FY 2026 · 2024-09

PROJECT ABSTRACT Opioid Use Disorder (OUD) is a complex medical condition characterized by compulsive and maladaptive use of opioid substances, including prescribed pharmaceuticals (such as oxycodone) and illegal agents (such as heroin). It causes physiological, psychological, and sociological effects, including tolerance, withdrawal symptoms, relapse, and impaired daily functioning. Managing opioid use disorder (OUD) involves addressing withdrawal symptoms and relapse risks during abstinence, which can vary throughout different stages of recovery. During the initial phase of opioid withdrawal, individuals often encounter the most severe and debilitating symptoms. These symptoms typically peak within the first few days of refraining from drug use and gradually subside with prolonged abstinence. Nevertheless, the most significant challenge during this critical stage of recovery is the sustained risk of relapse, even after the initial withdrawal symptoms have abated. This risk is further amplified by external cues that can trigger intense cravings and the compulsion to seek drugs. Hence, it is imperative to acquire a comprehensive comprehension of the neural mechanisms that underlie relapse during early and prolonged abstinence from opioid use. Rodent studies suggest that glutamatergic projections from the paraventricular nucleus of the thalamus (PVT) to the nucleus accumbens (NAc) are involved in the expression of negative affective states and relapse after abstinence. Both PVT and NAc are heterogeneous and complex brain regions with diverse sets of cell types, functional connections, unique subregions, and neurotransmitter systems. Opponent roles of anterior/posterior PVT subregions, and D1- and D2-medium spiny neuron activity, has been found for approach/appetitive and avoidance/aversive behaviors. This research project addresses the critical question of how the PVT interacts with the NAc to modulate withdrawal symptoms during early abstinence and prolonged abstinence on the vulnerability to relapse. This project is an essential step towards my goal of becoming an independent researcher. Through the K99/R00 grant, I'll have the opportunity to improve my understanding and abilities in advanced neuroscientific methodologies, which will lay the groundwork for my research program focused on addiction neuroscience. The knowledge and data I gather during the K99 phase will be a solid foundation for a successful transition to the R00 phase, which will help me expand my research in this field. Additionally, this work will reveal the complex PVT-NAc neural mechanisms governing relapsing behaviors, which could lead to innovative strategies for addiction treatment and prevention.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The goal of this project is to refine our gene therapy strategy for Xeroderma Pigmentosum-Cockayne Syndrome (XP-CS), with the ultimate aim of improving the neurological outcomes and life expectancy for this disorder. XP- CS is a rare, inherited DNA repair disorder that is characterized by an accelerated aging phenotype and prominent, severe neurodegenerative complications mirroring those seen in classic Cockayne syndrome (CS), including cognitive dysfunction, brain atrophy, neurodevelopmental delays, peripheral neuropathy, brain atrophy, and dementia. There are several genetic subtypes of XP-CS, including one associated with pathogenic variants in the gene ERCC5 (XPG). We have found that the Xpg-/- mouse accurately recapitulates key features of the XP- CS phenotype, including neurological features. We have also developed a first generation adeno-associated virus (AAV) vector capable of delivering ERCC5 that shows great promise but requires further development prior to translation into human clinical trials. Our preliminary studies using the first generation vector in the Xpg-/- mouse point to a clear path towards optimizing this approach, including capsid optimization, promoter optimization, delivery optimization, dose tuning, toxicity studies, and biomarker evaluations. We expect that our proposed studies will lead to a gene therapy strategy that overcomes many of the obstacles to translation into a Phase 1 human clinical trial. The knowledge obtained from these studies will be generalizable, and will accelerate the development of gene therapies for other genetic subtypes of XP-CS.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Healthcare and research organizations, including the American Society for Clinical Oncology, acknowledge the common use of stigmatizing language in cancer care. However, stigmatizing language has not been comprehensively defined, and drivers and outcomes of this language use have not been investigated in cancer care. One way that discrimination and stigma manifest in the healthcare system is through the electronic health record (EHR), which can reflect the author’s implicit and explicit bias. Reading stigmatizing language alters readers’ clinical decisions in vignette studies. Thus, there is an opportunity to evaluate EHR stigmatizing language as a modifiable mechanism of decreasing discrimination and improving outcomes in cancer care. The long-term goal is to evaluate sociocultural and healthcare system influences of EHR stigmatizing language and resulting changes in clinical decision-making in cancer care. The central hypothesis is that stigmatizing language is present in the cancer care EHR, inequitably experienced, and associated with altered clinical decision-making. The hypothesis will be tested via the following specific aims: (1) Determine the categories of stigmatizing language used by oncology clinicians when documenting patient encounters in the EHR; (2) Compare stigmatizing language in the cancer care EHR by patient and clinician characteristics; (3) Determine if stigmatizing language use is associated with disparities in medication prescription for cancer-related pain. This study will leverage EHR data from a large academic and community healthcare system in Minnesota. Aim 1 utilizes a qualitative study design to perform a directed content analysis of the unstructured, free text section of outpatient oncology EHR notes. Aims 2 & 3 use natural language processing to abstract stigmatizing terms and phrases for each individual with outpatient cancer visits in 2022. Multilevel models will be utilized to account for nested visit-level data within patient-level data within clinician-level data. This project is innovative in its characterization and modeling of stigmatizing language in cancer care and will have significant impact by informing interventions to reduce stigma, health disparities, and resulting negative health outcomes. By focusing on EHR stigmatizing language, this project addresses emerging opportunities and challenges as medical records become accessible to patients and persist throughout their lives. The applicant is an MD/PhD and Epidemiology PhD student at the University of Minnesota Schools of Medicine and Public Health. By expanding content knowledge in cancer survivorship and disparities, rigorous qualitative and quantitative analysis skills, tailored clinical training, and focused professional development opportunities, this fellowship will enhance her ability to excel in the MD/PhD program and become an independent academic physician- epidemiologist.

NIH Research Projects · FY 2025 · 2024-08

RESEARCH SUMMARY Alcohol use disorder (AUD) is characterized by the inability to control or stop the use of alcohol, even in the face of negative consequences or after long-term abstinence. Thus, it is important to understand the risk factors that contribute to this loss of control such as environmental cues that can contribute to an increase in probability of relapse, compulsive drinking, and withdrawal symptoms after abstinence. Previous research has shown that ventral tegmental area (VTA) dopamine (DA) neurons can modify the learned value of reward- associated cues to alter reward-seeking behavior by driving an increase cue reactivity and cue-driven reward- seeking. It is also known that VTA DA neuron activity increases compulsive alcohol seeking and cue-induced relapse of alcohol seeking. However, which receptors control the activity of VTA DA neurons on cue-related behaviors have yet to be determined. Systemic GABAB receptor activation is shown to reduce the mentioned alcohol-related behaviors in rodents in addition to reducing the ability of cues to reinstate alcohol seeking. Baclofen, a direct GABAB receptor agonist, has been shown to have a dose-related reduction in these behaviors while related studies showed that the VTA was implicated as baclofen’s key site of action due to intra-VTA injections having suppression of cue-elicited reward seeking in rats. Yet, the specific neuronal populations in the VTA responsible for baclofen’s effects remain unknown. Thus, the broad goal is of the proposal is test the significance of a potential molecular target from a reward-related neuron population on alcohol cue reactivity, cue-evoked aversion-resistant drinking and relapse plus on baclofen’s seen effects. The objective of this proposal is to investigate the impact of deleting GABAB receptors in VTA DA neurons on cue-evoked relapse (Aim 1) and aversion-resistant drinking (Aim 2). Additionally, to test the role of these receptors on the previously seen effects of baclofen with the addition of intra-VTA microinjections of baclofen. Given that these receptors and neuron population have been shown to influence these behaviors in rodents, I hypothesize that GABAB receptors in VTA dopaminergic neurons are responsible for constraining the cue-elicited alcohol-related behaviors and for the previously seen baclofen induced effects. To test this, I will use the cutting-edge CRISPR-Cas9 approach by bilaterally microinjecting high-titer AAV viral vectors harboring guide RNAs targeting GABAB receptors or control (Rosa), and a Cre-dependent GFP for visualizing expression (Experiment 1A and 2A). Additionally, a separate subject group will also have a bilateral guide cannula implant for intra-VTA baclofen delivery (Experiment 1B and 2B). Following this, the aforementioned behaviors will be tested and an analysis of lever presses and g per kg of alcohol consumed will take place. That said, during this proposal I will gain valuable technical and theoretical training in genetic manipulation, behavioral methods, histological processing, imaging techniques, intracranial surgeries, and computational analysis. Therefore, allowing me to become a successful independent addiction neuroscientist.

NIH Research Projects · FY 2025 · 2024-08

Project Summary/Abstract Cutaneous viral infections, including vector-borne viruses, cause significant morbidity and mortality. Vector-borne viruses are transmitted first to the skin through mosquito bites, then disseminate, causing a broad spectrum of frequently devastating disease. Yet, strategies to thwart cutaneous viruses remain elusive. Resident memory T cells (TRM) represent a promising target due to their potent effector functions and localization at barrier tissues including the skin. In contrast to recirculating memory T cells, TRM stably occupy nonlymphoid tissues (NLT) where they rapidly detect pathogen reinfection and initiate protective anamnestic immune responses. In fact, skin TRM can provide complete protection against cutaneous challenge through direct killing of infected cells and innate-like effector functions that establish an antiviral state. Extensive preliminary data supports the broad range of TRM functions that can be leveraged therapeutically. It is unknown, however, if skin TRM can be directed to limit viral spread in acute infection after targeted immunization. By focusing on antiviral CD8 TRM populations in the skin, this proposal will identify TRM functions in host immunity that may be harnessed against skin-borne infectious diseases. Building on preliminary data, Aim 1 will determine whether CD8 TRM reactivation orchestrates immune cells in the skin. Aim 2 will determine the extent to which skin TRM influence distal immunity. TRM must function from a fixed location, yet it is unclear if they are to serve as a local alarm or one that is amplified to enhance immunity at other sites. Observations that local inflammation has far-reaching effects on other tissues, creating a cascade of responses that heighten immunity at an organismal level lend credence to the idea TRM provoke systemic immune effects. By understanding how we can utilize TRM through TCR-dependent processes, we may be able to wield this population in a more broad manner. Given the many parallels between mouse and human TRM, findings in my studies using reductionist mouse models may readily be applied to clinical therapeutics.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Parkinson’s disease (PD) is a prominent neurodegenerative disease with over 90,000 cases being diagnosed annually. Little is known about the pathogenesis of abnormal trunk posturing/impaired postural control in PD. Trunk postural control is particularly problematic during both standing (e.g. excessive forward and lateral flexion) and turning (“en bloc” turning). Corticospinal, reticulospinal and vestibulospinal systems contribute to the control of trunk muscles, but their roles in the pathogenesis of disordered trunk control are unclear. To date, no studies have investigated the function of descending neural pathways on the control of the trunk during static postures and dynamic movements in people with PD. This proposal will use two noninvasive neuromodulation techniques, transcranial magnetic stimulation (TMS) and electrical vestibular stimulation (EVS), to characterize: (i) the excitability of corticomotoneuronal (corticospinal and corticoreticulospinal) projections to trunk muscles during quasi-static postures and prior to turning, and (ii) the engagement of vestibulospinal projections during standing and turning. Aim 1: (A) Compare trunk muscle corticomotoneuronal and intracortical excitability (via TMS) in sitting and standing between people with PD and healthy controls. (B) Examine the relationships between TMS responses and quantitative assessments of posture and gait. Trunk muscle responses to single and paired-pulse TMS of the primary motor cortex trunk region will quantify the excitability of corticomotoneuronal and intracortical (inhibition and facilitation) pathways in quasi-static postures (sitting and standing). Aim 2: (A) Compare the modulation of corticomotoneuronal pathway excitability to trunk muscles (via TMS) immediately prior to turns in people with PD and healthy controls. Single pulse TMS will quantify the change in excitability of corticomotoneuronal pathways immediately prior to a 90° turn. Aim 3: Compare the modulation of (A) EVS-ground reaction force (GRF) coherence and (B) EVS-trunk electromyograph (EMG) coherence prior to and during turns in people with PD and healthy controls. Vestibulo-postural coupling will be tested by computing the coherence between EVS and the (A) GRFs used to maintain balance and (B) surface EMG from the trunk muscles. This work will provide novel insight into the pathophysiology of disordered trunk control in PD. This proposed study is part of a fellowship training plan that will include training in (i) quantitative motor assessments using biomechanical and EMG techniques, (ii) clinical neurophysiological and neuromodulation techniques, and (iii) professional development skills that are essential for a successful career as a rehabilitation scientist. The University of Minnesota’s expansive research infrastructure, the multi-disciplinary Program in Rehabilitation Science, and the Movement Disorders Laboratory create an ideal environment for completing this research and training.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Natural killer (NK) cell engagers are a promising anticancer therapy that potently leverages the immune system while providing an exceptional safety profile. Trispecific killer cell engagers (TriKEs) are NK cell engagers that mediate NK cell killing of tumor cells through multispecific binding. TriKEs contain a tumor binding domain, an IL-15 cytokine, and a CD16 engager. The IL-15 and CD16 engager stimulate robust NK cell activation and tumor cell killing while the tumor binding domain targets the therapy to the tumor microenvironment. Expansion of the TriKE platform to target new tumor-associated antigens requires integration of novel TriKE tumor binding domains. This process is bottlenecked by difficulties preserving TriKE functionality and developability (i.e. sufficient stability, aggregation, and recombinant yield for therapeutic use) upon the addition of a new tumor binding domain. This project will transform the TriKE discovery process by interrogating the impact of specific tumor binding domain properties on the resultant TriKE’s functionality and developability, including use of innovative hyperstable miniproteins. Specifically, Aim 1 will investigate the impact of tumor binder scaffold architecture by comparing the performance of several different scaffolds within TriKEs, including antibody fragments and hminiproteins. Aim 2 will investigate the impact of preemptively optimizing tumor binder stability and recombinant yield before insertion into TriKEs. This will be accomplished by systematically varying tumor binder stability and recombinant yield and quantifying the impact on TriKE functionality and developability. These investigations will involve the production and characterization of experimental tumor binding domains and TriKEs targeting B7-H3, an established tumor-associated antigen. The primary goal of this work is to inform the design of TriKE tumor targeting domains, thereby streamlining the expansion of the platform to new therapeutic targets. Furthermore, this project will advance the development of TriKEs as a therapeutic option for B7-H3 positive cancers.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Significance: Over 15,000 children aged <20 years will be diagnosed with cancer in 2023, but due to advancements in treatments and therapies, 85% of these children are expected to join the growing population of childhood cancer survivors (CCS) currently living in the US. On average, CCS will experience over 17 chronic health conditions by age 50, contributing to health complications (physical, mental, psychosocial) and early mortality. Access to specialized long-term healthcare is a barrier in achieving equity in quality and longevity of life, especially in disadvantaged populations, and this barrier is magnified as the population of CCS continues to expand. Existing research has shown that proximity to providers confers advantages in frequency of care and better health outcomes. However, partially attributable to the availability of adequate datasets, these studies have only examined the role of distance as it relates to cancer incidence rather than post- treatment survivorship. For CCS, and especially adolescent and young adults (AYA), survivors’ communication between and/or fluctuation of care providers adds complexity to sustained healthcare treatment across the life course. Aims: This project will (1) characterize the proximity of AYA survivors to Children’s Oncology Group (COG) survivorship care across the US, (2) determine the association between distance to care and early mortality, and examine whether this is influenced by socioeconomic status (SES) and/or race/ethnicity in AYA survivors. Approach: The proposed secondary analysis will leverage AYA cancer patient data from the COG’s Children’s Cancer Research Network (protocol #ACCRN07). Previous work to geocode patient residence and complete (pre- and post-diagnosis) residential history has allowed for study of patient residence in relation to survivorship care. Aim 1 analysis will measure distance to care and characterize patients’ residential environment (individual- and area-level characteristics). Poisson regression will be used to assess the number of survivorship care contacts per unit area (density). Aim 2 will assess the relationship between distance to care and early mortality (<5 years post-diagnosis) using Cox proportional hazards models adjusting for age and sex. Mediation analysis will be used to explore the influence of SES and we will evaluate race/ethnicity as a confounder. Fellowship Information: The applicant is a PhD student in Epidemiology at the University of Minnesota and a predoctoral trainee in the NICHD-funded T32 training program in Population Health Science. Through coursework and mentoring on pediatric cancer epidemiology, geospatial analysis, and health disparities along with guidance on communicating findings and writing grants, the proposed training plan will build on Ms. Thomas’ existing research skills. This training will enhance her ability to complete her dissertation research and become an independent cancer epidemiology researcher with expertise in childhood cancer survivorship.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT While expansion of antiretroviral therapy (ART) coverage over the past two decades has significantly decreased mother-to-child, or “vertical,” transmission, progress has stagnated in recent years. To address the remaining 130,000 new infections among children each year, we must take a broader approach, promoting maternal ART coverage within the context of additional interventions. The key question is, which additional interventions will most benefit elimination of mother-to-child transmission (eMTCT) efforts while also being economically feasible for a country to implement? Simulation-based modeling and decision science have played an important role in evaluating the benefits and costs of HIV treatment and prevention strategies, in order to inform guidelines and policy decisions. We propose to apply these methods to guide eMTCT health policy in sub-Saharan Africa, where the majority of infant infections occur. Most decision science work in this area has focused on adult HIV, while the limited number of eMTCT studies have largely focused on interventions downstream of ART initiation, despite the potential for interventions upstream of ART initiation to have significant impact. We have identified an eMTCT toolbox of six interventions that span the entire reproductive continuum, from preconception to postpartum: access to contraception to more safely time pregnancies, pre-exposure prophylaxis to prevent HIV infection among pregnant and breastfeeding women (PBFW), HIV re-testing to ensure prompt ART initiation among PBFW who acquire HIV, and long-acting ART, mentor mother programs, and viral load testing to increase viral suppression rates among PBFW who initiate ART. Implementing all six interventions at full-scale is ideal but not feasible given resource limitations. To identify implementation priorities, we will evaluate the population-level effectiveness and cost-effectiveness of each of these interventions, alone and in different combinations or “portfolios” of various sizes. Because the cost-effectiveness and affordability of an intervention will depend on country-specific factors, including economic resources, demographics, epidemic characteristics, and eMTCT progress to date, we will tailor our evaluation to the specific country contexts of Kenya, Nigeria, and Botswana. These three African countries all have a high HIV burden but also represent diversity in key relevant characteristics, making them useful case studies for a wide range of other African countries. Our findings from this comprehensive eMTCT intervention analysis will provide urgently-needed support for eMTCT policymaking in each of our three focus countries, paving the way for a new frontier in eMTCT progress in these and other African settings.

NIH Research Projects · FY 2025 · 2024-08

Abstract Globally, central nervous system (CNS) infections have one of the largest burdens of death and disability, particularly among persons with weaken immune systems due to the extremes of age, immunosuppressive medicines, or HIV. Cryptococcal meningitis causes 15-19% of AIDS-related deaths, and TB-meningitis is the deadliest form of tuberculosis (TB). These CNS infections are neglected diseases. This K24 Midcareer Investigator Award in Patient-Oriented Research proposal seeks to continue a successful clinical and translational research portfolio in humans with CNS infections to impact the international guidelines for what is the standard of medical care in low-, middle-, and high-income countries. The research portfolio includes leading and mentoring clinical cohorts and randomized clinical trials on: 1) FDA-field trials for meningitis diagnostics; 2) meningitis treatment; 3) optimizing supportive care for CNS infections; 4) preventing cryptococcosis; 5) exploring immunopathogenesis in humans relative to survival and 6) neurocognitive outcomes; as well as 7) using health economics to inform international and US policy. This proposal is submitted by a mid-career investigator focused on improving the diagnosis, treatment, and prevention of neuro-infections. In 16 years as a faculty, the candidate has mentored >60 students, trainees, and junior faculty. Current mentees include: 6 K-awardees, 1 Wellcome Trust PhD fellow, 1 MD/PhD student, 12 under-represented minorities, as well as MD and MPH students. The candidate serves as program director for a T32 training award for infectious diseases fellows. Since 2019, the K24 candidate has published 163 manuscripts (NIH iCite RCR mean = 3.47, ~85th percentile), reflective of effective leadership of a highly productive interdisciplinary meningitis research team conducting relevant research. The K24 seeks to continue a productive research platform for HIV-related neuro-infections, which are neglected diseases. There is a track record of creativity, innovation, and pursuit of clinically relevant research which impacts clinical care in the U.S. and abroad to improve the prevention, diagnosis, and survival of those persons living with HIV. Specific Aims are: 1) Enroll a prospective cohort of HIV+ persons with meningitis to enable diagnostic field trials and mentee substudies; 2) Develop new clinical trial protocols to investigate new agents for cryptococcal meningitis and TB meningitis; 3) Develop immunologic framework to characterize distinct subsets of AIDS- related neuro-infections in the setting of HIV therapy with a focus on future host directed therapy. Training objectives of this K24 include 1) further refinement of leadership skills to lead a multi-disciplinary team; 2) developing further mentoring skills through formal training and workshops; 3) developing proficiency in single-cell RNA-sequencing to better characterize CSF immune responses.

NIH Research Projects · FY 2026 · 2024-08

ABSTRACT Mortality from cryptococcal and TB-meningitis in individuals with HIV is unacceptably high and better therapeutics are needed. The future landscape of treatment against these infections involves either development of new therapeutics, which has been slow, and/or the optimization of current therapeutics with improved formulations or dosing regimens. The CNS is a significant site of infection for these pathogens; however, current understanding of drug penetration into the CNS is limited, based on cerebrospinal fluid (CSF) concentrations. However, CSF is not brain tissue. Furthermore, pharmacokinetic targets for therapy have been largely based on systemic or plasma concentrations with limited pharmacology assessments performed in CSF or brain parenchyma. Improved understanding of drug exposure to and within the brain compartments where pathogens reside, and how these exposures relate to pathogen clearance will be critical in the development and optimization of effective regimens. Our long-term objective is to reduce mortality from CNS infections. Herein, we aim to use pharmacokinetic/pharmacodynamics modeling to: 1) define CSF drug concentrations or AUC/MIC ratios, that predict rate of fungal clearance 2) determine the relationship between CSF drug concentrations and with inflammation, resistance, neurocognitive outcome, and survival 3) determine drug distribution in brain parenchyma using post-mortem specimens This project builds on existing research collaboration, infrastructure, and progress made with our R21 NS108344. This project represents a unique synergy between existing strengths of the study team members. Early stage-investigator Melanie Nicol, PharmD, PhD has advanced training in clinical pharmacology and performing drug distribution and pharmacokinetic studies. Robert Lukande, MMed, PhD is an experienced pathologist who can provide expertise in the performance and interpretation of autopsies. Drs. David Meya and David Boulware are leaders in cryptococcal and TB meningitis and lead multiple clinical trials in these areas, allowing us access to research participants on a variety of drug regimens. The findings from this R01 are expected to fill critical gaps in our understanding of the dose-concentration-response relationships of antifungal and anti-TB drugs for the treatment of CNS infections in individuals with advanced HIV and ultimately reduce mortality with improved regimens. The R01 will also support critical infrastructure and capacity building in Uganda in regards to drug distribution assays and the implementation of autopsy procedures.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Preterm birth and the hospitalization of infants in the neonatal intensive care unit (NICU) are well-documented as stressful events for mothers. Although maternal milk is critically important to promote optimal health and neurodevelopment for preterm infants, the effects of maternal postnatal stress on maternal lactation and feeding outcomes and milk composition have not been systematically examined. The goal of this proposed Pathway to Independence Award is to pair a detailed examination of lactation and feeding outcomes for preterm infants in the NICU with a biological systems approach to understanding human milk to examine the hypothesis that maternal stress is associated with feeding outcomes and markers of impaired neurodevelopment for preterm infants and alters human milk and infant gut profiles in ways that affect preterm neurodevelopment. The proposed research directly aligns with the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s scientific priorities to reduce the incidence of neurodevelopmental disorders, optimize outcomes for preterm infants by understanding nutrition/feeding and the microbiome, and to understand human milk composition in relationship with maternal characteristics. During the K99 phase, measurement of perceived, biological, and known maternal stressors in the NICU will be conducted and assessed in relation to maternal lactation and feeding outcomes (milk production, mothers’ own milk vs donor milk vs preterm formula) (Aim 1). Infants will also undergo neurodevelopmental testing via electroencephalogram before NICU discharge and at 4 months corrected age to assess the relationship between maternal stress and preterm neurodevelopmental outcomes (Aim 2). Career development activities in the K99 phase, including training in stress physiology and infant neurodevelopment, developing expertise in lactation/feeding outcomes for preterm infants in the NICU, and learning techniques for assessing human milk and infant gut composition data and their interpretation will take place in the excellent research environment at the University of Minnesota School of Public Health Division of Epidemiology and Community Health and will provide the skills needed to successfully examine associations of maternal stress with characteristics of maternal milk and preterm infant gut composition in the R00 phase. Targeted and untargeted metabolic approaches and microbial analyses will be used to elucidate the relationships between human milk and preterm gut composition with maternal stress and preterm neurodevelopmental (Aim 3). The proposed research lays the groundwork for future clinical interventions designed to mitigate the effects of maternal postnatal stress through psychosocial support and/or nutritional supplementation and will also provide foundational data for the successful launch of an independent research career focused on promoting nutritional practices which yield optimal neurodevelopment for preterm infants.

NIH Research Projects · FY 2024 · 2024-08

Summary/Abstract Osteoarthritis (OA) is a chronic debilitating joint disease, affecting over 32 million people in the USA with an economic impact of $550 billion/year. OA is characterized by degeneration of articular cartilage, typically affecting the back, hands, knees, and hips. A significant correlation between inflammation and disease severity has been observed in human and animal models of OA. Increased inflammation in the synovial fluid has also been shown to inhibit chondrocyte proliferation limiting cartilage repair and promoting OA disease progression. No therapy is available to slow the progression of OA and current treatments only attempt to relieve the symptoms. New therapeutics that promote regulation of inflammation have the potential to alleviate the OA pathology and arrest the disease progression. The impact of fetal development on the immune system varies depending on the stage of embryo development with a delicate balance between immune tolerance and protective immunity. Several extrinsic and intrinsic factors through epigenetic and transcriptional programs skew the adaptive immune response towards increased expression of immunosuppressive signaling intermediates including Helios that favors the expansion of Tregs. Exosomes play a critical role in cross talk between different biological systems. In this study we will leverage the immunoregulatory mechanisms in play during the fetal development to treat OA by identifying the stage of muti-tissue organoid (MTO)-development that yields exosomes with anti-inflammatory and chondrocyte proliferation potential in in vitro studies using human PBMCs to facilitate clinical translation. We will analyze the epigenetic and transcriptomic reprograming induced by the MTO-derived exosomes that promote expansion of iTregs that can play a critical role in the regulation of inflammation in OA. We will also test the MTO- derived exosomes to alleviate OA symptoms in a rat model of OA. The studies will also identify protein and miRNA in the MTO-derived exosomal cargo that correlates with anti-inflammatory and chondrocyte proliferation potential that can be developed into potency assays for use in future clinical trials for evaluation of the MTO-derived exosomes.

NIH Research Projects · FY 2025 · 2024-08

Summary Type I diabetes (T1D) is one of the most common chronic diseases in childhood. Sequelae of pediatric T1D include neurocognitive dysfunction in attention, psychomotor speed, mental efficiency, visual-motor skills, memory, and learning possibly due to damage to posterior white matter tracts and associated gray matter regions. Emerging evidence suggests that diabetic ketoacidosis at time of diagnosis, glucose control, diabetes device use, sleep, and caregiver distress may be important factors that influence neurocognitive development. However, there is minimal data in this area and existing studies are limited by small sample size, short follow-up time, and a lack of diversity in patient populations. A contemporary, adequately powered longitudinal study in a diverse cohort of prepubescent children is needed to understand the mechanisms associated with neurocognitive perturbations, critical periods for prevention and intervention, and strategies to mitigate the risk of neurocognitive complications in later life. Our research team is uniquely qualified to serve as the Biostatistics Research Center (BRC) for the Understanding Neurocognition in Youth with Type 1 Diabetes (UNYT1D) nation-wide consortium combining extensive experience in the coordination of multi-site clinical studies and research networks, biostatistics expertise in the analysis of complex observational data, and expertise in T1D, glucose variability, neurocognition, and neuroimaging. Our application leverages the existing infrastructure of the University of Minnesota’s Coordinating Centers for Biometric Research (CCBR), which has internationally recognized expertise in coordinating complex, large-scale, multi-site studies and networks and over 50 years of experience These substantial strengths enable the BRC to accomplish the following specific aims:1) Partner with NIDDK to provide scientific leadership in the design of a longitudinal cohort study to characterize the neurocognitive impact of new onset T1D in pre-pubertal children; 2) Provide overall coordination of the national multisite consortium in the planning and implementation of and adherence to the protocol; 3) Provide consortium-wide resources for data harmonization, pipelines, management and sharing; 4) Provide expertise in all aspects of study reporting, data analysis and dissemination. The BRC will play a crucial role in the success of the consortium. Our research team has a proven track-record of high-impact research in the clinical management of T1D, a history of developing novel approaches to neuroimaging data acquisition and analysis, and extensive experience coordinating the activities of and providing statistical and data management support for multi-site clinical studies and research networks. Leveraging this experience and capitalizing on the existing infrastructure of the CCBR, we are uniquely suited to serve as the BRC and support high-quality, robust, and reproducible research through the UNYT1D consortium.

NIH Research Projects · FY 2026 · 2024-08

Project Summary Altered cerebrovascular health is strongly associated with aging. PET and MRI studies have found age dependent reductions in resting cerebral blood flow (CBF) and neurovascular coupling (NVC) that correlate with poorer cognitive function and higher risk of dementia. Yet paradoxically, brain energy consumption is close to normal. If there is sufficient O2 delivery to support metabolism, how do reduced CBF and neurovascular coupling impact function? Answering this question is critical for interpreting MRI data available via research efforts such as the Human Connectome Project on Aging (HCP-A), and for developing novel in vivo MRI metrics of brain health. To address this question, we recently developed and validated a novel computational Homeostatic Modeling (HoMod), which integrates for the first time NVC with neurometabolic coupling (NMC) – i.e., the increase in proton and lactate production from glucose and glycogen metabolism. Using MRI or PET data, HoMod allows calculation of regional brain tissue and capillary blood levels of not just fuels (glucose, O2), but also metabolic waste products (pH, CO2, lactate). Extensive behavioral and EEG/MEG studies have found cognitive function is highly dependent on homeostasis of these products. Using HoMod we showed for the first time that, in healthy young adults, both resting state CBF and the large increase in NVC during activation, are crucial for maintaining homeostasis of pCO2, pO2, and pH. Motivated by these findings, our objective is to use HoMod to test our general hypothesis: reduced resting CBF and NVC in the elderly impair brain function via loss of pCO2, pO2, and pH homeostasis. Preliminary findings from human brain PET and MRI group datasets strongly support this hypothesis, however same subject measurements of OEF, NVC, and NMC are needed for validation and extension to resting state fluctuations. Our approach pursues prospective calibrated fMRI and fMRS studies in young and elderly subjects, and extends and further validates HoMod, through the following aims. Aim 1: Use HoMod to calculate pCO2, pO2, and pH maps in young and elderly subjects from resting awake OEF maps measured with calibrated fMRI at 3T to determine if there is loss of homeostasis in elderly subjects. Aim 2: Use fMRS and calibrated fMRI at 7T to determine if there are age associated reductions in NMC and NVC during visual stimulation, and use HoMod to assess impact on homeostasis. Exploratory Aim: Measure amplitude of calibrated fMRI resting state fluctuations at 3T, calculate NVC, and estimate possible age associated homeostasis alterations during fluctuations. Achieving these aims is highly impactful for brain aging research and beyond because HoMod is an emerging methodology that allows for the first time assessing whether abnormal NMC and NVC lead to loss of pCO2, pO2, and pH homeostasis. Such an opportunity is potentially critical to determine the impact of homeostasis on brain cognitive health in aging, as well as to guide potential interventions to improve or preserve brain health in aging and in other neurological conditions such as dementia, stroke, traumatic brain injury and cancer.

NIH Research Projects · FY 2025 · 2024-08

Project Abstract The HIV/AIDS associated fungal pathogen Cryptococcus neoformans (Cn) is responsible for 20% of global HIV-related mortality and has been designated on the World Health Organization Critical Fungal Patho- gens list. Cn is the causative agent of cryptococcal meningitis (CM), a severe infection of the central nervous system that causes irreversible neurological damage and death. Mortality rates from CM are >30% depending upon global region. To reduce global mortality from CM, a greater understanding of host immune responses and better in vivo models are needed to produce clinically translatable findings. Cn is found ubiquitously in the environment and inhalation of Cn spores leads to infection of the alveoli and deep pulmonary tissue. In immu- nocompetent individuals, Cn infection is contained within pulmonary granulomas leading to containment of Cn cells. Granulomas are formed through signaling between the innate and adaptive immune responses, specifi- cally between macrophages and CD4+ T cells. Advanced HIV coinfection causes depletion of CD4+ T cells and disrupts the signaling needed to maintain granuloma structure. Granuloma breakdown leads to fungal es- cape and disseminated CM disease. Better understanding of granuloma formation and breakdown can lead to the development of therapeutics to prevent dissemination in immunocompromised individuals. However, cur- rent in vivo models do not replicate human the necrotic Cn granulomas observed in humans. My preliminary data identified C3HeB/FeJ mice as producing Cn granulomas that better recapitulate necrotic granulomas in humans. In addition, these mice have better survival when infected with Cn compared to C57Bl/6 (B6) mice. However, the mechanism and genes that drive this phenotype are unknown. Previous studies using Mycobac- terium tuberculosis (Tb) showed that deficiencies in the immune regulating gene Sp140 is involved in the C3HeB/FeJ necrotic granuloma response against Tb. Therefore, my central hypothesis is that sp140-deficieny is responsible for the production of necrotic Cn granulomas and increased resistance against Cn. To test my hypothesis I propose the following Aims: Aim 1) Determine the role of sp140-deficiency in the immune re- sponse against Cn by measuring differences in survival, fungal burden, Cn blood antigen level, cytokine abun- dances, and immune cell populations; Aim 2) Define the histological and transcriptional profiles of sp140-defi- cient Cn granulomas over time using microscopy and spatial transcriptomics, and determine the mechanisms by which CD4+ T cell depletion leads to granuloma breakdown. These findings will expand our understanding of protective host immune responses against Cn, establish a method for modeling human-like Cn granulomas in mice, and provide insight into the mechanism of granuloma degradation during advanced HIV coinfection.

NIH Research Projects · FY 2025 · 2024-08

Establishing Mechanisms of Benefit to Reinforce the Alzheimer's Care Experience AD/ADRD Roybal Center: EMBRACE https://reporter.nih.gov/search/UduQofL_lECIBvB5y-nUoA/project-details/10875109 Abstract Text Program Summary/Abstract-Administrative Core Robust research infrastructure capable of advancing the science of dementia care interventions in the home and community is necessary. Such infrastructure should reflect the integration of concentrated and synergistic areas of scientific expertise encompassing all components of the NIH Stage Model, dementia care interventions, community engagement, and recruitment and retention. Our proposed AD/ADRD Roybal Center, Establishing Mechanisms of Benefit to Reinforce the Alzheimer’s Care Experience (EMBRACE), addresses this need by assembling an interdisciplinary team that synergizes these areas of expertise to establish a strong research infrastructure to facilitate the science of mechanistically driven dementia care interventions. The primary objective of the Administrative Core (AC) is to provide governance, oversight, and systematic coordination of activities of EMBRACE. The AC will provide focused leadership and structure for all EMBRACE activities including its solicitation, review, awarding, and monitoring of clinical trials; coordination of the External Advisory Committee (EAC); evaluation of the overall Center and progression of awarded Investigators; coordination with the Roybal Coordinating Center to advance the overall mission of NIA’s Roybal Program; and dissemination and network building with other Roybal and NIA-funded Centers. Together, these activities will create a vibrant community of scientists engaged in testing mechanisms of action in dementia care interventions as emphasized in RFA-AG-24-007. The Specific Aims of the EMBRACE Administrative Core are to: 1) Provide governance and administration of EMBRACE; 2) Support the scientific activities and functions of EMBRACE by coordinating solicitation and review of applications with the Behavioral Intervention Development Core; and 3) Facilitate the development of research networks and collaborations within and beyond EMBRACE that advances a mechanistic science of dementia care interventions. In accomplishing these Aims, EMBRACE will in turn achieve its objective of generating extensive and substantive research capacity to advance the development and advancement of potent and mechanistically oriented dementia care interventions in home and community settings across the NIH Stage Model.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Chronic cough affects millions of people in the US and around the world, and has a significant negative impact on quality of life, especially when it is refractory to treatment. Existing treatments for chronic cough can help, but up to 50% of patients have persistent cough symptoms despite receiving standard treatments. Identifying effective treatments for refractory chronic cough aligns with the mission of the NHLBI to advance the treatment of lung and related diseases, enhancing “the health of all individuals so that they can live longer and more fulfilling lives.” A promising approach to treating refractory chronic cough is laryngeal vibrotactile stimulation, which changes sensory input to the larynx with the goal to break the vicious cycle of cough causing laryngeal irritation and increased sensitivity, which in turn causes more cough. Chronic cough is associated with abnormalities in laryngeal sensorimotor cortex activity in areas that can be modulated by the use of laryngeal vibrotactile stimulation. In preliminary findings, the use of laryngeal vibrotactile stimulation was associated with an improvement in cough-related quality of life and cough counts, and participants expressed interest in increased laryngeal vibrotactile stimulation dosing. In Aim 1 of this proposal, dose refinement for vibrotactile stimulation will be performed, using a series of escalating dose conditions. The most favorable dosing will be identified, taking into account acceptability and tolerability for participants as well as changes in cough-related quality of life and objective cough counts. In Aim 2, a pilot randomized controlled trial will be conducted to measure the effect of 4 weeks of laryngeal vibrotactile stimulation use on key cough outcomes. Data on acceptance of randomization and retention will be collected. Changes in cough-related quality of life, cough severity, and objective cough counts will be measured. These aims will be conducted by a multidisciplinary research team with expertise in pulmonology, laryngeal physiology and function, clinical trials, biostatistics, and medical devices, in partnership with an extensive and engaged network of referring providers. Completion of these aims will provide necessary and sufficient information about the feasibility and acceptability of a subsequent randomized clinical trial to definitively test the effect of laryngeal vibrotactile stimulation on refractory chronic cough. In addition, the proposed project will provide a preliminary estimate of the effect of laryngeal vibrotactile stimulation on cough-related quality of life as well as an estimate of the resources needed to conduct a subsequent definitive clinical trial. This study has the potential to lead to a non-invasive, portable, repeatable treatment free of systemic side effects for the millions of people who suffer from refractory chronic cough.

NIH Research Projects · FY 2025 · 2024-08

Abstract Infections of the central nervous system (CNS) cause a disproportionate burden of mortality and morbidity in Sub-Saharan Africa. This D43 training program builds upon an existing, successful multidisciplinary research partnership focused on CNS infectious diseases which has been ongoing since 2005, particularly in the realm of HIV-related cryptococcal meningitis and TB meningitis. This new application proposes a Minnesota-Makerere-Mbarara training program in Uganda for neuro-infectious diseases with multidisciplinary training in clinical research, biostatistics, epidemiology, immunology, microbiology, neurology, ophthalmology, pharmacology, and psychiatry. The meningitis research platform has in the past decade published >150 manuscripts, enabled 3 Ugandans to secure independent NIH research funding as a PI, facilitated funded PhD training for 6 Ugandans, as well as provided research projects and support for 16 Ugandan Master's students. We seek to continue this successful partnership and training portfolio through providing translational research training in the gap after Master's of Medicine (MMed) graduate medical training (i.e. equivalent to a U.S. graduate medical residency) and before PhD training or research faculty posts. We propose a 2-3 year intensive mentored research experiences to publish Master's theses, gain new research skills, generate preliminary data for new projects, and apply for funded PhD training, research grants, and/or faculty appointments. The D43 training faculty draws on 19 primary research mentors of whom, 9 are Ugandan, and 10 are American with a multinational training advisory committee overseeing the D43 program. Specific Aim 1. Expand needed research expertise in Uganda in the areas of neuro-infectious diseases by training at least 12 physician scientists. Post-graduate fellowships represent a current career gap between initial research experiences in MMed graduate medical training and future PhD training positions and/or faculty appointments. Specific Aim 2. Build research capacity in Uganda through workshops and short-term training focused on: scientific communication, leadership, research methodologies, clinical trial experiences, applied biostatistics, and translational laboratory mentored research experiences in Uganda and with short term U.S. exchange visits, as needed. D43 Fellows will have the opportunity to gain clinical trial experience as well as implement nested research projects into ongoing investigator-initiated randomized clinical trials for cryptococcal meningitis, TB meningitis, or advanced HIV disease.

NIH Research Projects · FY 2025 · 2024-08

Project summary Basic research opens the door to better understand, treat, and ultimately prevent existing and emerging public health threats. NIAID has prioritized fundamental research into underpinnings of the HIV-associated chronic immune activation despite the control of viral load by daily antiretroviral medication. Recent findings of the HIV-1 RNA cap hyper methylation reveal a new paradigm of viral RNA regulation that finely tunes viral gene expression for adaptive and sustained virus replication in host immune cells. Revealing preliminary research on a new generation of HIV drug, which compromises replication of HIV clinical isolates without positive selection for drug resistance, has exposed inhibition of host TGS1 hypermethylation of HIV-1 m7G-Cap on RRE- containing RNAs, thus establishing this small molecule will be a powerful molecular probe to investigate the molecular interactions that regulate HIV cap hypermethylation. The HIV intron- containing (ic)RNA, which contains RRE, has been reported to trigger innate immune signaling in myeloid cells, and the communications induce T cell markers of exhaustion. Preliminary data posit the hypothesis icRNA is distinguished by its TMG-Cap, which hosts use to alleviate excessive innate immune signaling. However, it remains poorly understood how the Rev/RRE on the 3’- of viral RNA participates in the cap hyper methylation on the 5’- end. Now, by integrating ample preliminary cryoEM studies, HIV RNA-protein co-precipitations, and documentation of the specialized translation pathway licensed by the hypermethylated HIV-1 m7G-Cap, we propose an innovative and breakthrough model that explains previous controversial observations and unclear mechanism of Rev/RRE functionality at the 5’-end of HIV-1 RNA and in translation control. Specifically, host RNA helicase A (RHA) homo-dimerizes upon binding cognate RNA structures in the HIV-1 RNA through bipartite arrangement that tethers Rev/RRE in proximity to nuclear cap binding complex. Interdisciplinary tools are employed to delve into the basic science of the HIV TMG-Cap pathway linked to Rev/RRE. Our preliminary results posit that dysregulating the TMG- Cap pathway triggers host innate immune signaling leading to outcomes that are advantageous for the host. The overarching project goal is to define the structural basis of the HIV cap hypermethylation regulation for viral post-transcriptional control of gene expression and define its linkage with HIV’s ability to modulate host innate immune signaling. At the project completion, the new information is expected to arm scientists for developing next-wave treatments to neutralize deleterious immune signaling in HIV-immune cell environments.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Ostechondritis dissecans (OCD) is a developmental orthopaedic disease affecting children and young adults. It is characterized by formation of osteochondral flaps or fragments within joints which causes pain and disability and predisposes to early onset osteoarthritis. Although recent studies demonstrated that discrete areas of epiphyseal cartilage necrosis (termed osteochondrosis), caused by focal failure of vascular supply, are the clinically silent precursor lesions of OCD, it is yet to be established how the extent of the inciting vascular failure, along with exposure to biomechanical trauma, determine whether these lesions heal or progress to clinically apparent disease. The overall objective of this proposal is to use porcine models to understand factors that influence the development, progression, and healing of OCD lesions. To achieve this objective, we will use two specific aims to test our central hypothesis that the extent of ischemic epiphyseal cartilage necrosis determines the development of OCD, and that lesion progression is influenced by biomechanical stress. Specifically, our aims have been designed (1) to investigate the relationship between the severity of vascular injury to the femoral trochlear epiphyseal cartilage and the formation and progression of OCD precursor lesions and (2) to determine the role that low vs. high impact biomechanical stress plays in the formation of subclinical osteochondrosis lesions and their progression to clinically apparent OCD. Our study will establish how the extent of vascular failure and exposure to biomechanical stress drive the clinical course of OCD and determine characteristic gene expression profiles across OCD lesion types. Conducting these studies in a large animal model will ensure timely translation of our results to inform clinical decision making in human patients, and will also help establish controlled exercise as a component of non- operative treatment. Importantly, these findings will also have applicability to other juvenile orthopaedic disorders of vascular origin such as Legg-Calvé-Perthes disease.

NIH Research Projects · FY 2024 · 2024-08

Human milk is recommended as the exclusive mode of feeding for infants, but the factors influencing the hundreds of nutritive and bioactive factors in milk and their functions in the infant remain mostly unexplored. A genomics approach enables investigation of human milk as a biological system and can identify the most important factors connecting human milk composition with infant health. One such approach is milk metabolomics, which reflects the biology of the lactating mammary gland and the bioactive and nutritive components of milk that shape its function in the infant. This proposal leverages metabolomics and other cutting edge technologies to comprehensively profile the composition of human milk and its impacts on infant development. The results will provide foundational data for advancing milk research and help advance our knowledge of human nutrition during the critical first 1000 days of life. Aim 1 will identify genetic variants influencing specific milk metabolites and the genes underlying these associations, and investigate connections between the milk metabolome and infant gut microbiome. In Aim 2, the effect of human cytomegalovirus (HCMV) reactivation in the mammary gland on the milk metabolome will be assessed. HCMV is a highly prevalent virus, and postnatal exposure to HCMV via breast milk often has serious clinical consequences for preterm infants. This aim will also test for impacts of mammary HCMV reactivation and the milk metabolome on infant serum markers of inflammation. The first two aims will occur primarily during the K99 period, and will be accompanied by training in virology, immunology, and computational methods for integration of multimodal datasets. Aim 3, during the R00 phase, will investigate the impacts of human milk composition on the systems-level development of the preterm infant immune system and gut microbiome, utilizing a new cohort of preterm infants. Longitudinal sample collection will enable disentangling of the connections across these dynamic biological systems. Training in the K99 period will take place at the University of Minnesota – Twin Cities, a major research institution, with state-of-the-art core facilities for genomics and clinical/translational research. The PI will receive training from an interdisciplinary team of mentors in the departments of Pediatrics, Epidemiology & Community Health, and Genetics, Cell Biology and Development. This training plan will result in the trainee acquiring the skills and a scientific foundation to launch an independent academic career.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Chronic respiratory diseases (CRD), such as asthma and chronic obstructive pulmonary disease, impact over 554 million people worldwide and are major contributors to the non-communicable disease burden in the United States. Individuals with CRD show pronounced disparities in disease risk by factors such as age, sex, community type, and environment. Air pollution is one environmental risk factor of concern with nearly 135 million people in the U.S. residing in counties experiencing poor air quality. Evidence suggests that air pollution regulatory standards, despite their design to protect public health, may be inadequate for CRD populations who exhibit elevated sensitivity to even low levels of air pollution exposure. It is critical to estimate air pollution health effects, specifically for vulnerable populations, and identify the underlying and unexplored factors that elevate risk, including the intersection between personal and community-level disadvantage. Minimizing vulnerabilities across groups and by environment is a core principle of environmental justice. Our central hypothesis is that individuals with diagnosed CRD represent a high vulnerability population who display increased mortality risk from acute exposure to fine particulate matter (PM2.5) and ozone air pollution. An additional emphasis is to identify which individual and neighborhood characteristics increase air pollution inequities among CRD patients and unpack their joint contribution to poor health outcomes. To test our hypothesis, we will utilize 20 years of records from the Veterans Health Administration (VHA) and spatiotemporally align individual patient data with state-of-the-art high-resolution air pollution models, environmental metrics, and community sociodemographic and social vulnerability characteristics. Detailed VHA records provides data innovations absent from many large cohorts, including diagnosis of comorbidities, geocoded home addresses to reduce exposure misclassification, and individual characteristics and behavior, such as smoking status and body mass index. In Aim 1, we will estimate the mortality risk in CRD populations attributed to daily PM2.5 and ozone exposure and identify individual characteristics that exacerbate susceptibility. In Aim 2, we will evaluate the intersection between individual vulnerabilities and neighborhood inequities for air pollution associated mortality risk in CRD populations and estimate the differential risk of these contributing causes. In Aim 3, we will estimate the association between air pollution exposure and underlying mortality cause, and quantify non-linear exposure-response relationships, including low-dose exposures. Our research will have a meaningful public health impact by informing air quality regulations as they pertain to individuals with CRD and provide evidence for behavioral interventions and treatment of CRD populations to reduce mortality risk. As a modifiable risk factor, reductions in air pollution will disproportionately benefit CRD individuals and reduce potential health disparities in this high vulnerability group.