University Of Arizona

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY Several transition metals are essential nutrients in human physiology: their acquisition and distribution are highly regulated, and alterations of metal homeostasis are associated with multiple pathological conditions including neurodegeneration and cancer. Metal-binding pharmaceuticals are employed clinically to treat metal overload; however, these chelators target systemic metals rather than intracellular metal dysregulation. Our research program aims at the design of chelation systems to increase the current understanding of metals in disease conditions and to modulate metal dysregulation for therapeutic applications in the long term. Our current experimental focus is on the role of iron in cancer progression. Because malignant cells require higher iron levels to sustain fast proliferation rates, we are engineering antiproliferative chelators that are activated upon cellular uptake to interfere with the availability of the labile iron pool. We employ disulfide bonds and arylsulfonate moieties as activation switches in prochelators that are activated following reaction with abundant thiols intracellularly. Exploiting the physiological differences between malignant and normal cells, we design bioconjugation approaches that increase the selectivity of prochelators for cancer cells. Further enhancing selectivity, we will also pursue the activation of prochelators by specific proteins that are overexpressed (or uniquely expressed) in cancer cells. In addition, we will deploy pro-oxidant strategies that enlist the redox chemistry of chelator-bound iron and copper complexes to generate reactive oxygen species in targeted cells. A new class of prochelators based on tetrazolium cations will be employed to pilot an initiative to image iron chelation via photoacoustic methods. Our experimental approach blends principles of coordination chemistry and chemical biology to produce a new generation of advanced chelation strategies. Detailed mechanistic studies will delineate the cellular uptake of our prochelators as well as their impact on cell cycle, cell death, and iron signaling. Because iron is a fundamental player in malignant behavior, this research offers opportunities to impact a broad spectrum of cancer phenotypes. These molecular design strategies are poised to enhance the scope of chelation in cancer research and potentially in other pathological conditions associated with metal dysregulation.

NIH Research Projects · FY 2026 · 2024-04

Abstract Atrial fibrillation (AF) is the most common arrhythmia especially in the aging population. It is associated with increased risk of mortality and morbidity. At the present time, management of AF has focused on risk factor modification, rate or rhythm control and anticoagulation. Evolution of clinical trials in the management of AF have revealed that ablation seems superior in reducing the burden of AF and controlling the symptoms compared to pharmaceutical agents. However, the benefit of ablation decreases over time and patients frequently require more than one ablation. Earlier ablation in the course of the disease is more beneficial as failure of therapy is related to duration of AF and size of left atrium. After two decades of investigations with varying methods of ablation, we have only marginally improved the clinical outcome. The ablation procedure is time consuming and only a fraction of patients are undergoing this procedure. A robust criterion of prediction of successful ablation will be beneficial for patient selection and maximize the utilization of invasive therapies. With this highly collaborative and multiscale study, our long-term goal is to develop effective models and discover factors that indicate severity of AF that can be helpful as therapeutic targets and to predict prognosis. Our objective is to identify patients who have increased risk of recurrence after ablation for AF by taking advantage of the intracardiac electrograms from left atrial map and inflammatory biomarkers from blood samples obtained pre-procedure. The central hypothesis is that domain-specific machine learning/ artificial intelligence algorithms derived from multimodal data can predict the type of AF, severity of AF as indicated by abnormal areas in the left atrium and clinical outcomes of AF ablation. To directly test the hypothesis, we will enroll prospective consecutive consenting patients who present for AF ablation therapy. Pre-and post-ablation left atrial map and blood samples drawn for biomarker analyses will be used for study purposes.

NIH Research Projects · FY 2026 · 2024-03

ABSTRACT Despite advances in neonatology, necrotizing enterocolitis (NEC) remains the most common GI emergency of premature infants with significant morbidity and mortality. The pathophysiology of NEC is unclear, non- surgical treatments are mainly supportive, and no predictive tests are currently available. In experimental models of NEC, we have shown that bile acids (BA) play a critical role in NEC pathogenesis. Recently, using prospectively collected, serial fecal samples from premature infants, we have shown that infants who develop NEC have significantly higher coefficient of variation of total fecal bile acids (CV-TBA) than matched controls. Importantly, these variations occur well prior of diagnosis. We hypothesize that variation of TBA can predict development of NEC and aim to build and validate predictive models from daily fecal samples collected from the NICUs at Banner University Medical Center - Tucson and Vanderbilt University Medical Center. Successful completion of this proposal could lead to implementation of the first predictive test for this devastating disorder.

NIH Research Projects · FY 2025 · 2024-03

Neisseria gonorrhoeae and Neisseria meningitidis affect more than 100 million people worldwide every year, despite the existence of treatment and prevention methods. The emergence of antimicrobial resistance will curtail our ability to effectively manage these infections, making it critical to expand our knowledge of Neisseria biology. Commensal Neisseria provide a tool by which we can dissect one common but poorly understood facet of pathogenic Neisseria behavior, asymptomatic infection. N. gonorrhoeae and N. meningitidis descended from a commensal ancestor and share many host interaction factors with human adapted commensal Neisseria. The central hypothesis of this application proposes that the mechanistic roots of Neisseria asymptomatic infection are commensal in origin, and that the study of conserved host interaction factors provides insight into commensal colonization and asymptomatic infection alike. To test this, I utilize a mouse-Neisseria model of asymptomatic carriage to systematically evaluate a subset of conserved host interaction factors, guided by preliminary data obtained from a transposon mutagenesis and screening approach. In Aim 1, I examine the impact of Type IV pilus retraction during host modulation and inter-bacterial signaling. In Aim 2, I evaluate the contribution of previously uncharacterized polysaccharide biosynthesis genes on structure and function of commensal capsule. In Aim 3, I test the activity and repertoire of a putative Neisseria Type XI secretion system homolog to identify novel surface expressed host interaction factors. My career development strategy supports my research goals through a rigorous schedule of workshops and trainings on grant writing, laboratory management, and mentorship. These activities are designed to help me successfully transition to independence, making me uniquely positioned to improve our understanding of Neisseria-host interaction

NIH Research Projects · FY 2026 · 2024-02

Climate change is increasing the risk of wildfires which frequently extend into the wildland-urban interface (WUI). WUI fires burn a mixture of vegetation, structures and vehicles and there is a marked research gap regarding population exposures and health effects. Woodsmoke contains a toxic mixture of known and suspect carcinogens including but not limited to benzene, aldehydes, and polycyclic aromatic hydrocarbons (PAHs). However, wildland fire exposure monitoring has generally been limited to particulates for the general public and PAHs for firefighters. Firefighters, a high exposure group, are requesting participatory research to measure WUI fire exposures and effects and identify effective interventions. Silicone wrist bands can measure exposure beyond PAHs, and urine metabolomics can identify both exposures and effects. While cancer or other diseases caused by firefighting exposures can take many years to develop, metabolomic and epigenetic (microRNA and DNA methylation) endpoints can serve as sub-clinical biomarkers of toxicity. Interventions of firefighter interest include rapid provision of exposure data, improved personal protective equipment (PPE), more rapid dermal decontamination, and administrative controls. We hypothesize that: a) use of silicone wristbands and targeted urinary analyses (hydroxylated PAHs) will identify high-exposure settings and activities, and that untargeted metabolomics will reveal novel environmental compounds of concern; b) the urine metabolome and microRNAs will change acutely with exposures and cumulative exposures will be associated with long-term DNA methylation changes in firefighters; and c) interventions chosen by firefighters will significantly reduce exposures. We will test these hypotheses through evaluating firefighter exposures during WUI responses, measuring toxic effects, and evaluating interventions to reduce exposures. Our fire service research champions have enrolled Los Angeles County and Orange County firefighters who could respond to WUI fires in the Fire Fighter Cancer Cohort Study (FFCCS), a fire service-academic community-engaged research collaborative. For the proposed research we will measure exposures of firefighters during WUI responses using silicone wristbands and pre- and post- exposure urine for targeted (hydroxylated PAHs) and untargeted (metabolomics) analyses. Occupational fireground characteristics (type of fire, PPE, time at fire, activities) will be recorded. Using urine and blood collected at baseline and post-exposure, we will evaluate acute effects with changes in endogenous metabolites (pre/post urine) and microRNA (pre/post blood). Longer-term changes in DNA methylation will be evaluated comparing baseline blood samples to three years afterwards. Exposure reduction interventions selected by the fire service will be evaluated comparing intervention and activity control groups with pre- and post-exposure wristband and urinary PAH metabolite measurements. We anticipate that the proposed research will provide a more complete measure of the WUI fire exposure and associated toxicity, and identify interventions that significantly reduce chemical exposures to firefighters and inform overall public health responses.

NIH Research Projects · FY 2026 · 2024-02

ABSTRACT Adolescence is a time of substantial development attributed to the maturation of brain circuits that underlie the acquisition of new cognitive, emotional, and social skills. It is also a time of maximum vulnerability for mental disorders. In the past decade, the incidence of anxiety, depression, and suicide increased by ~60% in adolescents, remarkably more in females than in males. The social isolation during the COVID-19 pandemic added to the severity of the national and international statistics. To fully address the current youth mental health crisis, we need to understand how and why the dramatic reorganization of the adolescent brain contributes to the increased vulnerability to mental disorders. The studies proposed here rest on the assumption that the remodeling of the reward circuits of the brain creates the shared foundation of cognitive, affective, and social maturation during adolescence. Our multifaceted project addresses foundational gaps in our knowledge on how reward-driven motivational states inform adolescent behaviors such as risk-taking, pleasure-seeking, impulsivity, and a range of emotional responses to challenges of the social environment. We designed a within-subject, longitudinal study that spans the 2.5 - 3-year duration of adolescence in non-human primates. During this period, we will obtain repeated samplings of neurophysiological data recorded from the amygdala and orbitofrontal cortex in the context of the same behavioral tasks. In parallel, we will longitudinally monitor morphometric and microstructural changes in the gray and white matter of the brain through serial MRI scans, complemented by physical and hormonal measures of pubertal maturation. The three specific aims address the neural basis of three different aspects of reward processing in the subcircuit of the amygdala and orbitofrontal cortex. First, we will use a delay discounting task to determine the cellular and circuit level changes that underlie the increasing tolerance (or lack thereof) for delayed rewards. Second, we use a social reward-allocation task to test the neural underpinning of social reward processing in a self-oriented and an other-oriented social frame of reference. Finally, we will determine where and how social status is processed in the adolescent brain. Understanding social status relies on the ability to form abstract representations and is also a prerequisite for the successful integration of the individual into a hierarchical adult social group. The team, with combined expertise in human and non-human primate social behavior, neurophysiology, neuroimaging, and endocrinology, will apply conceptually and technically innovative approaches to generate unique and translational data, at both cellular and circuit levels, that account for the emerging cognitive, affective, and social skills acquired during adolescence.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY/ABSTRACT (limit 30 lines of text) Cleaning and disinfection (C&D) activities pose work-related asthma (WRA) risks for nurses. C&D involves an inherent “risk-risk tradeoff”: increased C&D leading to increased WRA risks and simultaneous decreased occupational infection risks. Our preliminary data from a risk-risk tradeoff survey indicate that nurses are generally willing to increase infection risks to maintain lower asthma risks, if they think they think they will recover. Translating these concerns to C&D protocol changes is challenging due to logistical constraints and lack of awareness about asthma risks from C&D. My long-term goal is to advance methodologies for relating tolerable occupational respiratory disease risks to public health policy interventions. Specific training aims are proposed: 1) Develop independent competency in designing behavioral economic surveys for studying risk perceptions and risk tolerances of WRA, 2) Develop independent competency in conducting health policy analyses in intervention contexts with qualitative methods, 3) Apply bioethics and public health policy principles to risk-risk tradeoff methodologies for assessing evaluations of WRA risk and risk perception. These training aims will be accomplished through formal coursework, involvement in the American Thoracic Society, qualitative research and health policy trainings, and assigned readings and discussion with mentors. The University of Arizona is an ideal environment for the proposed training, offering opportunities for training through faculty at the Asthma & Airway Disease Research Center and the Southwest Environmental Health Sciences Center. This training will be applied through 3 specific research aims: 1) Administer a C&D risk-risk tradeoff survey to 1,000 nurses in the state of Arizona to collect data for microbial risk assessments, 2) Understand barriers to C&D policy changes in the workplace, 3) Identify, describe, and assess C&D policy options with health policy analysis. Aim 1 will involve adaption of a current risk-risk tradeoff survey and recruitment of 1,000 registered nurses. These data will be used in a microbial risk assessment to inform the needed frequency and intensity of C&D to achieve acceptable risks. Aim 2 will involve interviews with registered nurses (n=40) and key informant interviews with facilities management, legal and workers’ compensation staff, occupational health specialists, and infection preventionists (n=2-3/group). Aim 3 will involve the use of a policy Delphi method (n=75). Translating risk-risk tradeoff analysis to inform C&D policies will increase the impact of behavioral economics translation in respiratory occupational health research. Understanding barriers to C&D protocol changes and identifying feasible policy change strategies will inform future efforts (NHLBI R01) to quantify acceptable OA and infection risks, including the perspectives of patients, to implement and evaluate C&D policy changes nationally.

NIH Research Projects · FY 2025 · 2024-02

PROJECT SUMMARY Approximately 7.5 million American women are unable to become pregnant or carry a baby to term (impaired fecundity). The ovary is considered a critical target organ in infertility cases based on the large number of women seeking infertility treatment who are unable to release a viable egg from their ovaries. Folliculogenesis is the process through which ovarian follicles, the functional units of the ovary, develop into a form capable of sustaining hormone production and ovulating a healthy egg for fertilization. Any environmental exposure that causes damage to the ovarian follicle has the potential to impair fecundity in women. Most of what is known about toxicity to ovarian follicles has been uncovered in laboratory rodents, but there is little available data on toxicant exposure and related mechanistic toxicology studies in the nonhuman primate, the closest laboratory animal model to humans. There is, therefore, a critical need to develop alternative approaches and tools that synergize the accessibility and versatility of laboratory rodents with the physiological relevance of the nonhuman primate to deliver high quality ovarian follicle toxicity data. To meet this need, this proposal will support the formation of a virtual research consortium with expertise in mouse and nonhuman primate ovarian biology, toxicology and computational modeling. The proposed consortium will generate lab-based data on the physiological and toxicant-induced behavior of ovarian follicles in both species, using phthalate as a model toxicant, to create computational models capable of effectively predicting ovarian follicle responses to chemical insults in nonhuman primates. The experimental measures captured in the in vitro and in vivo model will be specifically chosen to align with the needs of the modelers. To achieve this goal, the proposed consortium will complete three specific aims. Specifically, the ovarian biology/toxicology team will quantify the physiological and toxicant-induced behavior of computationally useful markers of in vivo and in vitro folliculogenesis in mice (Aim 1) and nonhuman primates (Aim 2), while the computational modeling team will construct in silico models that match the physiological behavior of folliculogenesis in each species and predict follicular responses to phthalate insults in both species. Our virtual consortium includes researchers from five institutions and will create a transdisciplinary group that includes both experimental and computational expertise. The tight coupling of these two domains will provide the needed communication pathways to develop translational models for IVIVE as well as cross-species extrapolations in reproductive toxicology.

NIH Research Projects · FY 2025 · 2024-01

PROJECT SUMMARY/ABSTRACT Despite cardiovascular disease (CVD) being the leading cause of death in the U.S. and worldwide for over a century, traditional risk factors (e.g., diabetes, blood pressure, cholesterol) account for only 50% of the variance in CVD outcomes. Over four decades of research provide robust, replicated, consistent evidence that psychological stress is linked to CVD outcomes and hypothesized behavioral and biological paths of risk. Thus, there is a critical need for understanding how stress gets “under the skin” to cause CVD. This work begins with an ecologically valid understanding of how stress is experienced and connotes risk. One major contemporary theory, the Generalized Unsafety Theory of Stress (GUTS), conceptualizes stress as a “default state” of emotion with concomitant physiological sequelae. Robust data supports GUTS framework by demonstrating associations between structural indicators of contextual safety, acute stress reactivity profiles, and risk of heart disease. Another major contemporary model, Social Safety Theory (SST), also points to the importance of perceived indicators of security. SST emphasizes the human propensity for social engagement, positing exposure to perceived social threat drives physiological stress reactivity and perception of available social safety cues moderates such stress responses. Extensive work supports perception of social safety and exposure to social threat as contributors to inflammatory stress response patterns associated with CVD progression. Both theories suggest humans are in a constant state of environmental safety evaluation or “vigilance” influencing a constellation of behavioral, physiological, and psychological reactions. The overarching goal of this proposal is to investigate, for the first time, a harmonized model detailing stress as an ecologically valid risk determinant of CVD. I will use existing longitudinal data from an NHLBI-funded R01 to address this goal through three aims. Under aim 1, I investigate the relationship between environmental safety, social safety, daily social vigilance, and 2-year change in carotid intima-media thickness (cIMT) as a preclinical marker of CVD. With aim 2, I examine the extent to which social vigilance mediates associations between environmental safety, social safety, and 2-year change in cIMT. Finally through exploratory aim 3, I characterize how blood pressure and inflammatory markers account for relationships among environmental safety, social safety, daily social vigilance, and 2-year change in cIMT. A highly experienced mentorship team of investigators will support my research and training to become a leading psychosocial mechanism scientist contributing to understanding nontraditional determinants of CVD. Through the proposed training opportunities, I will: 1) deepen conceptual understanding of contemporary stress models related to cardiovascular health; 2) develop methodological understanding of key pathways from stress to disease; 3) gain advanced knowledge in CVD etiology; 4) enhance my professional development and research dissemination; and 4) improve my grantsmanship skills and apply for future grant support.

NIH Research Projects · FY 2025 · 2023-12

Three major thyroid hormone receptor (THR) isoforms, expressed from two genetic loci (Thra and Thrb), are present in mammals: THRA1, THRB1, and THRB2. Thyroid hormone (TH) acting through THRs regulate food intake metabolism and the hypothalamic-pituitary-thyroid (HPT) axis in man. Our laboratories have long been interested in the THRB2 isoform as a central regulator of the hypothalamic-pituitary-thyroid (HPT) axis, given its unique and limited-expression pattern. We recently found that THRB2 is heavily phosphorylated by both TH and AMP kinase (AMPK) at an N-terminal serine site (S101-mouse, S102-human), not found in other THRs. Based on increased food intake, obesity, and TH resistance in mice carrying a mutation of this phosphorylation site (S101A), we hypothesize that an AMPK-dependent THRB2 S101 phosphorylation pathway in the hypothalamus suppresses food intake and the HPT axis. We also hypothesize that dysfunction of this pathway results in leptin resistance, increased food intake, and obesity (Fig. 1). Three closely related aims are proposed: Specific Aim 1: Functionally co-localize hypothalamic THRB2 and AMPK action on feeding. Both the arcuate (ARC) and ventromedial nucleus (VMN) regulate feeding in a THRB- and AMPK-dependent manner. To begin to functionally localize THRB2 action in the hypothalamus, THRB2 will be removed from the POMC neurons in the ARC and SF-1 neurons in the VMN using Thrb2 floxed mice and cell-specific Cre drivers. Cell- specific KO of AMPKa2 in the same neurons will also be performed to understand AMPKa2’s role in feeding and in the p-THRB2 pathway. Both male and female mice will be studied, given higher THRB2 expression in female HA-tagged THRB2 mice. Specific Aim 2: Determine the role of THRB2 phosphorylation in feeding and mediating hypothalamic leptin signaling. Previous studies have clearly demonstrated that leptin regulates both the HPT axis and feeding. A potential mediator of leptin action is p-THRB2, given that S101A mice demonstrate leptin resistance. A phospho-specific antibody was developed to probe this pathway further and will be used in a time- course study of THRB2 phosphorylation during the fed-fasting transition. Furthermore, a phosphomimetic S101D KI mouse model was generated to determine if this change protects against diet-induced obesity. Specific Aim 3: Define the locus of TRH regulation by THRB2 during fasting. While fasting-induced suppression of the HPT axis is mediated by reduced TRH expression in the paraventricular nucleus (PVN), it remains unknown how HPT axis suppression is maintained in the setting of low TH levels. Strikingly, S101A mice display resistance to fasting-induced TRH suppression, suggesting that THRB2 S101 phosphorylation is critical in the sensing of low TH levels. This aim will determine the locus of fasting-induced and TH-dependent TRH suppression by targeting neurons in the ARC and PVN. The mechanism of suppression will be explored further by studying if THRB2 phosphorylation is a common mechanism regulating the HPT axis and food intake.

NIH Research Projects · FY 2025 · 2023-12

Project Summary Microbial communities are dynamic and are influenced by a broad suite of biotic and abiotic factors. One of the most important factors providing structure to microbiomes are direct interactions among members of these communities, and therefore a deeper understanding of the molecules produced by and which affect other microbes as well as resistance mechanisms to these molecules will greatly inform our ability to engineer microbial communities. Bacteriocins are molecules produced by bacterial cells that are thought to specifically target different strains of the same species or closely related species. Tailocins are a subset of bacteriocins coopted from phage tails, which are durable, possess highly specific killing activities, maintain one-hit-one-kill dynamics, and appear to be effective prophylactic treatments for preventing bacterial invasion of plants. The Baltrus lab has broadly characterized a class of phage derived bacteriocins produced by the plant pathogen Pseudomonas syringae as well as other Pseudomonads, and we show that the host range of some of these molecules is broader than originally thought in that they can target some human pathogens that are often found associated with plants. Specifically, we have discovered that Pseudomonas sp. 43A maintains tailocin-like killing activity specifically against E. coli O157:H7 and not against a variety of other E. coli or Salmonella strains. Experiments within this proposal will confirm and characterize the genetic basis of this tailocin-like killing of E. coli O157:H7. Overall, experiments within this proposal could allow for fine scale engineering to enable tailocins to specifically and effectively target human pathogens associated with plants while avoiding off target effects associated with other agricultural antimicrobial treatments.

NIH Research Projects · FY 2025 · 2023-09

Methadone Patient Access to Collaborative Treatment (MPACT) is a staff-level trauma-informed practice change intervention for US opioid treatment programs (OTP). It is based on the theory that current OTP practice and culture likely contribute to the wide ranging methadone maintenance treatment (MMT) interruption (>30%) and relapse (>50%) rates known to increase opioid overdoses. OTP treatment culture has been described as “carceral,” and “not healthcare,” with patients reporting being bound to the clinic by required daily supervised medication dosing. Changes in OTP practices have been called for, but are recognized as ‘almost impossible.’ US federal regulatory flexibilities intended to facilitate OTP practice change during COVID did not result in wide-spread or sustained MMT delivery changes or service accommodations such as increased multi-day dosing for stable patients, less frequent urine analyses, or even telehealth. These accommodations would be highly beneficial to rural and home-bound patients. Evidence- based OTP practice change interventions are necessary if the US is going to effectively respond to the opioid overdose crisis. If this lifesaving treatment is available but not well used, we must look to the practice and culture of OTPs. Lack of practice change may be due to staff beliefs and experiences, including their own histories of substance use disorder treatment, traumatic experiences, and on-the-job exposure to vicarious trauma. When staff trauma is addressed, we expect OTP practice orientation will shift from punitive to harm-reduction/patient-centered. MPACT is designed to increase MMT retention and decrease in-treatment overdose and patient- and staff- reported posttraumatic stress symptoms (PTSS). MPACT has four evidence-based components: 1) a 4-module CME/CEU- accredited trauma-informed psychoeducation training program for OTP staff, 2) a trauma navigation model for patients and staff, 3) clinic trauma-informed care (TIC) self-assessment, and 4) separate reflective supervisory structures for counselors/case managers and medical providers. For this proposal, MPACT components will be adapted for OTP settings with patients and providers in a multilevel, trauma-informed planning process with guidance from the Arizona transdisciplinary Drug Policy Research and Advocacy Board comprised of methadone and buprenorphine providers, patients, people with lived/ing drug use experience, harm reduction NGOs, payers, trauma experts, and university researchers. MPACT will be finalized in year 1, pilot tested and refined in year 2, and tested in a cluster-randomized controlled intervention trial in OTP sites across the US in years 3-6. The primary means of gathering data are surveys pushed to staff and patients (baseline and monthly) and retrospective patient chart reviews. We enter a period of unprecedented regulatory change for MMT delivery. MPACT can facilitate and support MMT reform efforts that are planned or already in process. The future of OTPs and methadone treatment depend upon evidence-based OTP practice change interventions. The pivotal question is: Can OTPs adopt Trauma Informed Care (TIC) and, if so, does it improve patient outcomes? MPACT seeks to answer this question in a high risk/high reward proposal. If the answer is YES, then MPACT will be immediately implementable and scalable for any OTP in the US.

NIH Research Projects · FY 2024 · 2023-09

Project Abstract Human cytomegalovirus (HCMV) is a prevalent herpesvirus that establishes lifelong infection. HCMV infection causes severe disease in immunocompromised individuals and is a leading cause of congenital disabilities. Like all viruses, HCMV relies on host metabolism for the building blocks of viral replication, such as nucleotides for viral genome synthesis, amino acids for viral proteins, and lipids for the virus membrane. HCMV is highly species-specific, which limits molecular investigation of virus replication to cell culture models of infection. Prior research on HCMV metabolic remodeling of host metabolism utilized high nutrient culture media with a focus on obtaining optimal virus production. However, high nutrient media that supports optimal virus replication does not recapitulate the nutrient environment in the human body. This project will address this drawback by identifying how low nutrient environments alter nutrient utilization to support HCMV replication. I hypothesize that HCMV can replicate to sub-optimal levels in diverse nutrient environments via metabolic flexibility. I am initiating these studies by focusing on glucose utilization and alternative nutrient flow in glucose-free cultures during HCMV infection. Preliminary data demonstrate that viral genome synthesis, viral protein levels, and virus production are decreased during glucose deprivation. Rescuing viral genome levels does not restore virus production, suggesting that glucose supports multiple steps of virus replication. While lipids are normally made from glucose during HCMV replication, I found that lipids are synthesized during HCMV infection despite the loss of glucose, suggesting that alternative nutrient flow is occurring. In aim 1, I will determine how glucose loss impacts HCMV replication stages. These studies will define the stages of virus replication that require glucose and will determine which nutrients can compensate for glucose to support virus replication. In aim 2, I will identify how glucose loss alters nutrient flow to support lipid synthesis during HCMV replication. This work will determine if glutamine is compensating for glucose for lipid synthesis and investigate how glucose levels impact nutrient flow. These studies build upon prior research that identified the complexities of HCMV metabolic control. The resulting discoveries will increase our understanding of metabolic remodeling and alternative nutrient use during HCMV replication while providing insight for developing a more physiological-relevant model of HCMV interaction with host metabolism.

NIH Research Projects · FY 2024 · 2023-09

Methadone Patient Access to Collaborative Treatment (MPACT) is a staff-level trauma-informed practice change intervention for US opioid treatment programs (OTP). It is based on the theory that current OTP practice and culture likely contribute to the wide ranging methadone maintenance treatment (MMT) interruption (>30%) and relapse (>50%) rates known to increase opioid overdoses. OTP treatment culture has been described as “carceral,” and “not healthcare,” with patients reporting being bound to the clinic by required daily supervised medication dosing. Changes in OTP practices have been called for, but are recognized as ‘almost impossible.’ US federal regulatory flexibilities intended to facilitate OTP practice change during COVID did not result in wide-spread or sustained MMT delivery changes or service accommodations such as increased multi-day dosing for stable patients, less frequent urine analyses, or even telehealth. These accommodations would be highly beneficial to rural and home-bound patients. Evidence- based OTP practice change interventions are necessary if the US is going to effectively respond to the opioid overdose crisis. If this lifesaving treatment is available but not well used, we must look to the practice and culture of OTPs. Lack of practice change may be due to staff beliefs and experiences, including their own histories of substance use disorder treatment, traumatic experiences, and on-the-job exposure to vicarious trauma. When staff trauma is addressed, we expect OTP practice orientation will shift from punitive to harm-reduction/patient-centered. MPACT is designed to increase MMT retention and decrease in-treatment overdose and patient- and staff- reported posttraumatic stress symptoms (PTSS). MPACT has four evidence-based components: 1) a 4-module CME/CEU- accredited trauma-informed psychoeducation training program for OTP staff, 2) a trauma navigation model for patients and staff, 3) clinic trauma-informed care (TIC) self-assessment, and 4) separate reflective supervisory structures for counselors/case managers and medical providers. For this proposal, MPACT components will be adapted for OTP settings with patients and providers in a multilevel, trauma-informed planning process with guidance from the Arizona transdisciplinary Drug Policy Research and Advocacy Board comprised of methadone and buprenorphine providers, patients, people with lived/ing drug use experience, harm reduction NGOs, payers, trauma experts, and university researchers. MPACT will be finalized in year 1, pilot tested and refined in year 2, and tested in a cluster-randomized controlled intervention trial in OTP sites across the US in years 3-6. The primary means of gathering data are surveys pushed to staff and patients (baseline and monthly) and retrospective patient chart reviews. We enter a period of unprecedented regulatory change for MMT delivery. MPACT can facilitate and support MMT reform efforts that are planned or already in process. The future of OTPs and methadone treatment depend upon evidence-based OTP practice change interventions. The pivotal question is: Can OTPs adopt Trauma Informed Care (TIC) and, if so, does it improve patient outcomes? MPACT seeks to answer this question in a high risk/high reward proposal. If the answer is YES, then MPACT will be immediately implementable and scalable for any OTP in the US.

NIH Research Projects · FY 2025 · 2023-09

The All of Us Research Program has created a national research dataset unprecedented in size and scope to advance precision medicine. However, data utilization is not yet commensurate with the power and potential reach. All of Us’ innovative cloud-based, centralized data governance requires broad professional development training for researchers, with a focus on informatics literacy and technical resources to support analysis within the All of Us Researcher Workbench (AoURW). The University of Arizona (UArizona)-Banner AoU team will address this challenge through five Aims derived from our extensive experience leading interdisciplinary scientific teams to utilize AoURW and creating programs to engage researchers in biomedical and health sciences research. Aim 1: Advance and manage our Biomedical Informatics Core (BIC) support team dedicated to assist All of Us researchers nationally and empower them to conduct research in the AoURW. Aim 2: Maintain and expand the All of Us Data Fellows program to train and mentor researchers in leveraging the AoURW and subsequently engage in outreach at their own institutions to promote All of Us-focused research projects and awareness. Aim 3: Maintain an Advisory Council (AC) to oversee all initiatives. Aim 4: Maintain our existing partnership with the Pharmacogenomics Global Research Network (PGRN) to engage researchers in precision medicine. Aim 5: Aid All of Us in improving the AoURW to ensure data and resource availability and usability. Aims 1-5 will cultivate an active and sustainable pool of All of Us-focused researchers empowered by our resources and AoURW’s directive to advance precision medicine. We will engage researchers to utilize the AoURW using active engagement strategies, while maintaining the flexibility to work with existing All of Us partners and extend All of Us resources. Our UArizona-Banner All of Us team will assess the impact of our activities, disseminate promising practices to the broader scientific community, evaluate our initiatives against All of Us programmatic objectives, and ensure that our researchers’ perspectives inform AoURW development—driving All of Us further toward scientific discovery.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY Dysmenorrhea is a prevalent pain condition and a risk factor for developing other chronic pain conditions. Dysmenorrhea experiences vary significantly among individual women. Some women are symptom-free, and those with symptoms fall into three dysmenorrhea symptom phenotypes: mild localized pain, severe localized pain, and multiple severe symptoms. The mechanisms underlying this individual variation remain incompletely understood, creating barriers for expanding and personalizing dysmenorrhea treatment options. Given the role of the vaginal microbiota in inflammation and female reproductive health and the proof-of-concept data linking vaginal microbiota and dysmenorrhea phenotypes, the study of vaginal microbiota and their function is a promising avenue to understand individual differences in dysmenorrhea. Our central hypothesis is that vaginal microbiota contributes to dysmenorrhea symptoms by modulating the host inflammatory response in the genital tract. The purpose of this proposed, prospective, longitudinal study is to examine relationships among vaginal microbiome, inflammatory mediators, sex hormones, metabolome, and dysmenorrhea phenotypes. Racially diverse female participants (aged 14-39) will be recruited into four groups: three dysmenorrhea phenotype groups and one symptom-free group. These individuals will provide vaginal samples off- and on-menses, blood samples, and questionnaire data. The specific aims of the study are to (1) differentiate vaginal microbial taxa, genes, and pathways associated with dysmenorrhea phenotypes using shotgun metagenomic and qPCR methods; (2) differentiate inflammatory mediators and metabolites associated with dysmenorrhea phenotypes using immunoassays of cytokines and mass spectrometry-based metabolomics; and (3) identify taxonomic drivers of functional shifts in vaginal metabolome associated with severe dysmenorrhea symptoms. Network- based systems biology and predictive modeling approaches will be used to integrate phenotypic, demographic, behavioral, metagenomic, cytokine, metabolomic, and hormonal data. This multi-omics approach will provide rich information on the function of vaginal microbiota and metabolites to uncover mechanisms underlying individual differences in dysmenorrhea. The expected impact of this research is to (1) suggest new avenues for treating dysmenorrhea through modifying the vaginal microbiota or metabolites (e.g., using drugs, probiotics, and/or behavioral interventions), (2) reveal vaginal microbiota and/or metabolites as biomarkers, and (3) generate a rich resource with large microbial metagenomic sequencing, metabolomic profiling, and detailed phenotype, hormonal, and behavioral data to study mechanisms of dysmenorrhea and menstrual health. In the long term, this work has the potential to lead to additional dysmenorrhea treatment options with the ultimate goals of reducing pain and improving women's quality of life.

NIH Research Projects · FY 2024 · 2023-09

ABSTRACT Genetic variation in immune-related genes, as in the human leukocyte antigen (HLA) locus, plays a pervasive role across organ systems. HLA variation, called HLA alleles, is used to match organ donors, and has been associated with adverse drug reactions (ADRs), cancer, infections, and cardiovascular and neurologic diseases. However, most studies focus on the impact of HLA variation on specific immune-mediated diseases; the broader influence of HLA variation across all human disease has not been investigated in depth. The proposed research program will address the challenge of identifying immunogenomic influence on a broad spectrum of diseases and ADRs. Previous studies of HLA influence have almost exclusively focused on populations of European descent, thus differences across ancestral groups are not well understood. The availability of the All of Us Research Program (AoU), a large, diverse DNA biobank coupled to electronic health records (EHR) enables investigation of how HLA alleles influence many diseases across multiple diverse populations simultaneously. We propose to perform systematic investigation of the association of HLA alleles with disease, using a two pronged approach based on the phenome-wide association study (PheWAS). PheWAS is a disease-neutral approach that identifies the association between genetic variation across a broad set of diseases. In Specific Aim 1, HLA alleles will be determined using whole genome sequence data, and PheWAS will be deployed in AllofUs to determine the influences of HLA alleles across organ systems, and to explore ancestral differences in HLA associations. We will determine association of HLA-A, -B, -C, -DR, and -DQ alleles with a comprehensive set of diseases within and across major ancestry groups in AoU. Despite its power, PheWAS analysis is limited to identifying single-allele connections to phenotypes of interest, so influences that result from HLA interactions (either combinations of HLA alleles, or between an HLA gene and some other genomic context) may be missed. Specific Aim 2 will address this shortcoming – we will develop Machine Learning strategies to explore the effect of HLA allele interactions on disease, and explore the potential for recognizing pleiotropic influences of HLA alleles. This innovative PheWAS-based approach has the potential to discover novel mechanisms of many diseases, identify biomarkers that may predict disease, and create a roadmap by which future researchers investigate the impact of HLA variation in human disease. As indicated by our previous work, PheWAS has the potential to condense decades of immunogenomic discoveries into a single analysis. When applied to under- studied, diverse populations, this work has the potential to accelerate this field of research. This approach can be applied to many other genomic loci, differential associations by other characteristics such as sex and/or gender, and identification of pleiotropic effects across disease systems, creating a number of potentially fruitful avenues of future research.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY / ABSTRACT In our prior Miner Safety and Health Training Programs - Western United States (U60) grants, we developed the Learning Laboratories (LLs) program, which is an industry-academic collaboration involving three universities and more than 20 mining organizations and operators representing over 20,000 mine workers in the Western US. The LLs program provides needs-specific training resources and mentorship for miners, trainers, supervisors, and health and safety (H&S) professionals across all sectors of the industry. Operators participating in the LLs program have shown measurable improvements in H&S outcomes, including reductions in both average injuries and days lost, up to 23.6% and 72.5%, respectively. Building upon these successes, we will expand our LLs program through three specific aims: 1) Provide new pathways for training and research through collaborative learning laboratories. Our LLs program offers a powerful mechanism for collaboration between researchers, safety professionals, and industry trainers. The program will be expanded to meet all core elements of NIOSH’s Research to Practice (R2P) initiative. Specifically, we will increase partnerships with trainers serving contractors, small operators, and other underserved groups and MSHA State Grants programs. We will work with investigators in academia and at NIOSH to identify industry needs, deploy new and existing training materials, facilitate synergistic research agendas, and evaluate outcomes. We will enhance technology transfer by streamlining deployment of new computer and app-based materials to industry partners for use in training and continued development. We will improve communication among LL partners through meetings, workshops, and an online forum. We will facilitate evaluation through mentorship and a cloud-based data collection and analysis platform. 2) Improve health training. By adding new health modules to our training materials, many NIOSH National Occupational Research Agenda (NORA) cross-sector topic areas will be addressed, including chronic disease, musculoskeletal health, hearing loss prevention, respiratory health, and heat strain. We will also incorporate Total Worker Health topics such as mental health, substance abuse, and fatigue. 3) Develop, extend, and integrate a continuum of training resources. Successful training products developed by our program, NIOSH, and LL partners will be upgraded to incorporate new content, capabilities, and interoperability. We will develop resources addressing all levels of trainer capability, from easily integrated tabletop games to computer-based synthetic learning environments (SLEs). We will improve the accessibility of training and evaluation technologies, particularly for trainers serving smaller operators and at worksites lacking sophisticated computer hardware, using app-based mobile games and streaming services. Intermediate outcomes will include: 1) Improved H&S practices; 2) Workers empowered through active learning; 3) Increased sharing of effective training programs; and 4) An increased number of competent miners, trainers, supervisors and H&S personnel. The end outcomes of the program will include H&S culture change and reductions in mining injuries, illnesses, and fatalities.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Coronary microvascular dysfunction (CMD) is associated with coronary artery diseases (CAD), diabetic cardiomyopathy (DCM), ischemia with the non-obstructive coronary artery (INOCA), and HFpEF (heart failure with preserved ejection fraction). Patients with diabetes exhibit coronary endothelial dysfunction, characterized by impaired acetylcholine-induced endothelial-dependent relaxation. Impaired endothelium-dependent vasodilation (EDD) decreases coronary blood flow and myocardium perfusion, leading to myocardial ischemia without an obstructive coronary artery. However, the underlying mechanism of impaired coronary endothelial dilation in DCM is not fully understood. Our preliminary study finds that NO is the mediator of endothelium-dependent dilation (EDD) in small coronary arteries in healthy mice. However, in diabetic mice, we observe that hydrogen peroxide (H2O2) is the principal endothelial-dependent vasodilator. Such a unique preclinical diabetic model recapitulates a clinical observation of NO to H2O2 in CAD patients. Moreover, we find a deficiency of miR-21 that restores the NO-dependent vasodilation in isolated coronary arterioles of diet-induced diabetic mice. This application will address the functional consequence of the miR-21-regulated NO to H2O2 switch in myocardial blood flow and cardiac function and the underlying mechanism. We hypothesize that restoring “normal” coronary microvascular function (restoring endothelial-dependent vasodilation) by modulating miR-21can ameliorate diabetic cardiomyopathy (which is thought to be a disease related to impaired coronary microvascular function). We will test our hypothesis by an interdisciplinary approach encompassing a range of methods and disciplines from molecular and cell analyses and vascular biology to physiology and pathophysiology, engendering the study of a novel mechanism of coronary microvascular dysfunction, such as tissue-specific knockouts and lineage tracing with 3D fluorescent imaging, measurement of vasodilation and myocardial blood flow in vivo by contrast echocardiography and cardiac function by echocardiography along with RNA-seq, sc RNA-seq, etc. Completing this project may lead to a new strategy to treat microvascular dysfunction and diabetic cardiomyopathy and improve the cardiovascular prognosis of diabetes.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Abnormal activity of the cardiac ryanodine receptor (RyR2) leads to increased and untimely release of Ca2+ from the sarcoplasmic reticulum (SR), driving Ca2+-dependent arrhythmogenesis that can lead to sudden death in many cardiac disorders. Oxidative modification of RyR2 by reactive oxygen species (ROS) has long been established to enhance the sensitivity of the channels to Ca2+ within the SR (intraluminal Ca2+) in the failing heart. However, both the intracellular source of ROS, as well as the specific redox-sensitive residues of RyR2 which control intraluminal Ca2+ sensitivity, remain elusive. Our initial studies implicate the role of the SR oxidoreductase system in this control, whereby molecular chaperones and enzymes that facilitate protein folding also modulate activity of RyR2. We have identified intraluminal cysteines of RyR2 that elicit functional effects on the channel, as well as an oxidoreductase chaperone that associates with the channel in a redox-dependent manner. Moreover, we found upregulation of oxidoreductase enzyme in rodent models of cardiac disease, and observed RyR2 activity stabilization with pharmacological inhibition of this enzyme. We therefore hypothesize that dysregulation of the SR oxidoreductase system impairs luminal Ca2+ regulation of RyR2 via an ‘intraluminal SR redox sensor’ and promotes arrhythmogenesis. We will test our hypothesis by 1) defining the molecular components of the SR redox sensor that control luminal Ca2+ sensitivity of RyR2, and 2) determining the role of dysregulated SR redox homeostasis in Ca2+-dependent arrhythmogenesis. To address these aims, we will employ a multilevel experimental approach, investigating at the molecular, cellular, and whole heart level. We propose to use heterologous systems, biochemical approaches and human induced pluripotent stem cell cardiomyocyte (hiPSC-CM) technology to identify the RyR2 redox sensor. We also propose to study disease- associated perturbations of the SR oxidoreductase system in rodent models of inherited and acquired Ca2+- dependent arrhythmia, utilizing novel genetic biosensors, as well as adenoviral (AV) and adeno-associated viral (AAV) gain- and loss- of function approaches. With renowned experts in cardiac EC coupling, protein biochemistry and hiPSC-CM technology, The Ohio State University offers an exceptional training environment for the mentored phase of the award to reach these goals. Furthermore, building on my strong background in molecular biology, I will collaborate with an expert in CRISPR-mediated gene editing of hiPSC-CMs to study these mechanisms in a relevant human model. The achievement of the proposed aims will uncover novel regulatory mechanisms of RyR2 regulation, with potential to be therapeutically exploited. This proposal therefore addresses a fruitful and unexplored research area, relevant to a spectrum of cardiovascular diseases, which will lay strong foundations for an independent research career in cardiovascular physiology.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract The University of Arizona (UArizona) Training Program to Advance Translational Research on Alzheimer's Disease and AD Related Dementias (AZ-TRADD) is designed to address knowledge and experience gaps in AD therapeutic discovery and preclinical translational development. To meet this challenge, the UArizona Translational Research in AD and related Dementias (AZ-TRADD) training program is designed as a problem based translational learning experience for predoctoral Ph.D and M.D./Ph.D fellows. In alignment with the 2021 NIH Alzheimer’s Research Summit: Path to Precision Medicine for Treatment and Prevention and the 2011 National Alzheimer’s Project Act (NAPA), the goal of the AZ-TRADD training program is to fill critical gaps that exist for AD translational research in academic graduate programs. To achieve this goal, the AZ-TRADD program will: 1) recruit trainees across multiple scientific disciplines; 2) employ problem-based learning approaches to solve challenges in AD therapeutic development with emerging tools and techniques; and 3) equip AZ-TRADD trainees with career development and leadership skills necessary to conduct team science and manage multidisciplinary teams. Through this approach, we ensure that AZ-TRADD trainees develop deep translational research expertise necessary for AD therapeutic development, while: 1) cultivating the ability to creatively and collaboratively solve problems working with experts across the translational landscape as part of large-scale team science; 2) gaining an applied understanding of how data science, particularly using data generated by AMP-AD, M2OVE-AD and ADNI, can accelerate translational research and provide avenues to novel therapeutic insights; 3) connecting geno- and phenotypic variations and multifaceted etiology of AD to therapeutic targets; and 4) gaining essential professional and business skills to navigate a diverse funding landscape and translate discoveries into the clinical setting. AZ-TRADD fellows will receive career mentoring and leadership development skills to manage multi-disciplinary teams in the 21st century that is Patient Inspired and Data Driven. The AZ- TRADD training program will develop a diverse, cross-disciplinary, and translationally oriented workforce to meet the critical challenge of creating a workforce capable of advancing therapeutics to prevent, delay, and treat AD and AD related dementias.

NIH Research Projects · FY 2024 · 2023-09

ABSTRACT More than one million firefighters in the United States provide critical emergency medical services in communities they serve and have been on the front lines of healthcare delivery, including throughout the COVID-19 pandemic. As a result of exposure to occupational stressors, a high proportion of firefighters experience considerable stress-related illness burden, including chronic pain, psychological distress (i.e., anxiety and depression), and posttraumatic stress disorder. Although interventions have been developed to address this high need of reducing effects of occupational stress exposure in order to improve firefighter well- being (e.g., cognitive-behavioral therapy, resilience training), not all of these modalities appeal to all firefighters, nor are they easily implemented without direct, in-person contact. One modality that has shown promise to reduce distress in various populations is meditation, including meditation delivered by smartphone apps. To the best of our knowledge, no smartphone-based meditation interventions designed to cultivate both mindfulness and feelings of social connection to others have been tested with firefighters. This study will therefore test the efficacy of a 10-day, smartphone-based meditation app intervention among N=192 career firefighters. The app was developed by Health Minds Innovations (HMI, Madison, WI) and is designed to enhance both mindfulness (awareness) and social connection to others in order to reduce anxiety. Our group recently piloted tested this app and found that firefighters exhibited reduced anxiety (a key component of psychological distress) and burnout, as well as improved function of the stress hormone, cortisol, from before to after use of the app. Although these encouraging results suggest a low-cost, scalable smartphone-based meditation app may be effective to improve firefighter well-being, our pilot study lacked an attention control comparison needed to establish intervention efficacy. Therefore, in collaboration with 3 metropolitan fire departments in the United States, we will test the efficacy of the HMI meditation app to reduce psychological distress compared to a rigorous active attention control (i.e., a Health Education app, based on our prior work)(Aim 1). We will also determine whether the effect of the HMI meditation app of psychological distress is mediated by mindfulness and perceived social connection (Aim 2). The proposed research will provide important evidence of efficacy about a smartphone-based meditation app intervention, with likely high impact, that cultivates both mindfulness and social connection in order to reduce psychological distress in frontline workers in the fire service. This research supports NIOSH's Strategic Goal 7 / Activity Goal 7.14.1 (to develop interventions that integrate protection from work-related health hazards with promotion of prevention to advance worker well-being) and NORA Objective 6 (promote healthy work design and well-being).

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT Due to the introduction of combined antiretroviral therapy (ART), AIDS is now rare - instead HIV has become a chronic disease in much of the industrial world. Persons over 50 with controlled HIV (PWH) make up nearly half of all infected individuals (>0.6M people in the US alone) and their numbers are increasing. But these people are not cured: PWH experience multiple comorbid conditions at rates higher than, and earlier in life compared to, uninfected age-matched persons. These HIV-associated non-AIDS conditions (HANA) lead to premature accumulation of physical and cognitive functional deficits that resemble a pronounced/ accelerated aging phenotype. Inflammation and immune function decline accompany both HIV and aging, suggesting that both could potentiate and/or drive aspects of exacerbated aging in PWH. Persistent cytomegalovirus (CMV) infection has been implicated in immune aging and age-related inflammation too, but there are significant inter- person variations and an incomplete understanding of control of CMV with aging. Limited data suggests that the premature “aging” phenotype seen in PWH is only found in those co-infected with CMV, but the control of CMV in PWH remains poorly understood. Therefore, CMV could be a driver of disabilities in older HIV+ individuals, a marker with stratifying and predictive value, or neither. We have developed a battery of tests to measure CMV viral load, anti-CMV NK, T and B cell immunity, and concurrent levels of systemic inflammation, and have found that while <50% of HIV-negative participants exhibit anti-CMV neutralizing Ab (nAb), >90% HIV+ age-matched participants develop nAb. We hypothesize that anti-CMV nAb production is a direct function of CMV load and replication during, and maybe also in the aftermath, of the acute HIV infection. We have also developed and validated the upper extremity flexion (UEF) test that, coupled with cognitive testing, can provide simultaneous assessment of frailty, motility, cardiovascular and cognitive function, all of which provide deep functional insight into quality of life (QOL) and geriatric syndromes. We seek to use these tools to evaluate the impact of CMV and CMV-associated inflammation as biomarkers in predicting trajectories of functional decline in HIV+ individuals with aging. Our hypothesis is that PWH with signs of CMV reactivation (viral loads, high levels of anti-CMV nAb, T and NK cell activation) experienced prolonged and high CMV reactivation during acute HIV disease and/or in its aftermath, with a broad spectrum of immune and inflammatory abnormalities, that predispose them for aggravated chronic conditions and geriatric syndromes such as frailty, mobility/falls and reduced cognitive ability. We will test this hypothesis by multivariate analysis of immune and inflammatory mediators and geriatric assessment in three observational (one prospective) and one anti-CMV drug treatment cohort, including both sexes. This work will dissect the relationship between CMV, inflammation and reduced overall fitness, frailty and accelerated and/or unsuccessful aging in HIV+ individuals and could provide basis for broader anti-CMV treatment of older adults with HIV to improve their healthspan.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease related dementias (ADRD) significantly contribute to the 55 million people world-wide who suffer with dementia. This number is estimated to increase to over 139 million people by 2050 (WHO). A number of studies have shown that VCID and conversion to ADRD are strongly correlated with vascular disease, inflammation and decreased cerebral brain blood flow 1,2,3, 4,5,6, 7,8. The relationship between vascular disease, cognitive function and progression to dementia and possible AD have been recently reviewed 9. These authors successfully make the case for a close relationship between cardiovascular risk factors and risk for VCID and ADRD. Furthermore, conversion rates of VCI to dementia has been reported to be within 40-46% within 5 years of diagnosis of VCI 10,11. There is an urgent unmet medical need for therapeutics to prevent cognitive decline in individuals at risk for VCID. The goal of this proposed late-stage NIA U01 ADDP program is to complete FDA-required long-term toxicology and safety studies required to advance to a Phase 2 clinical trial of the anti-inflammatory peptide, PNA5, for treatment of persons with MCI and are at risk for VCID/ADRD. The peptide PNA5 is a novel pleotropic anti- inflammatory Angiotensin-(1-7)/MasR agonist that has outstanding brain penetration, enhanced bioavailability, decreases brain and cerebrovascular inflammation, improves cerebral blood flow and restores cognitive function in our preclinical VCID model 12,13,14,15. None of the other published studies with oral formulations of Ang-(1-7) related peptides or small molecules 18,19,20 have exhibited the excellent brain penetration that we have observed with our glycosylated peptides, which will be key for developing an effective CNS anti-inflammatory, cognitive protective therapeutic. With support from the NIA, we are completing our early stage ADDP program, have successfully completed our FDA pre-IND meeting, and will have our new FDA IND for PNA5 by Q3 2023. By the time of this review, we will have completed our formal initial 28-day toxicology and safety work for PNA5 required for Phase 1a first-in-human safety studies. In this application we are requesting support for 1) additional long- term exposure safety analysis,2) expanded GMP manufacturing and final formulation and packaging for a Phase 2 trial, and 3) FDA regulatory documentation and design of the Phase 2 trial required to advance to Phase 2 clinical trials in persons with MCI at risk for VCID/ADRD. Specific Aim I: Conduct six-month chronic toxicology studies in two species to determine the toxicokinetic and safety profiles for subcutaneously administered PNA5. Specific Aim II. Expanded GMP manufacturing and final fill and finish of PNA5 for Phase 2 trials in VCID. Specific Aim III: Complete regulatory assessments and documentation for submission to FDA and to generate Phase 2 clinical trial design and plan.

NIH Research Projects · FY 2025 · 2023-09

Summary Critical periods are time windows during development when experience-dependent plasticity is most robust. The developing visual system in the premier model for studying how circuits modified by experience-dependent plasticity are consolidated when a critical period closes. This model is clinically relevant because the closure of the visual critical period is implicated in the pathophysiology of amblyopia, a childhood visual disorder characterized by deficits in spatial vision including poor visual acuity and impaired depth perception. Effective therapy is more difficult after the critical period closes because the brain is less plastic. In animal models of amblyopia, monocular deprivation (MD) causes lasting deficits in ocular dominance (OD), binocular depth perception, and visual acuity. The closure of the critical period is coincident with the maturation of perineuronal nets in visual cortex, but how these extracellular structures may limit plasticity is not understood. In the proposed research, we will determine the role and cellular source of aggrecan, a principal component of perineuronal nets, in closing the developmental critical period for plasticity in visual circuits. Our hypothesis is that aggrecan operates outside of perineuronal nets to close the critical period. We will use a combination of behavioral assays of vision, multi-unit electrophysiology, calcium imaging in vivo, and slice electrophysiology in vitro, and genetic manipulations to determine how aggrecan regulates the plasticity of visual circuits. This project will improve understanding of the mechanisms by which experience-dependent plasticity is restricted in the maturing brain and may reveal new avenues for developing therapeutic approaches to treat developmental visual disorders such as amblyopia and central visual impairment.