University Of Colorado Denver

NIH Research Projects · FY 2026 · 2026-02

Project Summary Chronic liver diseases are a collection of disorders that result in significant morbidity and mortality worldwide. The overwhelming burden of these diseases results in the liver being the second most transplanted organ. As a result of a dramatic rise in the incidence of obesity and alcohol consumption, the rate of liver transplantation continues to climb world-wide. Despite the significant impact of chronic liver disease on society, there are no effective therapies to ameliorate disease outside of lifestyle modification and liver transplantation. Thus, a more rigorous understanding of the mechanisms that drive the progression of chronic liver disease is required to identify novel targets for therapeutic intervention. Our previous publication demonstrated a significant accumulation of T lymphocytes in the liver of individuals with Metabolic Dysfunction-Associated Steatohepatitis (MASH)-induced cirrhosis. However, the precise role of T cells in the progression of MASH has yet to be firmly established. The preliminary studies presented in this application have identified a yet to be appreciated role for T cell activation and clonal expansion during MASH. In this application we demonstrate that T cell clonal expansion is a common event that correlates with fibrosis stage in both humans and mice with MASH. These are the first studies to identify T cell clonal expansion in the liver of humans and/or mice with MASH and link T cell activation and function with MASH pathology. However, the exact antigenic cause of T cell activation or if these T cells are inducing or suppressing disease progression is unknown. The studies in this application aim to answer these two fundamental questions by defining (1) the antigens recognized by clonally expanded T cells, (2) if there are shared stimulatory antigens between human and mouse disease, (3) the antigen presenting cell (APC) that drives T cell clonal expansion, and (4) if eliminating T cell clonal expansion through depletion of either clonally expanded T cells or the APCs presenting antigens to these T cells results in prevention and/or resolution of disease. Completion of these studies will provide a paradigm shift in our understanding of the pathogenesis of MASH and will generate the tools necessary to define the role of T cells in the progression of other chronic liver diseases.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT Type 1 diabetes is an autoimmune disease where the immune system mistakenly attacks and destroys insulin-producing beta cells in the pancreas. Our research has discovered unique hybrid molecules, called Hybrid Insulin Peptides (HIPs), that form in beta cells when fragments of insulin fuse with other protein fragments. Various HIPs contributing to disease in humans and mice are generated by an enzyme called Cathepsin D and serve as key targets for the immune system’s attack on beta cells. Interestingly, while HIPs are consistently detectable in laboratory mice used to study diabetes, they are harder to detect in human tissue samples even when analyzing larger amounts. We discovered this difference stems from how HIPs are made: the human version of Cathepsin D requires more acidic conditions to function compared to the mouse version. This could explain why human and mouse diabetes look different under the microscope - mice show widespread inflammation throughout the pancreas, while humans show more localized damage. To better understand how HIPs form in human disease, we propose to create a new mouse model where we replace the mouse version of Cathepsin D with the human version. We expect these “humanized” mice will form HIPs less readily, similar to humans. This model will help us understand how environmental factors influence HIP formation and disease development, potentially identifying new ways to prevent or treat type 1 diabetes. This research could reveal important insights into why type 1 diabetes develops and how environmental factors might influence disease progression through their effects on HIP formation, potentially leading to more effective prevention strategies.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Candida glabrata, also known as Nakaseomyces glabratus, is a leading cause of invasive candidiasis, which can have mortality rates as high as 60%. C. glabrata typically colonizes the intestinal microbiome, serving as the main source of infection. While it is recognized that strong antifungal immunity is crucial for preventing opportunistic C. glabrata infections, our understanding of how immune interactions in the intestinal mucosa limit this fungus from becoming invasive is still limited. Defining these protective immune responses is essential for elucidating how C. glabrata escapes the gut in medically vulnerable patients and for developing therapeutics to prevent infections. We recently discovered that mucosal IgA antibodies play a significant role in limiting the invasive potential of another fungal species, Candida albicans, within the gut. Additionally, we found that intestinal IgA from humans and mouse models reacts against C. glabrata. However, the implications of these immune-C. glabrata interactions remain unclear. The aim of this proposal is to investigate the role of anti-C. glabrata IgA responses in limiting the pathogenic potential of this fungus during intestinal colonization. In preliminary studies, we found that intestinal anti-C. glabrata IgA responses vary by strain and correlate with pathogenic potential. Specifically, we observed that IgA preferentially targets C. glabrata strains that are particularly adhesive and invasive within the intestinal mucosa. We will leverage this strain variability, along with animal models of intestinal colonization, to 1) identify IgA-targeted C. glabrata effectors and examine their role in adhering to the intestinal epithelium and their ability to induce invasive infections and 2) assess the impact of anti-C. glabrata IgA in regulating the persistence of potentially pathogenic strains within the gut.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT Opioid overdose deaths remain at alarming levels, driven largely by illicitly manufactured fentanyl. Methadone is a highly effective medication for opioid use disorder (OUD) that reduces mortality by nearly 50%. Despite its demonstrated effectiveness, methadone's impact on OUD-related morbidity and mortality remains limited due to low treatment initiation and retention rates. Historical regulations have restricted methadone treatment to opioid treatment programs (OTPs) that are characterized by highly protocolized clinical workflows that limit patient- centered care. In February 2024, federal methadone regulations were updated for the first time in decades. The new regulations authorized greater flexibility in methadone treatment to promote patient-centered care, including decreased requirements for daily in-person dosing (increasing take-home doses), greater clinical discretion around initial dose strength, and more individualized treatment planning (optional counseling). The new regulations are a major departure from current OTP practices and there is a dearth of research on how to implement these changes into clinical practice to improve the adoption and impact of patient-centered methadone treatment. Through the proposed training and research in this K23 application, Dr. Christine will acquire crucial skills to achieve his career goal of becoming an expert clinician-investigator focused on comprehensively evaluating and implementing health policies to improve the health of people with OUD. With guidance from an experienced mentor team, Dr. Christine will combine training in qualitative and mixed methods research, partner-engaged implementation science, and trial design and evaluation to develop and pilot test the Improving Methadone Patient Centered Treatment (IMPaCT) implementation program. The goal of the IMPaCT program is to increase OTP adoption of patient-centered methadone practices to improve retention in treatment. This proposal will address the following aims: 1) Identify contextual factors that influence the adoption of patient- centered methadone practices through interviews with Colorado OTP clinicians, patients, and state regulators; 2) Partner with patients and clinicians from two distinct Denver OTPs to develop the IMPaCT implementation program designed to modify clinical workflows and tailor implementation strategies to increase the adoption of patient-centered methadone care; 3) Assess the feasibility, implementation-related outcomes, and preliminary effectiveness of the IMPaCT program in a 3-month pilot trial at two distinct Denver OTPs. The trial will use patient and clinician interviews and surveys paired with electronic health record data to assess the feasibility of a future larger trial. It will also assess adoption, implementation and reach of the IMPaCT program, and preliminary effectiveness on 90-day treatment retention. The overarching goal of this proposal is to give Dr. Christine the training necessary to help bridge the addiction policy-to-clinical practice divide. The findings from the proposal will inform an R01 application to test the IMPaCT bundle in a large, randomized trial with the goal of enhancing patient-centered methadone treatment, improving treatment retention, and reducing opioid overdose deaths.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT: CANDIDATE: Angelina Dixon, MD, is currently Chief Medicine/Pediatric Nephrology Fellow, and will join the faculty as an Instructor in July 2025 in the Division of Renal Diseases and Hypertension at the University of Colorado Anschutz Medical Campus (UC-AMC). Dr. Dixon has thrived in the field of research with a strong publication record and postdoctoral grant funding and awards. Dr. Dixon’s overarching career goal is to independently conduct research to improve outcomes for adolescents and young adults (AYA) with type 2 diabetes (T2D). CAREER DEVELOPMENT PLAN: Dr. Dixon’s proposed training plan is designed for her to develop proficiency in clinical and translational research methods, expand her professional development, and develop skills to progress towards research independence through presentations at seminars and national scientific meetings, coursework, grant writing and mentoring experience, leadership training, and regular interactions with her mentoring team. Her proposed project and training plan are a direct extension of the knowledge and skills she has acquired thus far in her mentor’s laboratory. ENVIRONMENT: The training environment at UC-AMC is outstanding. Dr. Dixon’s primary mentor, Dr. Kendrick has been continuously funded by NIH and has a strong record of successful mentoring junior investigators. Dr. Dixon’s mentorship team includes co-mentors, Dr. Bjornstad (pediatric endocrinology and expert in advanced methods of intrarenal hemodynamic function), Dr. Furgeson (expert in cysteinyl leukotrienes) and Dr. You (expert in biostatistics). Dr. Dixon will be provided with protected time, equipment, and other resources needed for the K23 by the Division. RESEARCH: Diabetic kidney disease (DKD) and cardiovascular disease (CVD) remain the leading cause of morbidity and mortality in AYA with T2D. T2D leads to release of proinflammatory lipid mediators, termed leukotrienes, which are implicated in endothelial dysfunction and microcalcification, resulting in increased renal vascular resistance (RVR) and arterial stiffness. Montelukast, a cysteinyl leukotriene inhibitor, widely used in asthma with an excellent safety profile in both pediatric and adult populations, may represent a promising intervention for AYA with T2D. Our group’s preliminary data show that using montelukast in mice with acute kidney injury prevents chronic kidney disease, and our observational data in adults suggest a significantly reduced risk of incident kidney failure with montelukast use. We also find attenuated arterial stiffness in mice treated with montelukast and lower systolic blood pressure in human participants exposed to montelukast. Dr. Dixon will conduct a randomized, double-blind trial in 50 AYA aged 12-24 years with T2D examining the effect of 6 months of montelukast vs. placebo on: intrarenal hemodynamics (RVR, glomerular pressure) measured by p-amminohippurate and iohexol clearance (Aim 1); vascular endothelial function (measured by brachial artery flow-mediated dilation), and large elastic artery stiffness (measured by aortic pulse wave velocity) (Aim 2); and kidney and vascular inflammation (measured by urinary, blood, and endovascular cell markers) (Aim 3).

NIH Research Projects · FY 2026 · 2026-02

PROPOSAL SUMMARY The inner lining of the uterus, the endometrium, is an important determinant of gestational outcomes even prior to the implantation of an embryo. In humans, a thin endometrium increases risk for miscarriage, preterm delivery, and low birth weight. Currently, it is unknown what causes a thin endometrium and how it leads to the later gestational outcomes. Much of what is currently known about the endometrium relates to how the epithelium and underlying stroma respond to steroid hormone signals. We know substantially less about what other downstream cell signaling occurs to thicken the endometrium. Members of the Hedgehog (Hh) signaling pathway, including Gli2, change expression dramatically across the 4-7 day mouse estrous (menstrual) cycle and are known to have important roles in implantation. Prior work in the field has shown that decreased Gli2 expression in mouse placentas results in decreased blood flow to the fetus and changes in the structure of the labyrinth layer of the placenta. There is also decreased Gli2 expression in human placentas affected by preeclampsia. However, the cell and molecular role of Gli2 in either the cycling endometrium or gestational success is largely unknown. Therefore, the overarching objective of this proposal is to close this knowledge gap by investigating the role of Gli2 in endometrial remodeling and placental development. In order to accomplish this, we developed a mouse model with conditionally deleted uterine Gli2. My preliminary data shows that the endometrium does not expand normally during the estrous cycle, resulting in a thin endometrium. These animals are still able to produce offspring, but each litter has fewer pups compared to controls. My preliminary work also shows that Gli2 deficiency does not affect the initial number of implantation sites, so the subfertility is likely occurring after implantation and before birth. Therefore, my central hypothesis is that Gli2 is necessary for supporting gestation by regulating cell proliferation at three important times: in the cycling uterus, at decidualization, and during syncytiotrophoblast expansion. To test this hypothesis, I will conditionally delete Gli2 in the uterus and in the placenta. In Aim 1, I will use high-resolution imaging to analyze stromal and decidual proliferation at two estrous cycle phases and gestational timepoints, respectively, in order to identify perturbations with loss of uterine Gli2. Aim 2 will utilize the placenta-specific knockout of Gli2 to assess changes to fertility when endometrial Gli2 remains intact. I will also use this placenta Gli2 ablation model to measure proliferation of syncytiotrophoblasts, a key placental labyrinth cell type, using imaging techniques congruent to Aim 1. Collectively, these data will significantly advance our understanding of the cell signaling underlying endometrial thickness and ability to maintain gestation. Additionally, it will describe Gli2 as a common factor that is necessary in both endometrial and placental functions to prevent gestational failure. This proposal will have broad implications in understanding how a thin endometrium occurs and subsequently contributes to unfavorable gestational outcomes.

NIH Research Projects · FY 2026 · 2026-02

Project Summary This research project seeks to develop and characterize a novel mouse model to address the limitations of current systems for studying mucosal-associated invariant T (MAIT) cells. MAIT cells are a conserved subset of T lymphocytes that bridge innate and adaptive immunity by recognizing microbial metabolites presented by MR1 molecules. They play critical roles in infection control, cancer immunity, and tissue homeostasis. Despite their functional importance, MAIT cells are rare in commonly used laboratory mouse strains, including C57BL/6 (B6), which restricts their study under physiological conditions. Existing approaches, such as TCR transgenic mice or artificial expansion through infection, alter the natural TCR repertoire or rely on inflammation, complicating the study of MAIT cells' development and function. This proposal leverages a genetic engineering strategy to generate the MAIT-Boost Knock-In (MBKI) mouse model, which increases MAIT cell frequency while maintaining natural TCR diversity and thymic selection. By replacing Trav19 with Trav1 and Traj56 with Traj33, the MBKI model redirects TCRa recombination to favor the canonical Trav1-Traj33 configuration required for MAIT cell development. This approach is designed to boost MAIT cell numbers without the unintended consequences of existing models, offering a physiologically relevant system for studying their biology. The project aims to characterize the frequency, tissue distribution, and functional properties of MAIT cells in MBKI mice. It will also assess the broader impact of these modifications on TCRa rearrangement dynamics and other immune subsets, including gd T cells and iNKT cells. Finally, the MBKI model will be used to evaluate whether increased MAIT cell frequency enhances melanoma tumor control, addressing their potential for cancer immunotherapy. This work will provide fundamental insights into MAIT cell biology and create a platform for developing therapeutic strategies targeting infections, cancer, and immune dysregulation.

NIH Research Projects · FY 2025 · 2026-01

ABSTRACT Cardiovascular disease is a leading cause of death, with an uptick in cardiovascular disease mortality rates in recent years, due in part to the growing obesity crisis. Obesity is associated with many cardiovascular risk factors and increased adiposity can lead to cardiac remodeling and heart failure. One strategy to increase weight loss and improve cardiovascular outcomes is to target beta-adrenergic receptors (β-ARs) in adipose tissue to increase activation of protein kinase A (PKA) and increase energy expenditure. PKA also has important regulatory roles in cardiac tissue. PKA activation increases calcium cycling and contractility in the cardiomyocyte, thus increasing heart function. β-AR agonists, however, were not beneficial for long-term use in heart failure patients. We therefore need alternative mechanisms to activate and regulate PKA in the heart. We recently published that inhibiting histone deacetylase 11 (HDAC11) in adipocytes increased PKA activity and improved metabolic health. HDAC11 does not act like a classic HDAC, but rather, regulates protein function through lysine demyristoylation. Lysine demyristoylation is an understudied post-translational modification, and the biological functional consequences of lysine myristoylation/demyristoylation remain mostly unknown. Our preliminary data demonstrate that inhibition of HDAC11 increases the phosphorylation of PKA substrates in the cardiomyocytes. Our central hypothesis is that increasing lysine myristoylation in the cardiomyocyte (facilitated by HDAC11 inhibition) will beneficially increase heart function by increasing PKA activity. Aim 1 will determine the mechanism of HDAC11 inhibition-mediated increase in PKA activation by quantifying the myristoylation of the A kinase anchoring protein, gravin-α, which is known to facilitate HDAC11 inhibition-mediated PKA activation in adipocytes, through myristoyl-tag click chemistry and gain- and loss-of-function assays. We will also look for novel HDAC11 demyristoylation targets in the cardiomyocyte using click chemistry and mass spectrometry. Aim 2 will determine the functional effects of HDAC11 inhibition in the cardiomyocyte. We will evaluate the effect of HDAC11 inhibition at the cellular level by measuring calcium transients and function in isolated cardiomyocytes. We will generate a novel, inducible, cardiomyocyte-specific HDAC11 knockout mouse and assess cardiac structure and function in vivo using echocardiography, pressure-volume loop hemodynamics, and histological approaches. Finally, we will determine the functional effect of HDAC11 inhibition-mediated increase in PKA activation on disease pathogenesis and measure cardiac structure and function of wild-type and HDAC11 cardiomyocyte specific knockout mice before and after transverse aortic constriction. Together, successful completion of these aims will support the development of HDAC11 inhibitors as a novel therapeutic mechanism to regulate PKA activation and beneficially increase heart function.

NIH Research Projects · FY 2026 · 2026-01

PROJECT SUMMARY The incidence of diastolic dysfunction increases dramatically in women after menopause, which has long been attributed to loss of protection from female sex hormones, specifically estradiol. The mechanisms underlying estradiol-mediated cardioprotection are still unknown. A better understanding of biochemical pathways that are modulated in the female heart in response to estradiol has the potential to improve how we treat post-menopausal women with diastolic dysfunction. We have found that sarcomeric relaxation is significantly prolonged in healthy women after menopause compared to women who are pre-menopausal. We hypothesize that changes in sarcomeric PTMs due to decreased estradiol may contribute to this prolongation in relaxation. In addition to prolonged relaxation, we have also found that crotonylation of proteins is upregulated in old female hearts. In an unbiased screen of aged human hearts using mass spectrometry, we found a specific enzyme, short-chain enoyl-CoA hydratase (ECHS1), is significantly down regulated in the hearts of females over 60 years of age. Lower levels of ECHS1 increase crotonyl-CoA. This increase in crotonyl-CoA, in turn, leads to higher protein crotonylation, which is a novel PTM that occurs on lysine residues. The enzymes that facilitate this PTM include p300 and the enzymes that remove crotonylation from proteins are class I histone deacetylases (HDACs). While it has been shown that sarcomeric proteins are crotonylated, the role that estradiol plays in crotonylation and the functional effects of crotonylation are completely unknown. The objective of this proposal is to determine the role of estradiol in regulating cardiomyocyte crotonyl-CoA thereby modifying sarcomeric crotonylation. In this proposal, we will establish if lower ECHS1 in aged female cardiomyocytes is due to decreased estradiol (Aim 1) and determine the functional role of sarcomeric crotonylation (Aim 2). We hypothesize that reduced estradiol levels in aged female hearts lead to decreased ECHS1 in cardiomyocytes, increasing cellular crotonyl- CoA, sarcomeric protein crotonylation, thereby contributing to prolongation of sarcomeric relaxation. This R21 exploratory proposal will identify a completely novel mechanism underlying changes in cardiac diastolic function in response to estradiol. There are no data examining the role estradiol plays in regulating crotonylation nor data about how crotonylation of sarcomeric proteins modulate function. Completion of the proposed experiments will provide critical insights into specific modifications that occur in female hearts after menopause as well as contributing critical data necessary to elucidate our understanding of how an unexplored post-translational modification impacts cardiac function.

NIH Research Projects · FY 2025 · 2025-11

PROJECT SUMMARY: CD8 cells play a critical role in the immune response to infections as well as in prevention and restriction of cancer growth. Cytotoxicity and cytokine production have been identified as the primary mechanisms by which CD8 cells mediate their immune functions. Furthermore, chemokine-directed migration of CD8 cells is critical for their localization to lymphoid tissue for immune priming and to sites of infection and inflammation. However, after CD8 cells traffic to their target tissues, basal cell motility of effector CD8 cells within the tissue is an aspect of immunity that is poorly understood. Basal cell motility, defined as random walk and exploratory spread, is essential for effector CD8 cells to locate and engage their cell targets within inflamed tissue, such as a tumor. Little is known about the factors which could impact motility characteristics (distance, trajectory, speed) of CD8 cells. Mitochondria have been shown to play a critical role in cell motility through mitochondrial ATP and mitochondrial Ca2+. Mitochondrial Ca2+ enables cell motility through decreasing actin cytoskeleton stiffness. My recent studies show that IL-21 enhances motility of effector CD8 cells in the absence of TCR signals. I show that upon activation, effector CD8 cells expanded with IL-2 proliferate and survive but lose their cell polarity, adopting a round morphology and minimal motility capacity. In contrast, effector CD8 cells expanded with IL-2 plus IL-21 are highly motile. In addition, effector CD8 cells expanded with IL-2 plus IL-21 exhibit increased mitochondrial membrane potential, mitochondrial ATP, mitochondrial Ca2+, and in vitro cancer cell killing, compared to those expanded with IL-2 alone. In T cells IL-21 primarily signals through STAT3, and STAT3 has been shown to translocate to mitochondria and enhance mitochondrial respiration. My data also shows elevated mitochondrial STAT3 levels in CD8 cells expanded in the presence of IL-2 plus IL-21 compared to those expanded with IL-2 alone. Therefore, I propose that during the expansion of effector CD8 cells, IL-21 enhances CD8 cell motility by increasing mitochondrial ATP and/or mitochondrial Ca2+ through mitochondrial STAT3, leading to improved motility within solid tumors, which contributes to a more robust anti-tumor response. To address this hypothesis, I will: 1) Determine whether IL-21 induces effector CD8 cell motility by increasing mitochondrial ATP and/or mitochondrial Ca2+ through mitochondrial STAT3 (Aim 1) and 2) Examine whether effector CD8 cells expanded with IL-2 plus IL-21 exhibit increased motility within solid tumors and enhanced anti- tumor effects (Aim 2). This study will provide insight into improving effector CD8 cell motility through the IL-21- mitochondrial STAT3 signaling axis, which can be leveraged in modifying motility of these cells for improving adoptive T cell cancer therapies and/or reducing progression of CD8 cell-mediated autoimmune diseases, such as Type I Diabetes.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Family violence, including child maltreatment and intimate partner violence, is a common and costly public health problem with long-lasting impacts on victims. Infants experience the highest rates of child maltreatment, and the risk of intimate partner violence has been shown to increase in the period after the birth of a child. Yet, few family violence prevention policies target this critical period. In response to RFA-CE-25-029, this Mentored Research Scientist Development Award (K01) Application proposes to leverage novel data linkages to study the relationship between the implementation of a state paid family leave policy and family violence. Specifically, the proposed study will pursue the following aims: 1) evaluate the completeness of a novel multi- year data linkage developed for the purposes of this study using records supplied by the Colorado Department of Labor and Employment (state paid family leave records), the Colorado Department of Public Health and Environment (vital birth and death records), and Colorado Department of Human Services (child protection records); 2) estimate factors that predict the use of state paid family leave, leveraging linked data at the person level; and 3) estimate the causal effect of state paid family leave on family violence indicators during infancy using a county-level difference-in-differences research design. Together, these aims will inform state and federal conversations about paid family leave and assist agencies in the upstream prevention of violence. The proposed research study addresses two research priorities of the CDC National Center for Injury Prevention and Control—specifically, the evaluation of (1) economic supports to families to prevent maltreatment, and (2) promising IPV prevention strategies. The PI aims to obtain formal training in causal effects study design while expanding her expertise to encompass more forms of cross-cutting violence. The PI will work with an interdisciplinary team of mentors who are internationally recognized experts in family violence prevention, causal inference, and the linkage and analysis of population-based, administrative records. The research and training proposed will provide the PI with the foundation she needs to become a future leader in the field of violence prevention whose research findings contribute to policy development on a national and global scale. The results of this study will support an R01 proposal to evaluate the synergistic effects of numerous policies that support and economically strengthen families to prevent cross-cutting violence, a CDC Injury Center research priority.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY People with diabetes are at high risk of developing a range of diverse microvascular, macrovascular and neuropathic complications that are associated with high morbidity and erode their quality of life. Diabetes is expected to take an increasingly large financial toll in in the United States (U.S.) in the future, particularly among working age adults. Ongoing, timely and efficient surveillance of incidents and prevalent type 1 and type 2 diabetes diagnosed among youth and young adults is essential to identify health disparities and inform health care systems and the public health community on prioritizing strategies to prevent diabetes and its complications. The Colorado CASSIDY surveillance team is ideally situated to generate timely and accurate estimates of the prevalence and incidence of diabetes in youth and young adults from a near complete representation of health systems throughout our state, established in SEARCH, expanded in the Assessing the Burden of Diabetes by Type in Children, Adolescents, and Young Adults (DiCAYA) and further enriched for CASSIDY to allow our state to function as a health system site with a demographically and geographically representative population under surveillance. Our longstanding leadership in diabetes surveillance and research, institutional and statewide healthcare system partner commitment and the opportunity to directly validate the coverage and representativeness of statewide, deduplicated utilization-based denominators make us a valuable partner for the CASSIDY project. Our integrated surveillance approach was honed during our participation in DiCAYA, utilizing a combination of algorithms, incremental record linkage and chart review to identify individuals with diabetes, distinguish diabetes type and estimate date of diagnosis. Our specific aims are: Aim 1: SURVEILLANCE (Prevalence)- To ascertain cases of prevalent diabetes among individuals aged <45, by age, sex, race/ethnicity, geography and diabetes type; Aim 2: SURVEILLANCE (Incidence)- To ascertain newly diagnosed diabetes cases in young adults age <45 years at diagnosis, by age, sex, race/ethnicity, geography and diabetes type; Aim 3: EVALUATE PUBLIC HEALTH SURVEILLANCE METHODS - To evaluate the strengths and challenges of our integrated surveillance approach to determine the burden and risk of diabetes among youth and young adults by assessing validity, completeness and representativeness of case ascertainment methods and the potential utility of utilization-based denominators.

NIH Research Projects · FY 2024 · 2025-09

Abstract The population of people with HIV (PWH) older than 50 years now accounts for over 50% of PWH in the U.S. and is estimated to near 70% by 2030. As this population continues to age, they are faced with myriad health problems that impact quality of life (QoL). The National HIV/AIDS strategy 2022-2025 has acknowledged that we must focus interventions aimed at aging PLW beyond comorbidity and medication management to provide whole-person care that considers health-related social needs that impact up to 80% of health outcomes. In this project we will address the gap in the current understanding of QoL drivers and develop strategies for improving QoL for aging PWH that are centered in concept of whole-person care. The aims are to 1: conduct an environmental scan of the definition of QoL and barriers to improving QoL through a systematic reviews, surveys and qualitative methods; 2: develop strategies for intervening to improve QoL in adults aging with HIV through partner engagement around community-generated themes; 3: broadly disseminate recommended strategies to researchers, care providers, community organizations, community members and policy makers. This work has high potential to have an impact on clinical care, community programming and local policy through the connections of the study team to broad networks of clinicians (both geriatricians and HIV specialists), community organizations and various policy and advocacy boards, leading to care practice shifts, new conversations around QoL in community service organizations and discussions of legislation that could promote recommended strategies. Our broader dissemination strategy aims to reach nationally, to influence ideas about novel interventions and strategies to improve aging PWH lives, and we will continue to evaluate outcomes and disseminate successful strategies as they are implemented and demonstrate effectiveness at improving QoL for the aging PLW community.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Alcohol use disorders (AUD) are a leading cause of morbidity and mortality in the US, but existing treatments show only modest efficacy, and some have medical contraindications which limit their utility. Identification of safe, novel AUD medications is a high research priority. Cannabidiol (CBD) has generated interest as a treatment target due to preclinical studies showing that it reduces alcohol intake and data suggesting it is safe and well- tolerated in humans. Human research has mainly tested pure CBD (which does not contain other components of the cannabis plant). However, emerging data, including our own preliminary work, indicate that when CBD is combined with a small (<1%) amount of delta-9-tetrahydrocannabinol (THC), its effects—including its ability to reduce drinking—are enhanced. Thus, a compelling, largely unexplored potential treatment is full spectrum CBD (fs-CBD, which contains mostly CBD, plus a small [<.3%] amount of THC and other cannabis plant components). Notably, fs-CBD is already widely available commercially in the US and is the most popular CBD product on the market. Thus, if it shows promising effects, it could be rapidly integrated into clinical care. The overarching goal of this proposal is to conduct a randomized, placebo-controlled trial comparing the effects of fs-CBD relative to broad-spectrum CBD (bs-CBD, which is the same as fs-CBD except that it does not contain THC) and placebo, on alcohol consumption (in the lab and in the real world [Aim 1]) and on several clinically relevant AUD pheno- types (Aims 2 and 3), among adults with AUD. Specifically, we will test effects of fs-CBD (vs. bs-CBD and pla- cebo) on a battery of AUD phenotyping measures (corresponding to the Addictions Neuroclinical Assessment [ANA] domains) that could aid in identifying individuals for whom fs-CBD is likely to be an effective treatment (Aim 2) and on the gut microbiome (Exploratory Aim 3), which has been shown to play an important role in the etiology and maintenance of AUD. No prior study has evaluated effects of fs-CBD on alcohol consumption in the lab or explored potential mediators of its effects. We will recruit adults with AUD to be randomly assigned to take fs-CBD, bs-CBD or placebo daily for 4 weeks, during which they will report on their alcohol use via daily surveys. They will complete a lab session at the end of the 4 weeks involving an alcohol self-administration (bar lab) task, ANA assessments, and a blood draw (to measure an alcohol biomarker and circulating gut markers). Participants will provide fecal samples for assaying the gut microbiome. The ANA battery and blood and fecal samples will also be collected at baseline, so that post-intervention change in the proposed mediators can be measured. Given that fs-CBD is already widely used, results would have immediate public health and clinical impact. Find- ings could also inform a precision-medicine approach (using ANA phenotyping or phenotyping based on gut characteristics) to identify AUD patients likely to respond to CBD treatments. Finally, results will shed light on the interaction between CBD and THC in the context of AUD and could deepen our understanding of the link between the endogenous cannabinoid system and AUD, to provide foundational data for future research.

NIH Research Projects · FY 2025 · 2025-09

High blood pressure (BP) is the leading modifiable cause of cardiovascular disease (CVD), the number one cause of death in the US. Despite widespread availability of effective, safe, and inexpensive antihypertensive medications, BP control rates remain suboptimal, partly due to the strategies applied at treatment initiation. There are two general approaches to initiating treatment for high BP: stepped care (initiate one medication at low doses, slowly increase the dose, then add another medication, etc.) or combination therapy (initiate ≥2 medications at once). Stepped care theoretically minimizes pill burden and maximizes patient safety, but it requires significant time and resources to achieve BP control. Initial combination therapy may be more effective and safer than stepped care (especially at low doses), leading to better short-term outcomes, but has not been evaluated against stepped care for long-term outcomes (≥1 year). The unifying theme of this K01 proposal is to provide mentored career development and accelerate Dr. Derington’s transition to an independent investigator. It will establish the foundation for achieving her long-term goal of bridging gaps in CVD care through evidence-based health services research. Her K01 research objectives are to understand and evaluate antihypertensive initiation strategies and generate evidence for a future pragmatic trial testing a feasible and acceptable patient self-titration program to improve initiation of evidence-based antihypertensive medication regimens. The research aims are (1) identify barriers and facilitators initiating antihypertensive combination therapy vs. stepped care (Aim 1), (2) determine the real-world, long-term comparative effectiveness of initial antihypertensive treatment strategies on patient-centered outcomes (Aim 2), and (3) refine a pilot intervention to increase initiation of antihypertensive combination therapy (Aim 3). This work will leverage existing resources and data available in the Veterans Health Administration (VHA), for which the study team has already generated a dataset of 1,005,919 Veterans initiating antihypertensive treatment. Dr. Derington’s training and experience in clinical pharmacy, pharmacoepidemiology, and observational research will be complemented with additional training in qualitative research, causal inference, and pragmatic trials. The University of Utah, including its CTSI, and the VHA Salt Lake City Health System provide an ideal environment for achieving the proposed objectives and Dr. Derington’s long-term goals. Dr. Adam Bress, an internationally recognized expert and mentor in CVD pharmacoepidemiology and causal inference, will lead a multidisciplinary mentorship team composed of experts in qualitative research (Dr. Susan Zickmund), pragmatic trials (Dr. P. Michael Ho), biostatistics (Drs. Daniel Scharfstein and Tom Greene), health services (Dr. Jordan King), and antihypertensive medication use (Dr. Anthony Rodgers). The integrated mentored research experience and training will allow Dr. Derington to compete for R01 funding and become an independent clinician-scientist, with the ultimate goal of preventing CVD-related morbidity and mortality.

NIH Research Projects · FY 2025 · 2025-09

The University of Colorado Cancer Center (UCCC) is the only NCI-designated Cancer Center in Colorado serving a primary catchment area of the State of Colorado. The vision of UCCC is to prevent and conquer cancer. Together. Dr. Wood joined the faculty and UCCC in 2021. She is a leader in cancer screening and prevention research at the national level, with a long history of participation in the Alliance for Clinical Trials group. She is the Deputy Director of the Cancer Control Program and Co-chair of the Prevention committee and has been the national principal investigator (PI) for four clinical trials, one of which is open and accruing (A212102: A Blinded Reference Set for Multicancer Early Detection Blood Tests). She is also involved in the newly formed Cancer Screening Research Network (CSRN), serving on the Clinical Integration Committee for the network. She is a member of both the NCIs Cancer Prevention Steering Committee and prevention CIRB. Since joining the faculty of University of Colorado, she has been the medical director of the University of Colorado Cancer Clinic trials office (CCTO). During this time she has worked with the team to improve accrual, finally seeing a 10% increase in Q4 of 2024 and significant increase in Q1 of 2025, which if sustained will be a 4 year high in accrual. She has also assisted in efforts to improve diversity with now over 20% of accruals being from underrepresented groups. Finally, she has launched a new modality team within the CCTO focused on cancer prevention and survivorship. However, there remains a critical need to increase accrual to clinical trials, especially among underrepresented populations, and a significant need for greater focus on cancer screening and prevention trials both locally and nationally. Dr. Wood proposes a 3-part approach to increasing accrual and diversity though: 1. Increased number of NCTN trials in the area of cancer prevention and survivorship. 2. Engagement and mentoring of advance practice providers to act as site PIs for NCTN trials and 3. Bidirectional work with the Cancer Prevention and Survivorship team and the community outreach and engagement (COE) office to increase community awareness of trials in the cancer screening and prevention area. She will work towards expanding studies in cancer screening space focused on the developing area of Multicancer Early Detection (MCED) testing. Support from the Research Specialist grant will ensure that Dr. Wood has the protected time to support the above efforts. By focusing in the areas of cancer screening, prevention and survivorship Dr. Wood will not only increase accrual to NCI funded trials but advance the UCCC goals of performing highly innovative and accessible clinical trials and advancing health equity and reduce disparities across the continuum from prevention to survivorship. Support from the Research Specialist grant will ensure that Dr. Wood has the protected time to support the above efforts.

NIH Research Projects · FY 2025 · 2025-09

Modified Project Summary/Abstract Section The human obligate bacterium Mycobacterium tuberculosis (M.tb) infects approximately a quarter of the world's population, leading to chronic disease with an annual death toll exceeding 1.6 million. The disruption of services during the COVID-19 pandemic resulted in a 4.5% increase in cases, exceeding 6 million new cases in 2021, with Africa bearing a critical burden. The incidence in USA is increasing by 16% per year. Not all infected individuals progress to active disease, and we have shown in genome-wide association studies (GWAS) that human host genetic factors contribute to disease outcome. To identify new ways to improve disease outcome, human studies to characterize the genetic factors involved in TB and its interaction with the immune system are urgently needed. Here, we focus on the genetic susceptibility to active TB, focusing on HLA and its interactions with the KIR genes of natural killer (NK) cells, critical in shaping the immune response against TB. In this study, we propose to uniquely leverage the diversity of South African populations (sub-Saharan African, European, and South-East Asian ancestries) to perform multi-ethnic associations with broad applicability. Specifically, we aim to: 1) Generate population-level data (HLA, KIR, and SNP array) on 5,000 case/control samples, characterizing genetic diversity across multi-ancestry individuals from South Africa; 2) Perform binding and cytotoxic assays to functionally test/develop interaction scores for newly discovered alleles, and determine their specific NK impact on NK cell function 3) Develop appropriate, well-powered statistical models for association of HLA/KIR variation and HLA/KIR interaction with disease susceptibility. The Northern Cape Province, South Africa provides an ideal location to perform this study; the extremely high community TB incidence results in lower misclassification bias introduced by unknown or low infectious disease exposure. Outcomes include: a) studying a large TB case-control dataset of DNA, clinically-active cases and epidemiological variables of 5,000 participants; b) clarifying the role of NK cells in TB pathogenesis; c) appropriately calibrated statistical models of HLA/KIR association in admixed populations. We have an outstanding track record of collaboration, including ≥ 40 co-authored publications, as well as expertise in clinical epidemiology, statistical and population genetics, and immunogenetics, uniquely positioning us to address this critical research question using innovative methods -- including direct HLA and KIR allele sequencing and functional validation of their interactions. Through direct genetic assays, complex interaction analyses, and advanced statistical approaches, this study aims to shed light on the genetic risk factors and the immunogenetic landscape critical for understanding and combatting TB.

NIH Research Projects · FY 2025 · 2025-09

Project Summary: Inflammatory bowel disease (IBD) affects 3.1 million people in the United States, yet the precise mechanisms underlying its pathogenesis remain incompletely understood. Genome-wide association studies have identified multiple genes linked to IBD, including IKZF3, which encodes the transcriptional repressor AIOLOS, a protein exclusively expressed in lymphocytes. While these findings suggest a role for AIOLOS in immune regulation, the exact mechanisms by which it contributes to immune dysregulation in IBD are not fully elucidated. In our preliminary studies using murine models, we demonstrated that AIOLOS plays a crucial role in restraining the activation of CD4⁺ and CD8⁺ T cells. Specifically, AIOLOS-deficient mice exhibited heightened T cell activation and exacerbated disease in a mouse model of immune-mediated colitis. Mechanistically, we found that AIOLOS regulates T cell responsiveness to interleukins IL-2 and IL-12, which signal through the STAT5 and STAT4 pathways, respectively. These findings highlight the importance of AIOLOS in maintaining immune homeostasis and preventing excessive inflammation in the gut. Building upon these findings in mouse models, we aim to investigate whether similar mechanisms operate in humans and contribute to IBD pathogenesis by analyzing biorepository samples from healthy individuals and patients with IBD collected and stored at our institute, University of Colorado. We hypothesize that altered expression or function of AIOLOS in human T cells leads to excessive activation of CD4⁺ and CD8⁺ T cells in some IBD patients, resulting in chronic intestinal inflammation. In Aim 1, we will investigate the functional role of AIOLOS in human T cell activation by utilizing CRISPR-Cas9 genome-editing technology to delete AIOLOS in human T cells. After AIOLOS deletion, we will assess how its absence impacts T cell functions, including cytokine production and proliferation in response to cytokine stimulation. We will also analyze the transcriptomic changes resulting from AIOLOS deletion using RNA-seq. In Aim 2, we will compare AIOLOS expression patterns between healthy individuals and patients with IBD. We will isolate peripheral blood mononuclear cells (PBMCs) from both groups, stimulate T cells with various cytokines (IL-2, IL-6, IL-12, IFNα), and analyze AIOLOS expression using flow cytometry. Additionally, we will compare AIOLOS expression in T cells isolated from the inflamed intestinal tissues of IBD patients to those from healthy control intestines to determine whether its expression is altered in the local immune environment. By integrating our murine findings with human studies, we aim to create a comprehensive understanding of AIOLOS's role across species, strengthening the translational potential of our research. This approach allows us to build on established mechanisms from murine models while assessing their relevance to human health and disease. Overall, this study will enhance our understanding of AIOLOS’s role in human T cell biology and its potential contribution to immune dysregulation in IBD.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Mitochondrial dysfunction is rapidly emerging as a mediator in the pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease (CD). Recent mitochondrial studies from my lab have implicated chronic dysfunction in Paneth cells as a mediator of ileitis in mice (9). Paneth cells are secretory intestinal epithelial cells (IECs) most abundant in the ileum that contribute to gut homeostasis and innate immunity through secretion of antimicrobial peptides and intestinal stem cell factors (10). Paneth cell subsets have been identified with distinguishing transcriptomic signatures and secretomes based on intestinal location or disease state. 20- 50% of CD patients exhibit PCs with altered secretory granule phenotype that correlate with worse clinical outcomes, gut microbiota dysbiosis, and decreased expression of many mitochondrial-related genes including subunits of electron transport chain complex I. Our preliminary data suggest that these altered PCs also associate with increased CD74 expression, a marker of an inflammatory PC subset. As a novel model to mimic this mitochondrial dampening at complex I, we generated mice with deletion of Prohibitin 1 (PHB1) specifically in PCs driven by Defa6Cre (Phb1∆PC). PHB1 serves as a mitochondrial chaperone protein of the electron transport chain complex I subunits. Loss of PHB1 drives increased mitochondrial ROS (mtROS) due to malfunction of the electron transport chain. ROS are well-established signaling molecules often originating in the mitochondria, driving cell responses that are initiated by this organelle. Phb1∆PC mice develop spontaneous ileitis at 16-20 weeks of age that is preceded by Paneth cell abnormalities similar to those in CD ileitis patients and that our new preliminary data suggest is the manifestation of an inflammatory Cd74+ PC subtype dependent on mtROS. Counterintuitively, at 8 weeks of age prior to the onset of spontaneous ileitis, Phb1∆PC mice are protected when challenged with acute Salmonella typhimurium infection. Recently, host IL-18 has emerged as crucial for PC-induced defense, with specificity driven by predominant IL-18 receptor expression in PCs versus other IECs (23). Our preliminary data demonstrate that IL-18 induces TRAF6-dependent mtROS production and expression of Cd74 in PCs. PHB1 is K63-linked ubiquitinated during IL-18 treatment dependent on TRAF6, suggesting that PHB1 is a novel target of TRAF6-mediated ubiquitination, a post-translational modification linked to altered protein-protein interaction and altered protein trafficking (85). We will test the hypothesis is that IL-18 induces an inflammatory PC subtype driven by mitochondrial-derived reactive oxygen species (mtROS) signaling that is beneficial during acute infection, but when persistent, drives ileitis. We propose 2 specific aims: Aim 1) Define mitochondrial-induced expansion of CD74+ inflammatory PCs to impact intestinal homeostasis; Aim 2) Identify IL-18 mechanism driving mitochondrial signaling to induce ileal inflammatory PCs.

NIH Research Projects · FY 2025 · 2025-09

Sex chromosome aneuploidy (SCA) conditions are a family of genetic disorders resulting from an atypical number of X or Y chromosomes. The enduring outcomes of this project will be to unite SCA communities around clinical priorities for future translational studies and to facilitate community evaluation of available outcome measurement approaches. We will employ a comprehensive set of iterative community-based participatory research (CBPR) techniques to deeply engage a large group of SCA community stakeholder partners, including the many youths with SCA who have neurocognitive disorders such as autism spectrum disorder, attention deficit hyperactivity disorder, or learning disabilities. We will focus on adolescents and young adults between 13-25 years old, a period that captures the full transition and launch to adulthood period in SCA. Our CBPR approach will identify research priorities that are shared across SCA groups as well as priorities that are specific to individual SCA groups and patient vs. parent/provider stakeholders. Aim 1 will engage the SCA stakeholder team using a modified Delphi process to identify critical consensus priorities, approximately 2-4 cross-cutting priorities endorsed by most or all stakeholders (youth, parent, provider). In Aim 1, we may also identify critical subgroup priorities. The overarching goal is to identify patient-centered priorities for clinical trials outcome research. In Aim 2, available candidate outcome measures of critical stakeholder priorities are identified using a multi-input approach. Candidate measures will be identified using three approaches: (1) expert clinician providers from Aim 1 will complete brief interviews with study staff to discuss candidate measures of the key priority outcomes based on measures they use and endorse for youths with SCA or measures that know of that could be used; (2) rapid reviews will be conducted for each critical priority identified by the stakeholders, with the focused goal of identifying potential measures; and (3) the full investigator team across the NASCARR network will be asked to provide additional candidate measures for stakeholder priorities. In Aim 3, stakeholders will review available measures and propose top candidate measures for each of the Aim 1 identified stakeholder outcome measurement priorities: (1) measures that meet community/expert review standards for measuring a key outcome; (2) measures that—with revision—could meet community/expert review standards; and (3) key gaps in measurement (i.e., priority outcomes for which there is no satisfactory measure). Along with codifying measures according to the above schema, the richness of the stakeholder qualitative reactions to the measures will inform future measure revision and measure development. The short-term goal of this work is to understand stakeholder priorities around health- and quality of life-relevant outcomes that can be measured in clinical trials. The long-term goal is to develop a stakeholder-driven framework for outcomes measurement to facilitate SCA patient-centered clinical trials. Building on the connection and trust established in Project 2, the outcomes that emerge from this process will generate several types of impactful follow up studies to advance SCA clinical trial readiness.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Glaucoma is the second leading cause of blindness, characterized by progressive damage to the optic nerve. About 80 million people are globally affected by this disease, and nearly 11 million are blind from it. Primary open-angle glaucoma (POAG) is the most common type and accounts for up to 80% of all glaucoma cases. It is characterized by an open, normal-appearing anterior chamber angle and elevated intraocular pressure (IOP) with no specific ocular abnormalities. The elevation of IOP, a significant and only modifiable risk factor in POAG, is due to the greater resistance of the drainage system. About 80–90% of aqueous humor exits the eye via the trabecular meshwork (TM). TM cells synthesize and secrete extracellular matrix (ECM) proteins, which have negligible turnover and accumulate chemical modifications during aging. The overarching hypothesis of this proposal is that the accumulation of advanced glycation end products (AGEs) in TM promotes ECM protein synthesis by the TM cells and causes resistance to AH outflow in POAG. This hypothesis will be tested by the following two specific aims. In Aim 1, we will test the hypothesis that AGEs in the TM lead to ECM remodeling and TM cell dysfunction. To test this, we will compare AGE levels in TM tissues from POAG patients and controls, examine AGE-induced ECM and cellular changes, perform RNA sequencing to identify affected signaling pathways, and assess the therapeutic potential of an AGE receptor antagonist. In Aim 2, we will investigate whether increasing AGE levels in TM contributes to increased outflow resistance and IOP elevation, using a sustained-release system to deliver AGE precursors into mouse eyes. By targeting AGE receptor utilizing a receptor antagonist treatment or receptor-deficient mice, we will explore the therapeutic potential of targeting AGE-RAGE interaction to mitigate TM damage and reduce outflow resistance. The proposed project is expected to uncover a novel mechanism for aqueous outflow resistance, and the findings could lead to innovative therapies to reduce IOP in POAG.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Infants exposed in utero to maternal inflammatory disorders are at risk of long-lasting health impacts, such as altered neurodevelopmental outcomes or dysregulated immune responses. When maternal infections are the inflammatory stimulus, these adverse neonatal outcomes can occur in the absence of congenital infection. Our preliminary data show that infants who are HIV-exposed, but uninfected experience high rates of morbidity and mortality that are associated with maternal inflammation in a dose-dependent fashion. Early reports suggest that acute maternal infection with COVID-19 can have profound impacts on fetal immune development. Inflammatory signaling across the maternal-fetal interface during a critical fetal developmental window is likely to be responsible for these adverse neonatal outcomes. However, critical gaps exist in our understanding of how inflammatory signals are transferred across the placenta. The overarching goal of this proposal is to determine the cellular and molecular mechanisms involved in the transfer of inflammatory signals across the maternal-fetal interface in the setting of acute or chronic viral infection. We will capitalize upon access to samples from pregnancies complicated by either HIV, which results in chronic inflammation, or SARS-CoV-2, which causes severe acute inflammation, to address the following Specific Aims: 1) to profile the transcriptomic signatures of heterogenous maternal and fetal cell types in their in situ environment within placentas from pregnancies affected by HIV or SARS-CoV-2 versus healthy pregnancies; 2) to compare concentrations of inflammatory and regulatory biomarkers in maternal and infant peripheral blood, cord blood and placentas from term pregnancies affected by HIV or SARS-CoV-2 versus healthy pregnancies and determine their association with placental gene expression; and 3) to characterize inflammatory signaling across the maternal-fetal interface using a 3- dimensional in vitro model that incorporates key placental cell types. This proposal includes several innovative components, including the use of advanced bioinformatics to directly correlate placental gene expression data from a single-cell spatial transcriptomics assay to the peripheral concentrations of inflammatory biomarkers within the same participants, and the development of a novel Transwell-based model of the human placenta that can be used to mechanistically interrogate the role of each cell type in the transfer or inflammatory signals. Disentangling the mechanisms responsible for the transfer of inflammation across the maternal-fetal interface will ultimately allow for the identification of therapeutic agents to modulate inflammation in pregnancy, thereby preventing adverse neurodevelopmental and/or immunologic consequences to the fetus.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Acute exacerbations are the primary cause of morbidity and mortality among children with asthma. Current treatment for acute asthma exacerbations in the pediatric emergency department (ED) follows a “one-size-fits- all” approach, including inhaled bronchodilators and systemic corticosteroids. However, treatment response to initial protocolized therapies is variable and unpredictable presenting a significant management challenge for ED clinicians. The factors driving the heterogeneity in ED treatment response are poorly understood, which has impeded accurate prediction of treatment response, development of effective therapeutics, and advances in ED asthma management. Thus, there is a critical need to better characterize the factors driving treatment response to inform precise ED treatment strategies for asthma exacerbations. We have found that almost all ED asthma exacerbations are associated with a respiratory virus and that specific viral species influence ED treatment response. However, the role of nonviral causes of asthma exacerbations, such as outdoor air pollution and environmental allergens, are less understood. These critical environmental factors are strongly associated with asthma exacerbation occurrence and severity, but their impact on treatment response remains unknown. This R03 application proposes a proof-of-principle study to investigate the role of outdoor air pollution and environmental allergens in driving treatment response in children with asthma exacerbations in the ED. Leveraging robust clinical data and banked biosamples, we will determine the association between outdoor air pollutant exposure (Aim 1) and aeroallergen sensitization (Aim 2) and acute asthma exacerbation treatment responsiveness in the ED. This work builds on the PI’s K23 findings and will provide critical preliminary data for a multicenter R01 application aimed at validation of a comprehensive clinical prediction rule incorporating environmental, biologic, and physiologic predictors to differentiate ED treatment responsiveness early in the ED course. An effective prediction rule will improve outcomes by guiding clinical decisions and facilitating timely and appropriate therapeutic interventions and disposition decisions. This work represents a paradigm shift in the ED by moving from a “one-size-fits-all” to a personalized, phenotype- directed approach for the management of asthma exacerbations.

NIH Research Projects · FY 2025 · 2025-09

(PLEASE KEEP IN WORD, DO NOT PDF) Inherited Bone Marrow Failure Syndromes (IBMFS) constitute a rare set of disorders leading to an inability to generate functional circulating blood cells leading to morbidity and mortality. Many of these disorders are accompanied by pleiotropic developmental disorders. To date, we still lack definitive cures beyond highly toxic hematopoietic stem cell transplant. Decades of prior work has advanced our knowledge on these diseases and the fundamental roles that mutated causative genes play in normal hematopoiesis. However, nearly half of patients with IBMFS lack a clear genetic etiology, demonstrating the essential knowledge gap to understand genetic processes underlying marrow failure and devise new targeted therapies. Here, we present a novel, de novo, heterozygous mutation at Valine 343 to Methionine in Taspase1 (Tasp1V343M) in a child with an array of development anomalies and marrow failure. Tasp1V343M leads to failure of hematopoietic expansion and retention of early erythroid precursors in patient-derived iPSCs. Taspase1 is a highly conserved protease exerting effects on gene expression by proteolytic cleavage of target substrates. Molecular modeling demonstrates Tasp1V343M introduces intramolecular interactions leading to impaired flexibility of a domain allowing access to the proteolytic active site. Functionally, Tasp1V343M abrogates cleavage of TFIIA, a key member of the PreInitiation Complex (PIC) responsible for directing activation of RNA Polymerase II at promoters of mRNA. Furthermore, loss of TFIIA cleavage by Tasp1V343M leads to alterations of RNA Pol II promoter occupancy in iPSCs. These observations leave two unanswered questions of 1.) Does Tasp1V343M constitute a bone fide new marrow failure syndrome? and 2.) How does alteration of TFIIA reorchestrate transcriptomes in early development? Prior murine models of Taspase required homozygous deletion to manifest phenotypes implying Tasp1V343M is acting as a dominant negative. We will employ an array of genetic models including Tasp1V343M repair and non-cleavable TFIIA to demonstrate sufficiency of this mutation on hematopoiesis in vivo and delineate epistatic downstream mediators of Tasp1V343M marrow failure. Interestingly, noncleaved TFIIA has been postulated to direct RNA Pol II transcription in embryonic states independent of canonical PIC. We will investigate how uncleaved TFIIA alters RNA Pol II specificity genome wide, isolate determinants of target promoters and map these interactions across a model of erythropoiesis. This research will unlock a fundamental question on the diversity of mechanisms used to direct RNA Polymerase II in development and offer insight into a mechanism occurring early enough to impact pleiotropic tissue patterning and expand our knowledge of the pathophysiology of IBMFS.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT This NIMH Career Development Award will support Dr. Drew Winters at the University of Colorado School of Medicine to conduct a trial focusing on transcranial magnetic stimulation (TMS) for intervention development in psychopathy. Dr. Winters will enroll adults ages 18-60 years (n=60) with psychopathy to test whether inhibitory TMS to the right dorsolateral prefrontal cortex (dlPFC) and excitatory TMS the right temporoparietal junction (TPJ) can improve social cognition (Aim 1), cognitive processing (Aim 2) and functional brain architecture (Aim 3). The career development plan supports the research aims and includes these training goals: 1) Develop expertise in TMS as a research tool; 2) Develop expertise in randomized controlled trial (RCT) design, implementation and analyses; 3) Develop expertise in analysis of brain data from TMS experiments to make causal inferences; 4) Develop expertise in psychopathic mechanisms. His mentors, Drs. Sakai, Mikulich, Oathes, and Waller are recognized experts in TMS, neuroimaging, statistics, clinical trials, advanced computational methods and causal inference with brain data, as well as psychopathy. The training plan and research protocol proposed under this career development award would provide the needed experiences, skill development and pilot data to help to launch Dr. Winters’ career as an independent scientist focusing on the neural mechanisms underlying social cognition, cognitive processing, and functional brain architecture implicated in psychopathy and antisocial phenotypes, along with novel treatment development.