University Of Colorado Denver

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY Craniofacial anomalies account for one third of all birth defects and are a significant cause of infant mortality. Neural crest cells (NCC) give rise to the majority of craniofacial bone, cartilage, and connective tissue and un- derstanding their development is crucial for advancing the prevention of craniofacial birth defects. Disruptions in NCC development are known to underlie several craniofacial disorders including Treacher Collins syndrome, which is caused by mutations in TCOF1, POLR1B, POLR1C, and POLR1D. POLR1C and POLR1D are subu- nits of both RNA Polymerases (Pol) I and III and are important for transcription of ribosomal RNA. I previously demonstrated in polr1c and polr1d zebrafish models that ribosomal RNA transcription is reduced leading to Tp53-dependent cell death of NCC progenitors which results in craniofacial anomalies. However, how global disruptions in polr1c and polr1d specifically affect NCC development remains unresolved and the contribution of Pol III, which transcribes non-coding RNAs including 5S ribosomal RNA and transfer RNAs, to craniofacial development is not known. I hypothesize that in addition to disruption of Pol I transcription in the pathogenesis of Treacher Collins syndrome, Pol III transcription is also disrupted and contributes to the tissue-specific phe- notypes observed. Transcripts produced by Pol III, including tRNAs, have been shown in multiple systems to be tissue-specifically expressed. To generate a new understanding of the role of Pol III transcription specifically in NCC, I will receive training in profiling NCC for changes in Pol III transcripts and in evaluating the effect of these changes on translation. It has been postulated that distinct pathogenic variants in POLR3A, the largest subunit of Pol III, lead to differential effects on Pol III transcription. In order to test this hypothesis in a NCC- specific manner, I will use hiPSCs derived from patient fibroblasts with pathogenic variants in POLR3A and analyze them for proliferation, translation, differentiation, and Pol I and III transcription. Given the prevalence of dental anomalies in individuals with mutations in POLR3A, I expect to identify Pol III-specific effects in a subset of NCC derivatives. In the independent phase of this award, I will generate new zebrafish models to under- stand the role of specific variants in Pol III in a developmental context and assess NCC formation, migration, differentiation, and proliferation in combination with the effect on Pol I and III transcription. These models will provide new resources to the research community for the understanding of Pol III transcription. Altogether, I will receive the training necessary to analyze Pol III transcription and translation and model patient-specific var- iants in NCC which will form the foundation of my independent research program and further my goal of under- standing and preventing craniofacial birth defects.

NIH Research Projects · FY 2026 · 2024-04

Project Summary The proposed project will examine the mechanisms by which ethanol-related dementia is greater in older subjects. We live in a rapidly aging society which as been designed the “Silver Tsunami” of individuals aged 65 or older (i.e. advanced age, aged). Accordingly, the number of chronic diseases, including age-related dementia, is increasing and 90% of dementia cases are sporadic and driven by environmental cues. Approximately forty percent of aged adults consume alcohol and the prevalence of binge drinking in older adults is on the rise. Despite these trends, there are significant gaps in knowledge related to the health impacts of alcohol use and misuse in individuals with advanced age; this proposal aims to fill these gaps in knowledge. Chronic inflammation is a critical driving factor of neurodegeneration and cognitive decline and is independently increased by both age and alcohol. We and others hypothesize that heightened inflammatory responses predisposing older individuals to alcohol-induced end organ damage is at least partly attributed to the effects of low-grade chronic inflammation that increases with age, termed "inflamm-aging." Because both inflamm-aging and alcohol independently and negatively impact the resident macrophages in the brain, the microglia, is our working hypothesis that relative to young, older subjects have heightened inflammatory responses that fail to resolve, leading to excessive systemic and neuroinflammation and damage to critical organs like the brain. Accordingly, the associated hippocampal damage will drive accelerated cognitive decline and early onset dementia. In this proposal, we will explore how age and alcohol impact the expression of regulatory miRNAs in microglia, and determine if these changes result as 1) a direct effect of ethanol toxicity and 2) an indirect effect via the gut-brain axis. To investigate the role of alcohol and age on neuroinflammatory responses, in Aim1 we will make use of a novel mouse model of binge ethanol exposure to establish the neurotoxic effects of alcohol on disease progression and early onset dementia in aged mice. We will also make use of primary microglia from young and aged mice and profile the microRNA/mRNA landscape in response to in vivo ethanol exposure. In Aim 2, we will examine the role of miR223 as an important regulatory factor modulating inflammatory responses in microglia and will establish if gene therapy replacement of miR223 will prevent ethanol-induced neuroinflammation and dementia in aged mice. Finally, Aim 3 will focus on the gut-brain axis and will be able, for the first time, to monitor age-related shifts in the microbiome and determine if age-related intestinal dysbiosis can predispose neuroinflammatory responses to alcohol, via elevated systemic inflammation and changes to regulatory miRNAs in microglia. These studies will expand our understanding of how components of “inflamm-aging” lead to dysregulated miRNA profiles in immunomodulatory components in the brain, which are critical sensitizing factors during bouts of ethanol exposure and withdrawal. Importantly, this work may highlight/discover novel targets leading to the development of therapeutic strategies to improve or prevent early onset dementia in patients of all ages.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY Age related hearing Loss (ARHL) is one of the most common chronic conditions affecting nearly one third of the world's population over 60 years. Hearing aids (HAs) are the most commonly used and effective treatment for people with ARHL. However, hearing aid uptake is low with only one in 4 people with hearing loss using HA in high-income countries. This low uptake has been attributed to several multilevel factors including awareness, high cost of the device, stigma, and perceived need. To address accessibility and affordability issues with HAs, the U.S. Congress passed a new Over-the-Counter Hearing Aid (OTC HA) act in 2017. In August 2022, the FDA finalized this legislation creating a new OTC HA category, which allows consumers to purchase a HA without consulting a hearing care professional (HCP), significantly reducing the cost of these devices. Unlike a traditional gold standard HA acquisition model where users need an in-person consultation with HCPs to obtain prescription hearing aids, OTC HA do not have any requirements for consultation with HCPs. In anticipation of OTC HA, several new service delivery models for HA provision have become evident in the US. These include: OTC HA fit by a HCP using audiology best practices (OTC-HCP), OTC HA fit to individual users using some best practices via remote consultation (OTC-R), and users purchasing self-fit OTC HAs without any clinical support from HCPs (OTC-SF). These new service delivery models, if proven effective, are likely to improve accessibility and affordability of HAs. However, concerns remain about their safety and unproven efficacy given that these models are newly emerging. The overall aim of the proposed project is to evaluate the comparative effectiveness of emerging OTC service delivery models (OTC-HCP, OTC-R, OTC-SF) with the gold standard traditional HA-HCP model. We propose a prospective four-arm randomized controlled trial (RCT) design with longitudinal repeated measures. This trial will be a type 1 hybrid effectiveness-implementation study in which we will simultaneously examine the implementability of the different service delivery models. Aim 1 will focus on comparing the effectiveness of HA intervention delivered via four service delivery models (i.e., HA-HCP, OTC-HCP, OTC-R, and OTC-SF) using self-reported, behavioral, and cognitive outcomes in an RCT. In the same study, Aim 2 involves comparing the neurophysiologic outcomes between the HA service delivery models. Finally, Aim 3 focuses on optimizing implementability of OTC HA service delivery from multiple multilevel perspectives. The proposed research is conducted by a multidisciplinary team with expertise in audiology, cognition, neuroplasticity, health information technology, implementation science, digital hearing, qualitative and mixed methods approach, and healthcare economic. Results of our study will provide an urgently needed detailed examination of the effectiveness of emerging service delivery models for OTC HAs compared to the traditional gold standard HCP model for adults with mild-moderate ARHL informing clinical practice and policy recommendations.

NIH Research Projects · FY 2026 · 2024-04

The complement system plays an important role in a diverse spectrum of kidney diseases, including autoimmune glomerulonephritis as well as many conditions not traditionally thought of as immune-mediated. Factor H (FH) is a centrally important complement protein in the blood that serves as a major regulator of complement activation in both the fluid phase as well as on cell surfaces and interstitial matrices. Factor H- related proteins (FHRs) comprise a structurally related family of five genes in humans which have recently been identified as key pathogenic drivers of human kidney diseases by acting as modulators of complement and/or FH function. However, the functions of the FHRs are complex and controversial. In addition, animal models of individual FHR deficiency and FHR protein-specific monoclonal antibodies (mAbs) were not previously available for evaluating the in vivo roles of these proteins. Our proposal addresses this important knowledge gap. The overall hypothesis of this project is that individual FHRs competitively antagonize or otherwise modulate FH function and complement activation on specific surfaces in the kidney, and this has a profound effect on complement-mediated inflammation at these sites. Furthermore, by interfering with C3d- receptor interactions, the FHRs also have a strong effect on the upstream immune response to self and foreign antigens. To test this hypothesis we propose the following specific aims. Aim 1. Examine the functions of the different FHRs on distinct kidney surfaces. We have developed a “toolbox” for studying the FHRs in the kidney, including mice with targeted deletion of the individual FHRs, recombinant forms of the FHRs, and monoclonal antibodies to the FHRs. We will use these tools to map the interactions of the FHRs with healthy and diseased kidneys. Aim 2. Examine the roles of individual murine FHRs in the development of autoimmunity. We will use panel of FHR deficient mice to study the effects of these proteins on the development of antibodies to self and foreign antigens. Aim 3. Examine the role of the FHRs as downstream mediators of kidney inflammation. We will use FHR-deficient mice and recombinant FHR proteins to examine the role of the FHRs in causing complement dysregulation in glomerular and tubulointerstitial diseases. The studies in this proposal are innovative, because they utilize novel reagents and approaches to examine the function of the FHRs. This project is significant, because will improve our understanding of a family of proteins that are poorly understood but that have been linked with several different diseases.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY American Indian (AI) youth demonstrate early substance use initiation and subsequently high substance misuse rates. One factor contributing to this is the relative lack of prevention strategies that leverage contextual and cultural strengths to optimize effectiveness and sustainability. Rich cultural and traditional practices make interpersonal relationships particularly vital for AI youth, but these networks are largely untapped in prevention approaches. Research in other populations demonstrates social networks' roles in risk and resilience. However, data on AI social networks are sparse, and data on how networks relate to risk for early substance use is virtually nonexistent. Preliminary data from the Tribal Reservation Adolescent Connections Study (R21DA053789) confirmed suspicions that social network theories require some adaptation to the culture and context of AI communities. The proposed study will collect quantitative social network surveys among adolescents and community organizations and qualitative interviews with adolescents on a Northern Plains reservation to explore how these networks are structured, the principles under which they operate, and their influence on behavior over critical periods of adolescence. Network characteristics will be examined in relation to substance use, suicide, and exposure to violence, to understand how and when networks impact risk and resilience. A cohort sequential longitudinal and explanatory sequential mixed method design (QUAN → Qual) will be used to accomplish three specific aims: Aim 1: Identify changes in AI adolescents’ peer and kinship social networks over time. Hypothesis: Social network composition and structure will change from late childhood into late adolescence and those changes will include shifts in network size, proportion of family in networks, and gender homophily. Aim 2: Analyze community-based interorganizational networks among youth-serving institutions. Hypothesis: These networks will vary over time and location, resulting in varied coordination of youth services across communities. Aim 3: Test the relationship of peer, kinship, and community-based network characteristics to trajectories of substance use over time and in combination with violence and suicide. Hypothesis: Trajectories of substance use, violence, and suicide will be related and influenced by both stable and dynamic youth and community networks. This project will be led by a team of early-stage Principal Investigators who are American Indian and Alaska Native. They have expertise in substance use, exposure to violence and suicide among AIs, expertise in community-engaged research with tribal communities, social network analyses, and quantitative, qualitative, and mixed methods approaches. This leadership team will be supported by two senior researchers with experience in areas relevant to this study and 20 years of experience conducting research with the reservation where the study will take place and an expert in longitudinal social network analysis at the individual and community level.

NIH Research Projects · FY 2026 · 2024-04

Project Summary Taste buds are the end organs of the gustatory system and allow for the detection of sweet, bitter, umami, salty, and sour stimuli. In mammals, taste buds inhabit several areas of the oral cavity, including the fungiform papillae of the anterior tongue and the circumvallate papillae of the posterior tongue. Two separate taste nerves innervate the anterior and posterior tongue; the chorda tympani branch of the facial nerve innervates the fungiform taste buds, while the glossopharyngeal nerve innervates the circumvallate taste buds. While buds from both fungiform and circumvallate tissues can detect the five established taste qualities, several lines of evidence suggest differences between anterior and posterior taste buds in both form and function (Travers et al., 1987; Ninomiya & Funakoshi, 1989; Frank 1991; Ninomiya et al., 1991; Spector & Grill 1992; Hellekant et al., 1997; St. John & Spector, 1998; Tomchik et al., 2007; Yoshida et al., 2009; Lewandowski et al., 2016). Most of the anatomical taste bud data in the literature feature only the circumvallate taste buds—this is likely due to the relative ease of isolating taste buds from the closely packed buds of the circumvallate tissue rather than the sparse buds of the fungiform tissue. The cellular composition of taste buds, detailed taste cell morphology, and patterns of connectivity between taste cells and innervating nerve fibers have been reported in circumvallate tissue (Romanov et al., 2018; Yang et al., 2020; Wilson et al., 2022). The current proposal aims to close the anatomical knowledge gap across taste fields by examining fungiform taste buds via Serial Block Face Scanning Electron Microscopy (sbfSEM). This high-resolution imaging technique can produce serial electron micrographs through entire mouse fungiform taste buds. When aligned and imported into specialized imaging software, objects in the mass of the taste bud can be manually traced and reconstructed in digital 3D space. To augment the manual segmentation process, this project will also employ machine learning techniques to identify and segment a portion of the objects of interest in the dataset. Using micrographs and the 3-D reconstructions of objects therein, this project will unveil morphological details of fungiform taste cells. It will reveal whether or not morphological subsets of the three established mature taste cells exist in fungiform taste buds, and whether or not their morphologies differ from those described in the circumvallate. By reconstructing the nerve fibers that receive synapses from fungiform taste cells, the proposed project will also reveal the “connectome” of the fungiform taste buds. Anatomical patterns of connectivity between taste cells and innervating nerve fibers underlie the taste information coding from taste bud to the central nervous system. Understanding the connectome will thus provide new insight into how fungiform taste buds communicate taste quality information to the brain, and whether their patterns of connectivity differ from those of circumvallate taste buds. By elucidating and describing the morphological details and connectome of fungiform taste buds, this project will expand our understanding of both form and function in the anterior tongue.

NIH Research Projects · FY 2025 · 2024-04

Adoptive transfer T cell-based immunotherapies and checkpoint inhibitor immunotherapy have shown significant promise in the treatment of cancers. However, checkpoint inhibitor therapy still fails in a majority of patients and chimeric antigen receptor (CAR)-T cells are ineffective against most solid tumors. In large part, these failures are due to the fact that frequently tumors are mostly devoid of T cells or that T cells are present only in the tumor-surrounding stroma but largely excluded from the tumor mass. Tumors are often surrounded by extensive collagen-rich extracellular matrix (ECM) structures, which impede the entry of T cells into the tumor mass. T cell paucity or exclusion from the tumor site correlate with poor prognosis, limited efficacy of checkpoint inhibitor immunotherapies, and ineffectiveness of CAR-T cell therapy against solid tumors. Most cellular tumor immunotherapy approaches to date have focused on reversing T cell exhaustion and increasing persistence of tumor-specific T cells and CAR-T cells. However, these approaches generally do not solve the issue of recruitment and infiltration of therapeutic T cells into the tumor. The overall goal of this proposal is to engineer T cells to enhance their migration into tumors to increase their anti-tumor activity in ‘cold’ tumors and tumors that exclude T cells from the tumor mass. Our exploratory R21 proposal specifically addresses the unmet need to improve migration of T cells into tumors by creating T cells with increased capacity to migrate through restrictive environments. We have found that Formin-like-1 (FMNL1) promotes efficient T cell extravasation, motility through confined environments, and interstitial migration in vivo. Furthermore, our preliminary data using a melanoma model show that overexpression of FMNL1 significantly increases the number of tumor-specific T cells present at the tumor site. Thus, we hypothesize that T cells engineered to overexpress FMNL1, or its active mutants, will have increased trafficking to the tumor site, deeper infiltration into the tumor mass, and enhanced anti-tumor activity. We will test our hypothesis with the following Aims: Aim 1. Determine if overexpression of FMNL1 or its active mutants enhances tumor-specific T cell migration and accumulation within tumors. Aim 2. Determine if T cells engineered to overexpress FMNL1 have increased anti-tumor activity and improve the efficacy of checkpoint inhibitor therapy. Overall, we will establish and validate a platform for T cell bioengineering to improve T cell migration into tumor sites that can be applied to tumor-infiltrating lymphocyte (TIL) transfer therapy and CAR-T cell therapy for solid tumors. Our novel approach can both improve the ability of T cells to extravasate at the tumor site, and enhance the capacity of T cells to migrate through restrictive tissue barriers to infiltrate the tumor mass. From a future translational standpoint, an additional advantage of this system is that the T cell infiltration enhancement provided by FMNL1 is not limited to a particular tumor antigen and is not MHC restricted. Overall, our work has the potential to significantly improve the treatment of solid tumors using adoptive T cell transfer therapies.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY Thyroid cancer incidence is high, with 44,280 new cases diagnosed in the US in 2021. Thyroid nodule incidence is rising primarily due to increased detection, necessitating more procedures such as fine needle aspiration (FNA) biopsies to rule out cancer. However, most thyroid nodule biopsies produce benign, indeterminate, or non-diagnostic results and are potentially avoidable. Our long-term goal is to improve risk stratification of thyroid nodules, reduce the number of unnecessary biopsies, and minimize the burden of thyroid cancer diagnosis for patients and the healthcare system. Our central hypothesis is that thyroid cancer genetic risk estimate will improve risk stratification of thyroid nodules and reduce the number of avoidable FNA biopsies of benign thyroid nodules. Supported by robust preliminary data, the central hypothesis will be tested by pursuing two specific aims: Aim 1. Define the genetic architecture of thyroid cancer. Aim 2. Develop and assess the clinical utility of a genetic thyroid nodule classifier that discriminates between benign and malignant thyroid nodules. Under the first aim, we will explore genetic associations with thyroid malignancy independent of benign goiter to discover novel thyroid cancer biomarkers and develop a clinically useful polygenic risk score (PRS). We will use two approaches: 1) test genetic associations directly using a GWAS meta-analysis with 4,994 thyroid cancer cases and 20,917 patients with benign nodules as controls, and 2) use a computational GWAS-by-subtraction method to derive summary statistics for the thyroid cancer free from genetic associations with benign nodular goiter. We will use publicly available genome-wide association studies, such as from the Global Biobank Meta-analysis Initiative, and perform our meta-analyses using the Colorado Center for Personalized Medicine Biobank and other Biobanks from around the world. We hypothesize that a thyroid nodule classifier PRS in combination with standard of care Thyroid Imaging Reporting and Data System (TI- RADS) ultrasound schema will improve risk stratification of thyroid nodules and ultimately reduce the number of unnecessary thyroid nodule biopsies. We developed a thyroid nodule classifier PRS that differentiates malignant and benign thyroid nodules with an area under the receiver operating characteristic curve of 0.61. We will apply this score to ~600 thyroid nodules from genotyped patients with known cytologic or histopathologic diagnoses of benign goiter or thyroid cancer. Three expert physicians will estimate TI-RADS points and categories. We will evaluate the efficacy of the TI-RADS algorithm alone and in combination with our novel PRS to distinguish benign from malignant thyroid nodules. We will use the precisely defined genetic landscape of thyroid malignancy (Aim 1) to improve the thyroid nodule classifier PRS. This study will pave the way for personalized management of thyroid nodules and inform future mechanistic studies aimed at better understanding the risk of thyroid cancer.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY/ABSTRACT More than two million people live with limb loss in the United States, nearly one-third of whom express dissatisfaction regarding their socket prosthesis fit. To address socket-based issues, osseointegration is offered as a secondary procedure with a direct connection of the prosthesis to the residual limb through a bone-anchored implant. The direct prosthesis-to-bone connection offers a novel potential benefit to postural control through improved osseoperception (sensation of mechanical stimulation of bones), proprioception (knowledge of the static and dynamic body positioning), and prosthetic limb control. Up to 67% of patients with transfemoral amputation fall at least once annually leading to diminished self-efficacy, fear of falling, and physical activity avoidance. How individuals maintain postural control, an important objective in fall prevention, after osseointegration remains uninvestigated. This F32 study will test a conceptual framework for the impact of prosthesis osseointegration directly on postural control and indirectly through osseoperception and proprioception through a two independent-groups cross-sectional design in 30 patients with unilateral transfemoral amputation (osseointegrated-prosthesis group (n = 15) and socket-prosthesis group (n=15)). Aim 1: Osseoperception and proprioception. Osseoperception will be evaluated with a variable frequency and amplitude vibration platform to identify sensation thresholds. Proprioception will be evaluated with standing joint position reproduction of the knee. Aim 2: Standing and walking postural control. Standing control will be measured using center of pressure trajectories during eyes-opened and eyes-closed standing. Walking control will be measured by step length and width asymmetry and variability. Aim 3: Anticipatory and reactive postural control. Anticipatory control will be measured during the anticipatory postural adjustment phase of gait initiation. Reactive control will be measured with reaction time during standing treadmill perturbations requiring a single recovery step. This proposal will be impactful to the clinical care of people with transfemoral amputations because (1) prosthesis osseointegration offers a unique path to increased osseoperception and proprioception, (2) the effects of prosthesis osseointegration on postural control are largely unknown (3) we will comprehensively evaluate postural control, and (4) we will compare outcomes from individuals with an OI-prosthesis to those with a socket-fit prosthesis without significant fit problems. Achieving these aims will improve our ability to provide targeted postural control training, target decreased fall risk, and improve health outcomes for this new and growing population of people with prosthesis bone-anchored implants. The proposed research and training plan are impactful to Dr. Tracy’s preparation to engage in an effective independent research career centered on the study of postural control in populations at risk for falls by (1) learning clinical skills with a population at risk for falls, (2) developing clinical gait analysis expertise, (3) gaining neurophysiological and advanced statistical tools, and (4) engaging in professional development.

NIH Research Projects · FY 2026 · 2024-03

Cancer patients receiving most types of chemotherapy experience dysgeusia, i.e., distorted taste, which is associated with depression, malnutrition, morbid weight loss, and interruption of life-prolonging treatment. Cells within taste buds are continually and rapidly renewed, and this constant turnover makes taste prone to disruption by cancer therapies. However, the underlying and likely multiple mechanisms perturbed by cancer drugs that cause dysgeusia are not known. Here we focus on a small subset of six tyrosine kinase inhibitors (TKIs) used routinely to manage metastatic renal cell carcinoma (mRCC). These drugs target tumors by inhibiting VEGFR1-3 and PDGFR receptor tyrosine kinases (RTKs). Paradoxically, these receptors are not expressed in taste epithelium, leaving open the question of how these drugs distort taste. It is well known that mRCC TKIs inhibit many off-target RTKs, including the Kit receptor. Via investigation of TKI target data and comparison with RTKs expressed in taste epithelium, we find that Kit is one of the few “taste” RTKs inhibited by all 6 drugs. We now have extensive pilot data that suggest inhibition of Kit may in fact underlie dysgeusia caused by these TKIs and specifically sweet taste is impacted. Preliminarily we show: (1) in mice, Kit is expressed primarily in sweet taste receptor cells (TRCs); (2) TKI treatment of lingual organoids derived from adult mouse taste stem cells leads to reduced expression of Tas1r2, a marker of sweet cells; (3) mice given the TKI cabozantinib have fewer Tas1r2+ sweet TRCs after 2 weeks; and (4) mice have blunted sweet taste function after 4 weeks of cabozantinib. In sum, our preliminary finding suggest the multifaceted hypothesis that: TKIs used to treat kidney cancer impede production of sweet taste cells, and disrupt sweet taste function by inhibiting Kit signaling. Aim 1. To investigate if TKIs used to treat mRCC inhibit sweet TRC differentiation and/or survival. We combine molecular genetic lineage tracing of sweet TRCs with drug treatment in mice (Aim 1A) and organoids (Aim 1B) to assess if sweet TRCs fail to survive TKI treatment or if treatment blocks production of new sweet TRCS. Aim 2. To test if cabozantinib, which cause dysgeusia in patients, alters sweet taste function in mice. Our pilot data suggest sweet taste is specifically impacted, but we cannot rule out effects on other taste modalities. We will use both behavioral assays (Aim 2A) and taste nerve recordings (Aim 2B) to determine if sweet taste is altered in cabozantinib-treated mice and/or if taste function is more broadly impacted. Aim 3. To determine if paracrine Kit signaling within taste buds is required for sweet TRC production. In Aim 3A, we will use western blotting of lingual organoids to assess if Kit signaling is inhibited by mRCC TKIs. Our pilot data reveal SCF, the ligand for the Kit receptor is expressed by glial-like cells and sour TRCs within taste buds. In Aim 3B, we will use conditional molecular genetics in mice to test if glial and sour TRCs signaling via SCF to Kit+ sweet TRCs is required for sweet TRC differentiation and/or survival, and sweet taste function.

NIH Research Projects · FY 2025 · 2024-03

Project Summary: Our project aims to investigate the mechanisms behind the loss of Type 3 innate lymphoid cells (ILC3) in antiretroviral therapy (ART) treated People Living with HIV (PLWH) and the subsequent impact on intestinal epithelial barrier integrity. Chronic immune activation is a hallmark of HIV infection that persists in PLWH on ART and is linked to non-infectious comorbidities. Microbial translocation (MT) due to decreased mucosal barrier integrity is in part responsible for driving HIV-associated inflammation. Therefore, it is critical to understand mechanisms underlying barrier integrity in ART treated PLWH. ILC3s are essential for the maintenance of the gut epithelial barrier and are depleted during early HIV infection and are not restored with ART. Decreased frequency of these cells during HIV infection likely contributes to decreased epithelial barrier integrity leading to increased MT. Since ILC3s are not susceptible to direct HIV infection and a viable model to study their loss has yet to be developed, the mechanism behind their loss remains poorly understood. To address this gap in knowledge, we will use human intestinal explants as a model system to study early HIV infection. These explant tissues contain ILC3s, epithelial cells, and other immune cells that are susceptible to HIV infection. Our preliminary data show that these explant tissues remain viable for up to 7 days, can harbor HIV infection and ILC3s are depleted following HIV infection, providing this as a viable model to study HIV-associated ILC3 depletion. Furthermore, we and others have shown that ILC3s respond to specific bacteria found in the gut microbiome. This is emphasized as PLWH have a distinct enteric microbiome that is not reverted with ART. To fully model the intestinal environment during HIV infection, and the subsequent impact on ILC3 function, we will introduce an HIV-associated microbiome to the intestinal explant tissues. Ultimately, using these explants with HIV infection and HIV-associated microbiomes will shed light on the underlying mechanisms behind the loss of ILC3s and the effect on intestinal epithelial barrier integrity. This understanding could lead to the development of new therapeutic approaches to improve barrier integrity and reduce HIV-associated inflammation and comorbidities in PLWH.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY The heart combines several cell types and lineages to form a functional unit. The pericardium forms the pericardial cavity and outer-most epithelial layers around the heart. Often regarded as mere heart-surrounding mesothelium, the highly specialized pericardium provides mechanical support to the heart, sustains heart muscle and coronary vessel growth, coordinates the response to inflammation, and supports myocardial remodeling upon injury. Pericardial defects remain underdiagnosed and result in severe complications upon heart or lung surgery. Decoding the mechanisms of pericardium formation is critical to understanding congenital heart anomalies and improve regenerative approaches for heart injury and post-surgical healing. What developmental mechanisms endow the pericardium with its unique properties, how it controls its dynamic interaction with the heart, and how we can harness its plasticity in therapeutic settings, remain understudied. Studying pericardium formation has remained challenging due to missing means to visualize, track, and isolate earliest embryonic cells leading to its development. The goal of our research proposal is to uncover the mechanisms that drive pericardium development in coordination with the heart from lateral plate mesoderm (LPM); we will combine our unique in vivo tools in zebrafish for in toto live imaging, lineage tracing, enhancer discovery, and single cell-based transcriptome analysis. The zebrafish is an ideal model to study cardiac development with genetically malleable, visually transparent embryos. We established leading genetic means to observe, track, and isolate the earliest LPM progenitors, and we have used these advances to image first steps in LPM emergence, heart development, and mesothelium formation. Uniquely suited to pursue pericardium development, we now lineage-mapped and live-imaged its origin not among cardiac, but mesothelium progenitors, challenging our view of the pericardium as heart lineage per se. With single-cell approaches, mutants, and gene-regulatory experiments, we found that expression and function of the transcription factor Hand2 supports pericardial progenitors in the LPM, in part in cooperation with canonical Wnt signaling. We hypothesize that the pericardium forms as mesothelial lineage with input from Hand2 to convey unique properties in development and disease. In Aim 1, we will test the distinct lineage origins of pericardial versus heart progenitors using photocovertible- and multispectral Cre/lox-lineage labeling plus single-cell multiomics to define the gene-regulatory trajectory of pericardium formation. In Aim 2, we will test the synergy of Hand2 with canonical Wnt signaling and will pursue how individual target genes are controlled. Our work advances our concepts of pericardial orgins and mechanisms of its development, regeneration, and pathologies. Our molecular insights help guide and improve the in vitro generation of pericardial cells for regenerative applications.

NIH Research Projects · FY 2026 · 2024-03

Project Summary Firearms are the leading cause of death among children and adolescents in the United States. They are also the most lethal means of suicide - more than 90% of youth who attempt suicide with a firearm will die. Limiting access to firearms for individuals at elevated risk for suicide, a component of lethal means safety counseling, is an underutilized evidence-based suicide prevention strategy. In addition to being a safety net for vulnerable youth, Emergency Departments (EDs) across the country have begun screening patients for suicide risk. Yet, lethal means counseling does not occur in most circumstances in which it’s indicated. Previous studies have developed tools, for example Lock to Live, to support adults at elevated suicide risk in the ED setting. Existing lethal means interventions for teens were developed with caregivers of teens at elevated suicide risk, and engage only caregivers in lethal means safety planning, thereby failing to address the teen voice in limiting firearm access. This proposal aims to leverage user-centered design methods to develop a user friendly teen-centered lethal means safety planning tool for teens presenting to the ED by pursuing the following aims: 1) Assess perspectives of teens at elevated risk for suicide and their caregivers around current lethal means safety planning tools using qualitative methods, 2) Adapt an intervention with teens and caregivers to co-design a tool that addresses both teen and caregiver firearm access, and 3) Test the acceptability and feasibility of the intervention in a pilot trial. As a pediatric emergency medicine physician and prior administrative leader, Dr. Maya Haasz is familiar with the benefits, challenges, and operational considerations of implementing this intervention in the Emergency Department. Her clinical experience and research expertise position her to complete the proposed K23 research and training aims. Dr. Haasz’s long- term goal is to become an independent investigator with a research program focused on reducing firearm morbidity and mortality in children and adolescents. To this end, she has developed a detailed career development plan consisting of guided literature review, coursework, workshops, and hands-on research experience to develop her skills in qualitative research, human-centered intervention development, implementation, and clinical trial design. Moreover, she has assembled a nationally renowned multi- disciplinary team with relevant expertise and extensive mentorship experience to ensure her success in achieving her research and career goals. Her innovative proposal, which involves teens in developing an intervention to decrease firearm access among teens at elevated suicide risk, will also serve as a model for teen engagement in other mechanisms of firearm injury prevention. Moreover, this proposal will prepare Dr. Haasz to transition to an independent investigator and prepare her for future R01 funding.

NIH Research Projects · FY 2026 · 2024-03

PROGRAM SUMMARY Recent epidemiologic evidence highlights the significant unmet behavioral health needs of cancer patients in the United States. A strong evidence base now supports the use of digital health technologies to effectively extend the reach and impact of the cancer clinician and to improve the quality of care. However, training in the integration of these solutions into practice is essential to overcome barriers, ensure best practices, and successfully address the top concerns of cancer patients with digital versions of long-proven treatments. The proposed R25 program will train frontline cancer clinicians (physicians, advanced practice providers, psychologists, psychiatrists, nurses, and social workers) in the best-practice implementation of technology in cancer supportive care. Our overall goal is to promote effective integration of evidence-based digital health and telehealth solutions with established clinical interventions and care approaches for cancer-related fatigue, insomnia, pain, depression and anxiety. We will achieve this goal through three specific aims: 1) To implement a multimodal training curriculum to educate 600 cancer clinicians in technology-augmented care. Training will be provided through online webinars, skills- based workshops with both didactic and experiential learning, and post-workshop interactive online support both directly from program faculty and also from a learning community of trainees’ peers and colleagues. 2) To increase trainees’ ability to successfully implement and use digital health solutions in clinical practice. Trainees will learn to evaluate digital health interventions in terms of their empirical foundations and clinical utility; determine how to match interventions to specific populations; obtain and effectively use patient information from digital devices (e.g., sleep quality, physical activity, vital signs) to enhance clinical outcomes; and address challenges related to increased availability of patient data. 3) To assess the effectiveness of the training program. Formative and summative annual and five-year evaluations will assess trainee knowledge gained, confidence in technology implementation, and satisfaction with the overall program as well as its specific components. This proposal is supported by the success of our four prior R25 initiatives and is responsive to a high level of interest expressed by potential trainees, as identified through a recently-conducted needs assessment. In addition to online offerings, in-person workshops will be offered in New York City, Denver, and Pasadena to facilitate trainee attendance from across the United States. Program faculty are professionally, culturally, racially, and geographically diverse, and trainees who are from backgrounds underrepresented in medicine will receive priority access to program enrollment. CME credits will be provided for all eligible participants. To keep cost from being a barrier to participation, support will be provided to trainees who report financial need with preference to given to those underrepresented in medicine. To our knowledge, there are no other training programs that address our mission.

NIH Research Projects · FY 2026 · 2024-03

ABSTRACT The Cross-disciplinary Otitis Media Mentoring Network towards Diversity (COMMeND) is a first-of-its-kind program within the otitis media (OM) community that will formalize existing collaborations into a mentoring network and create new connections among OM researchers at different career stages, including early-stage or new investigators (ESI-NIs) and individuals from under-represented minorities (URM). As the main cause of the global burden of hearing loss in young children, OM is an important disease to study for its pathophysiology and epidemiology and for which to design new strategies of prevention, early diagnosis and treatment, research that are best done through international collaboration. Decades-long attrition in the OM workforce due to a very leaky pipeline has led to loss of scientific and career opportunities. The main objective of COMMeND is to promote the recruitment and retention of ESI-NIs and trainees from various disciplines and backgrounds in OM research. We have put together a highly experienced leadership team and a pool of qualified OM faculty mentors and lecturers, as well as garnered support from our home departments and two professional organizations with strong interest in OM, namely the International Society for Otitis Media (ISOM) and the Association for Research in Otolaryngology (ARO). To accomplish our goal, we have three Specific Aims: (1) To recruit into and retain experienced faculty mentors and the top mentees (trainees and ESI-NIs) in COMMeND, with enrichment for URM individuals using a holistic admissions approach; (2) To develop a mentoring network and program of activities that will provide scientific, career and cultural training and foster cross-disciplinary and cultural interactions among mentors and mentees, further enhancing our OM community; and (3) To monitor, evaluate and disseminate program outcomes by career stage and demographics and use the collected data to improve the COMMeND structure and activities. Following the successes of other training programs that are based on best practices and social science theories, we outlined a year-long schedule of activities: one-on-one mentoring sessions with an OM faculty mentor; webinars or didactics; grant reviews; travel awards to the ISOM and ARO meetings; subsidies to short skills courses; focus group discussions and interviews; and in-person socials. Mentors will undergo refresher courses including re-training on implicit bias, mentoring and the Responsible Conduct of Research (RCR). We will also enlist peer mentors-coaches to check in with our yearly cohort of mentees. The combination of these activities as applied to an international mentoring network backed by ISOM as a professional society is innovative. Short-term outcomes for evaluation will include new funding or alternative award mechanisms, graduation or promotion to the next stage, leadership positions in relevant organizations, presentation of OM research, and publications. We will track the long-term progress of our mentees and whether they continued with OM research at least 10 years after participation in the COMMeND program.

NIH Research Projects · FY 2026 · 2024-03

Project Summary Abstract Suicide is a leading cause of death in youth across the United States. Approximately 80% of youth who die by suicide interface with the medical system in the year preceding their death. Primary care practices (PCPs) serving youth are well positioned to detect patients at risk for suicide and intervene, and widely accessible toolkits are available for practices to use. However, effective ways to impact providers’ skills in actually implementing a clinical pathway to manage at-risk patients remain underexplored. Indeed, training without applied practice and support is likely insufficient to significantly impact these skills in the long term and less likely to improve patient outcomes. Practice facilitation is a powerful way to transform clinical practice, develop provider skills, and improve patient outcomes. Our team trains PCPs in the NIMH youth suicide prevention care pathway and, in addition, assists them in integrating the pathway into routine care with longitudinally with feedback, implementation support through practice facilitation and data collection. However, there is limited evidence for the effects of supplemental supports, such as practice facilitation or coaching, on primary care providers’ adoption of and competence in suicide risk assessment and management. Thus, guided by the combined Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM)/Practical Robust Implementation and Sustainability (PRISM) framework, this cluster-randomized trial will compare the impact of practice facilitation added to didactic suicide prevention training based on the NIMH youth suicide prevention care pathway (TO+PF) versus training only (TO). In this pilot type 3 hybrid effectiveness- implementation trial, Pediatric and Family Medicine practices in our practice-based research networks will be randomized to TO+PF or to TO. Providers in clinics randomized to the TO+PF arm will also receive practice facilitation for 6 months, involving monthly individual check-ins which include: 1) clinic- and provider-level data review of adoption data for the five components of the NIMH youth suicide prevention care pathway, 2) clinical coaching around implementing the different components of the pathway, and 3) logistical coaching in identifying multilevel contextual barriers (organized in PRISM domains) to implementation and strategies to overcome them. At the clinic/provider level, we will assess feasibility, acceptability, effectiveness, adoption, fidelity and implementation and all contextual barriers that emerge. At the patient level, we will follow youth assessed at intermediate or high risk and their family for 6 months following screening, collecting data on attempted suicides and suicide ideation as well as emergency room and behavioral health provider visits. The outcomes will provide preliminary support for a subsequent fully-powered type 3 hybrid effectiveness- implementation trial of the model, assessing its reach, effectiveness, adoption, implementation, and maintenance, with the goal of promoting broad implementation in diverse clinic contexts.

NIH Research Projects · FY 2026 · 2024-03

SUMMARY Despite the availability of targeted therapies for estrogen receptor positive (ER+) breast cancers, which comprise over 70% of breast cancers, most breast cancer-related deaths are attributed to recurrent ER+ breast cancer. Thus, there is an unmet need to identify novel targets for treating ER+ patients with metastasis. We have found that levels of Semaphorin 7a (SEMA7A) mRNA, which encodes for a membrane linked protein that can also be shed from the cell, are associated with decreased overall survival (OS) in ER+ breast cancer patients. Furthermore, ER+ patients treated with Tamoxifen exhibit shortened OS if their tumors are SEMA7A high, suggesting that SEMA7A may drive resistance to endocrine therapy resulting in tumor progression and metastasis. We have preliminary data to suggest that SEMA7A overexpression promotes resistance to endocrine therapies via activation of cell survival pathways in breast tumor cells. Additionally, we have shown that ER mediated transcription drives SEMA7A expression and that SEMA7A expressing cells are resistant to ER- and CDK4/6-targeted therapies, yet sensitive to inhibition of survival pathways. We have also discovered that decreasing expression of Singleminded-2s (SIM2s), a transcriptional repressor with known tumor suppressive activities, also results in activation of pro-survival signaling, as well as epithelial to mesenchymal transition (EMT), and resistance to ER-targeted therapy. Together, our preliminary data suggest that SIM2s binds to the SEMA7A promoter and represses SEMA7A transcription. We have also identified that ER+ breast cancers in women diagnosed within 10 years ofa pregnancy are enriched for the highly-proliferative ER+ luminal B subtype, frequently progress to metastatic disease while on endocrine therapy, and that SEMA7A can predict for relapse in this patient population. Thus, we propose that SIM2s mediated repression of SEMA7A may be lost in these postpartum breast cancers (PPBCs). PPBCs also exhibit increased expression of SEMA7A and in programmed cell death ligand-1 (PD-L1) and are sensitive to PD-L1 targeting in pre-clinical studies. Additionally, in TCGA SEMA7A expressingtumors are enriched for makers of immunosuppression including PD-L1, PD-1 and FOXP3. Based on these new results, we propose the hypothesis that a SIM2s/SEMA7A switch mediates ER+ breast cancer progression and metastasis by conferring mechanisms of intrinsic resistance to therapy, EMT and immunosuppression in the TME. To address this hypothesis, we propose three Specific Aims. In Aim 1, we will determine the SIM2s/SEMA7A switch in therapeutic resistance and progression in ER+ breast cancer. In Aim 2, we will definethe role of the SIM2/SEMA7A switch in altering immune suppression via PD-L1 to promote breast cancer progression. In Aim 3 we will analyze the relationship between SIM2s and SEMA7A in women with ER+ breast cancer as predictive factors for metastatic recurrence and resistance to standard therapy. We expect that dissecting the roles of SIM2s and SEMA7A in breast cancer will aide in developing novel therapeutic strategies.

NIH Research Projects · FY 2026 · 2024-03

Abstract Hemifacial microsomia (HFM) spans an array of human congenital craniofacial birth defect syndromes characterized by asymmetric malformation or underdevelopment of the orbits (maxilla and zygoma), mandible, outer and middle ear structures, craniofacial nerves and soft tissue structures. These elements are derived from cranial neural crest cells (NCCs) that populate the pharyngeal arches. HFM is the second most common facial birth defect behind cleft palate, though unlike cleft palate, very few genes have a proven association with HFM. One of the few genes found repeatedly in GWAS studies is the transcription factor GATA3, which is the basis of this proposal. We have recently shown that GATA3 is required for facial symmetry, as Gata3 mutant mouse embryos develop craniofacial defects resembling those seen in HFM, with one side more severely affected than the other. However, our preliminary data show that while Gata3 mutant mouse embryos have several changes in pharyngeal arch gene regulatory networks (GRNs), including expansion of Bmp4 expression and reduction in Fgf8 expression, these changes are bilateral. Further, it is not clear if these represent primary or secondary changes to GRNs and whether defects occur in NCCs before they reach the pharyngeal arches. We hypothesize that GATA3 is required for two specific aspects of facial development: 1) to ensure sufficient migrating NCCs reach the first arch; and 2) to repress Bmp4 expression in the arch ectoderm after NCC migration that would otherwise drive down Fgf8 expression and result in asymmetric jaw morphogenesis. To address these hypotheses, we will pursue three specific aims. In Aim 1, we will perform a detailed analysis of NCC migration, proliferation/cell death and later differentiation in Gata3 mutants. We will also assess if disruption of internal organ asymmetry randomizes sided defects in Gata3 mutants. In Aim 2, we will perform dual scRNA-seq/scATAC-seq (scMultiome) in wild type and Gata3 mutants to identify symmetric and asymmetric changes in gene expression. We will correlate this with chromatin accessibility changes and functionally analyze identified putative cis-regulatory elements in vivo. In Aim 3, we will reduce Bmpr1a expression or increase Fgf8 expression in the mandibular arch of Gata3 mutant embryos to determine if either approach can rescue the Gata3 mutant phenotype. Our long-term goal is to elucidate the basis of facial defects in the Gata3 mutant embryos and to identify the cue or cues that result in asymmetry. Such an understanding has the potential to substantially impact the quality of care for HFM patients and may potentially lead to avenues for future treatment regimens designed to improve differences associated with HFM.

NIH Research Projects · FY 2025 · 2024-03

PROJECT SUMMARY Cancer survivors with overweight or obesity (ow/ob) display increased morbidity and mortality even after amelioration of disease. Improvements in dietary and physical activity patterns can mitigate this risk and can be supported through comprehensive, multiple health behavior change (MHBC) interventions. Yet, translation of MHBC interventions to clinical practice is limited, in part because traditional “treatment package” approaches are not optimized for real-world implementation. Integration of multi-omic data can capture lifestyle exposures and biological responses, providing the potential to strengthen conclusions and overcome limitations of existing assessment methods. This approach could elucidate the biological underpinnings of how changes in modifiable behaviors influence individual phenotype during survivorship. Such knowledge would help to identify and tailor interventions for incorporation into survivorship care. Yet, this has not been conducted, posing a critical research gap. My goal is to create a sustainable and scalable MHBC program combining diet and exercise to support survivors with ow/ob and improve health in survivorship. Thus, the overall objectives for this NCI early K99/R00 award are to: (1) develop a survivorship nutrition intervention, BfedBwell, for implementation within an existing clinical exercise oncology program; and (2) determine the impact of the intervention on diet and health through the integration of multi-omic approaches. In the K99 phase, I will utilize the Multiphase Optimization Strategy (MOST) framework, an engineering-based approach to efficiently and systematically develop, optimize, and evaluate behavioral interventions, to test three social cognitive theory-based components: (1) 1:1 counseling with a registered dietitian, (2) behavioral skills development, and (3) group support for delivery alongside a core nutrition education curriculum within a clinical exercise oncology program. Post-treatment survivors (n=80) with ow/ob will complete a 12-week cluster-randomized 2^3 factorial trial to test candidate intervention components for feasibility and acceptability and to identify a set of components that demonstrates patterns of efficacy for increased adherence to lifestyle recommendations, weight loss, and improvements in cardiometabolic health. In the R00 phase, I will utilize targeted metabolomics to measure changes in biomarkers of dietary exposure through analysis of participant biospecimens collected before and after the intervention. I will then perform integrated network analysis using multi-omics (metabolome, proteome, microbiome) to examine the effects of the intervention on cardiometabolic health. My K99 mentorship and training plan will provide skills in behavioral weight loss trials, MOST study design, and multi-omics integration in survivorship. The R00 phase will advance my foundational knowledge as I become an expert in identifying and interpreting multi-omic findings and integrating them into behavioral interventions to predict and evaluate individual response. Completion of these aims will lay the groundwork for an R01-level optimization trial, leading to advances in care while spanning behavioral and biological domains to develop precision oncology nutrition strategies for improved survivorship.

NIH Research Projects · FY 2026 · 2024-03

Extracellular matrix turnover in pathological cardiac remodeling Heart failure remains a leading cause of mortality and morbidity. Matrix remodeling accompanies systolic and diastolic dysfunction in the failing heart, and is associated with an alteration of the structure and function of the cardiac extracellular matrix. Understanding the complex dynamical processes of extracellular matrix re-model- ing holds the promise for identifying targets and developing therapeutics that may arrest or reverse disease progression. In failing hearts, changes in extracellular matrix compositions are driven largely by matrix turnover, which occurs through the continual deposition and degradation of matrix components. Matrix deposition is, in turn, rate limited by underlying protein synthesis and secretion kinetics. Knowledge into the synthesis and deg- radation flux of the matrix proteome is therefore essential to understanding the plasticity of matrix adaptation. In prior work, our team investigated the extracellular matrix proteomes of remodeling mouse hearts to uncover evidence of hidden fibrotic remodeling in a heart disease model. We have also refined experimental protocols to measure protein turnover in animal models, and discovered new disease pathways in cardiac hypertrophy that are not apparent from steady-state protein levels. Spurred by these developments, here we aim to elucidate the dynamics and plasticity of matrix remodeling, using spatial and temporal proteomics screens that we hy- pothesize will allow novel targets for anti-fibrotic remodeling strategies to be elucidated. Specifically, we pro- pose to: (1) measure the individual synthesis and deposition kinetics of matrix proteins in animal models of heart failure, and examine their changes in relation to matrix composition and function during hypertrophy, systolic and diastolic dysfunction, and recovery; and (2) dissect regulatory principles of matrix degradation and examine the respective contributions of cardiomyocytes and fibroblasts in normal and fibrotic remodeling con- texts. Success will reveal insights into the sequence of molecular events that underpin matrix remodeling in cardiac remodeling and failure. This information may be broadly useful for uncovering new intervention targets and guiding the development of therapeutic strategies.

NIH Research Projects · FY 2025 · 2024-03

PROJECT SUMMARY / ABSTRACT Cannabis is commonly co-used by individuals who drink alcohol, such that their intoxicating effects overlap (known as `simultaneous use'). Simultaneous use is known to be associated with experiencing increased negative consequences, however, evidence is conflicting regarding whether cannabis acutely increases or decreases alcohol consumption. The neural mechanism(s) underlying simultaneous use are also not well understood. Existing research suggests that overlapping neural mechanisms underlie the effects of alcohol and THC (Δ-9-tetrahydrocannabinol, the primary psychoactive substance in cannabis), and this circuitry may affect motivation for alcohol misuse and simultaneous use. Specifically, cannabinoid receptors (i.e., CB1, to which THC binds as a partial agonist) are distributed throughout the mesolimbic brain regions that underlie alcohol reward. Activation of CB1 is thought to influence neural circuitry underlying reward signaling, such that reward signaling may be amplified by THC, however it is unclear whether THC sates or primes reward-responses to alcohol. An important limitation of prior work is that most studies have used THC doses that are significantly below the level used in the real world. Legal-market cannabis products containing high levels of THC are increasingly popular and available, but their effects neural reward processing and acute alcohol self- administration have not been studied in the laboratory. We propose to test the effects of a 20mg oral dose of THC (i.e., a dronabinol capsule) vs 0 mg THC (placebo capsule) on reward processing during alcohol and cannabis cue-reactivity tasks in 25 adults who drink alcohol and use cannabis. Participants will complete a baseline session and 2 experimental laboratory sessions in this double-blind pharmaco-imaging study with a crossover design. At one experimental session, participants will consume THC before undergoing a brain scan and participating in an intravenous (IV) alcohol self-administration session. At the other experimental session, they will undergo the exact same study procedures after consuming the placebo capsule. Session order will be counterbalanced. We will also examine if neural responses to THC are associated with real-world co-use patterns as assessed by two weeks of daily-diary data collection. The pharmacokinetics of oral THC provide a long time period of elevated blood THC levels, allowing us to perform an MRI scan and IV-alcohol session while THC remains at peak blood levels. We hypothesize that individuals who experience stronger neural reward signaling or reduction in aversive signaling following 20mg dronabinol vs placebo will self-administer more IV alcohol and report more frequent simultaneous alcohol and cannabis use during the daily diary period. Aims include examining the effect of oral THC on neural response to reward (i.e., alcohol and cannabis cues), examining the effect of oral THC on alcohol self-administration, and examining the relationship between neural reward responses and alcohol consumption.

NIH Research Projects · FY 2026 · 2024-02

PROJECT ABSTRACT Headache has been one of the top three causes of disability adjusted life years for the past three decades among adolescents and young adults. The inspiration for this research comes from the disproportionately higher burden that falls on girls and women starting in puberty, when prevalence rises more quickly in girls than boys, then continues to be higher in women throughout the middle years of life. Puberty also appears to be a sensitive period in brain development when sex differences in regions key to headache such as the amygdala are driven by pubertal hormones. Despite these sex differences, the role of pubertal hormones such as estrogen and testosterone are not yet well-enough understood to be targets for prevention. This proposal is focused on the innovative study of gender affirming hormone therapy with testosterone in transmasculine adolescents as a model of puberty in which the timing of estrogen and testosterone changes are controlled. The aims of this proposal are to 1) determine association between gender affirming hormone therapy with testosterone in adolescence and headache in a cross-sectional study from in a multi-center health record database, 2) determine change in headache burden in response to gender affirming hormone therapy with testosterone and 3) determine changes in brain structure and function in response to gender affirming hormone therapy with testosterone. The scientific objective of this proposal is to start to outline the key points in development at which pubertal hormones can alter risk for headache and the physiologic underpinning for this alteration. These targets can then be applied in future clinical studies of hormonal management of headache in adolescence. This is a five-year career development research proposal. I am currently an Assistant Professor at the University of Colorado School of Medicine’s Department of Pediatrics in the Division of Child Neurology at Children’s Hospital Colorado. The outlined proposal builds on my previous research and clinical experience in neuroimaging of pubertal brain development and pediatric headache by expanding to a model of transgender adolescent headache. The proposed research and training plan will prepare me with a unique skillset for translational research as an independent clinician scientist in the emerging field of the effect of sex steroids on neurologic conditions in transgender youth and in headache sex differences research.

NIH Research Projects · FY 2026 · 2024-02

Leveraging decades of NCI investments in clinical trials, data infrastructure, and cancer screening research, the I-SCREEN (Improving Strategies for Cancer Reduction through Early-detection and ENgagement) ACCESS Hub is well-positioned to efficiently and effectively address pressing issues around the emergence of new technologies for cancer screening. In collaboration with other ACCESS Hubs, we will evaluate the benefits and harms of new cancer screening technologies and their impacts on a representative sample of the United States (US) population. We will build on the University of Colorado Cancer Center’s (UCCC) successful administration of large cancer screening trials, including the Prostate, Lung, Ovarian, & Colorectal (PLCO) Cancer Screening Trial and the National Lung Screening Trial (NLST), along with their well-established Colorado Cancer Screening Program (CCSP), a statewide cancer screening network reaching the catchment area of the center. UCCC’s network of rural health centers will be complemented by Kaiser Permanente Colorado’s (KPCO) inclusive population from Colorado’s Front Range and extend existing collaborations between UCCC and KPCO in the NCI-funded Colorado Implementation Science Center for Cancer Control (COISC3). We will also build on the synergy between KPCO and Kaiser Permanente Hawaii (KPHI) as the only two sites in NCI’s Population-based Research to Optimize the Screen Process (PROSPR) Consortium that are also part of the Connect NCI Cohort Initiative and the Kaiser Permanente (KP) Research Bank (KP’s national biobank), both recruiting healthy patients and collecting blood biospecimens. The I-SCREEN Consortium consists of an NCI-designated Cancer Center, two integrated care delivery systems, one rural/suburban health system accepting >25 types of insurance, and one rural critical access hospital system. Our long-term goal is to reduce cancer-related mortality by rapidly investigating emerging, novel screening technologies in a population that is representative of the US population to ensure that efficacious new technologies have a broad reach. To accomplish this goal, we will: 1) collaborate with NCI, the CSRN Centers and ACCESS Hubs to build an ecosystem to evaluate new cancer screening technologies and strategies in multiple clinical settings; 2) Develop and execute the Vanguard feasibility study to inform the design of trials to evaluate new technologies for cancer screening of populations that are representative of the US population; and, 3) increase the impact of CSRN by collaborating with NCI to build a robust data/biospecimen repository available to CSRN investigators and external investigators for research to improve cancer screening and early detection and establish the provisioning of publicly available CSRN datasets. Through centralized Administrative, Recruitment and Biospecimens, Engagement, and Data Cores, we will ensure ACCESS Hub collaboration, communication, and progress towards CSRN deliverables. I-SCREEN will be a model for high-impact, translational research to test emerging cancer screening technologies to reduce cancer mortality in the US.

NIH Research Projects · FY 2026 · 2024-02

ABSTRACT Antiviral therapy (AVT) has been a pharmaceutical success story for the treatment of both acute and chronic viral infections in pregnant people, their developing fetuses, and newborns. Despite this, serious adverse effects can occur due to antiviral drug-hormone interactions (DHIs). These adverse effects can result in a substantial risk to both the patient, her fetus, and the newborn. Disruption of steroid hormone homeostasis is critical in this phenomenon, with reports associating AVT with dysregulation of estradiol levels in pregnancy, low birth weight and transient adrenal insufficiency in neonates, and neurodevelopmental impairments in children later in life. These serious adverse effects require our attention in order to understand the toxicological processes involved and inherent risks for some of the most vulnerable population groups, which is a primary goal of this NIH funding announcement, (PAR-23-130). In order to reduce the risk for adverse health outcomes with these drugs, we must first understand the underlying cause(s) for the toxicities associated with them. The hepatic drug and steroid metabolizing enzymes, e.g. the cytochrome P450 (CYP) and UDP glucuronosyltransferase (UGT) enzymes, are equally important in drug disposition and steroid homeostasis, thus they sit at the interface of the DHIs attributable to AVT. Our central hypothesis is that antiviral therapy interferes with the endogenous processes important for steroid hormone biosynthesis and metabolism via enzyme inhibition, induction, and/or activation and that hepatic enzymes, in particular CYP and UGT enzymes, are central in this interplay. Our approach consists of: 1) determining the effects of antiviral medications on estradiol homeostasis during pregnancy in order to generate physiologically-based pharmacokinetic (PBPK) models for DHI prediction of risk for estradiol metabolic imbalance, 2) quantifying the extent of antiviral drug- hormone interaction for the human steroidogenic CYP3A7-dependent fetoplacental endocrine signaling pathway, and 3) assessing the effect of lopinavir-ritonavir on hepatic bile acid homeostasis driven by CYP3A ontogeny in early infancy to understand the potential risk for long-term bile acid dysregulation. We expect that the successful completion of these specific aims will provide us with advanced mechanistic models to explain antiviral DHIs and will allow us to predict and prevent future antiviral-based adverse DHIs in some of the most vulnerable and understudied patient groups. This, in turn, will limit life-threatening complications and improve health outcomes for women and children treated with life-saving antiviral medications, an important goal of the NIH and this funding announcement (PAR-23-130).

NIH Research Projects · FY 2026 · 2024-02

ABSTRACT Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tau tangles (NFTs) which together contribute to neuroinflammation, neurodegeneration, and often cognitive decline. Down syndrome (DS) is the result of having three copies of chromosome 21 (T21) from conception. The Aβ peptide is a cleavage product of the amyloid precursor protein (APP) which is encoded by the APP gene. Given that the APP gene resides on chromosome 21, all people with DS accumulate higher levels of Aβ peptide in their brains. Accordingly, adults with DS will develop AD pathology (DS-AD), and many go on to develop clinical dementia. DS-AD has documented pathological differences from typical AD, including accelerated Aβ and tau accumulation and a more heterogeneous Aβ plaque composition. While there are numerous genetic and environmental contributors to AD risk, the APOE gene, and especially the ε4 variant (APOE4), has been identified as the greatest risk factor for typical AD besides age itself. Inheritance of APOE4 also significantly increases risk for AD and cognitive decline in individuals with DS. Cohort studies in people with DS have found an overall increased AD risk conferred by APOE4, but investigations of the mechanistic role of APOE4 in people with DS are lacking. Clearly, there is an urgent need for studies interrogating the mechanism of increased risk of AD for people with DS carrying APOE4. The overall goal of this proposal is to elucidate the role of the APOE4 genotype in the development of DS-AD and assess the potential of apoE4-drive Aβ fibrilization as a therapeutic target. Specifically, I will identify APOE4- driven mechanisms and pathways that contribute to the development of DS-AD neuropathologies and assess the efficacy of small molecular inhibitors of apoE and/or Aβ in alleviating these pathologies. To accomplish these goals, I will develop novel human induced pluripotent stem cell (hiPSC)-based models of DS-AD that carry APOE4. I will generate multiple human neural cell types and cerebral organoids (COs) from the hiPSCs to determine the specific effects of APOE4 in these models of the developing and aging human DS-AD brain. I will evaluate six validated small molecule drugs that have been shown to prevent and/or reverse apoE4-catalyzed Aβ fibrillization in my CO model system. My overall hypothesis is that APOE4 will accelerate and enhance the development of AD neuropathologies in hiPSC-based models of DS-AD and can be targeted with small molecule apoE inhibitors to alleviate those AD phenotypes.