University Of Colorado Denver

NIH Research Projects · FY 2026 · 2026-06

Project summary The 2026 Annual Meeting of the American Society of Pharmacognosy (ASP) will be held July 26–29, 2026, at the Denver Tech Center Marriott in Denver, Colorado. This multidisciplinary conference will convene scientists from academia, government, and industry to advance the accelerated discovery, characterization, and translational application of natural products. Natural products are small organic molecules produced by living organisms that play critical roles in biological systems. They serve as molecular probes and lead compounds for drug development, particularly in oncology and infectious diseases, addressing the core missions of the National Cancer Institute (NCI) and the National Institute of Allergy and Infectious Diseases (NIAID). ASP2026 will feature symposia focused on leveraging natural products for cancer and infectious disease therapeutics, integrating omics technologies, synthetic biology, biocatalysis, and emerging computational tools including artificial intelligence, among others. The meeting will include six plenary symposia, two poster sessions, contributed oral presentations in well-attended afternoon symposia, and career development workshops, as well as daily networking opportunities. Confirmed and invited speakers include leaders in natural products research and related fields, with a strong emphasis on early career investigators. A dedicated Younger Members Symposium and networking event will foster mentorship and collaboration. Funding is requested to support registration and accommodation costs for students, postdoctoral fellows, and early career researchers presenting at the meeting, as well as invited speakers. Priority will be given to participants from wide-ranging US institutions and geographic regions. ASP annual meetings are unique for the following reasons: 1) attendee research, reflected in the scientific program, represents the depth and breadth of natural products and their preclinical and clinical application, 2) the ASP has a long-standing and strong sense of community as a home society for US-based natural products researchers, and 3) our society’s support of student, postdoctoral, and early career members through dedicated networking and professional development opportunities. ASP2026 directly supports NIH strategic goals by promoting the discovery and translation of natural product-based therapies for cancer and infectious diseases. The conference will catalyze innovation, foster interdisciplinary collaboration, and ensure the continued vitality of the natural products research community.

NIH Research Projects · FY 2026 · 2026-06

Project Summary/Abstract An estimated 3 million children worldwide die from sepsis each year. Of those who survive, nearly 1 in 3 are discharged with disability. Recent work has found that different subgroups or trajectory-based phenotypes (TBPs) of septic shock in adults respond differently to some treatments, suggesting that septic shock requires treatment specific to TBP rather than a single treatment approach for all patients. Although some TBPs of septic shock have been identified in children, we cannot currently identify these TBPs in real- time, and we have not verified that treatments targeted to TBPs improve clinical outcomes. In Aim 1a, I will use trajectory modeling approaches to derive and validate potential TBPs of pediatric septic shock using both static patient factors (e.g. chronic diseases) and dynamic changes in patient state (e.g. vital signs). In Aim 1b, I will test the performance of a model that uses data from only one clinically meaningful time point (i.e. time of shock diagnosis), rather than data from the whole trajectory, to assign a patient to the predicted TBP(s) found in 1a. In Aim 2, I will emulate potential interventions in two ways. First, I will conduct multiple target trial emulations to test the effect of various resuscitation strategies (e.g. steroids) on clinical outcomes (e.g. shock-free hours) in children with identified TBPs. Second, I will construct a queryable model to estimate the probability of outcomes (e.g. change blood pressure) based on the interaction between patient’s physiology (e.g. lactate), resuscitation treatments (e.g. fluid administration), and prior outcomes, in order to determine the optimal resuscitation treatment sequence to improve outcomes (e.g. volume of fluid prior to starting vasoactive medication). I will then divide this population into the TBPs identified in Aim 1b, and repeat this process to assess for differences in optimal resuscitation treatment sequence across TBPs. I hypothesize that at least one TBP will respond differently to at least one common treatment or treatment sequence. In Aim 3, I will use the algorithm found in Aim 1b to implement and assess the performance of a silent screening tool in a single center’s electronic health record (EHR) to prospectively identify patients belonging to TBPs who may benefit from an intervention modeled after an emulated intervention from Aim 2. This aim will provide me with both a real-time screening tool and critical preliminary data for future clinical trials. The training aims of this award will solidify my content expertise in the application of data science in pediatric septic shock, and add training in causal inference methods, clinical trial design, and human-centered clinical decision support. Together, these will prepare me to be an independent investigator leading a team of statisticians, informaticians, clinical trialists, and clinicians to develop and validate simple, clear, interpretable, and evidence-based tools to bring machine learning-based knowledge to the bedside to improve outcomes in pediatric septic shock

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), is a leading cause of skin and soft- tissue infections in the United States and is known to exacerbate atopic dermatitis pathology. A debilitating symptom of atopic dermatitis is a severe, persistent itch that perpetuates a destructive itch-scratch cycle, exacerbating skin barrier damage and worsening patients' quality of life. Recent work has identified the S. aureus protease SspA as a direct driver of itch by activating protease-activated receptor 1 (PAR1) on sensory neurons. However, the specific mechanisms enabling the potent and efficient activity of SspA on these neurons remains a critical knowledge gap. Preliminary data suggests that SspA has a unique and conserved C-terminal domain (CTD) of unknown function that is dispensable for catalysis but is required for itch induction in vivo. Additionally, the CTD facilitates high- affinity binding of SspA to type I collagen, the primary component of the dermal extracellular matrix (ECM). The central hypothesis of this project is that the SspA CTD functions as a novel molecular tether, concentrating the protease in the ECM near PAR1-expressing sensory neurons, thereby enabling efficient neuronal activation to drive itch. The long-term objective is to define this new paradigm of virulence factor targeting and establish a foundation for novel anti-virulence therapies that disarm the pathogen without promoting resistance. This project tests the central hypothesis through two complementary aims. Aim 1 will define the biochemical basis of the CTD-ECM interaction using surface plasmon resonance to quantify binding kinetics and will assess the electrostatic nature of the interaction with physiologically relevant competitive inhibition assays. This aim culminates in the use of immunofluorescence microscopy to confirm that the CTD mediates SspA localization to the ECM-rich dermal-epidermal junction during murine skin infection. Aim 2 will elucidate how this localization drives neurogenic itch by using live-imaging of skin explants to visualize SspA accumulation on neurons, quantifying PAR1 activation in primary sensory neurons via calcium imaging, and utilizing a chimeric protease to test the sufficiency of the CTD to confer itch-inducing activity to a homologous protease in vivo. Successful completion of this project will provide fundamental insights into this clinically relevant host-pathogen interaction and will be the first described function of the SspA CTD. By identifying the CTD-ECM interaction as a critical and druggable point in pathogenesis, this work will provide a direct translational path toward developing therapies that can alleviate a debilitating symptom of S. aureus colonization and infection and disrupt the itch-scratch cycle, directly addressing the mission of NIAID.

NIH Research Projects · FY 2026 · 2026-06

Project Summary Each day, cells experience DNA damage from both external factors and normal cellular processes. To overcome this and maintain genomic stability cells rely on multiple cellular programs dedicated to repairing DNA damage. Failure to repair damaged DNA is detrimental to cells and can contribute to many diseases, including developmental disorders and cancer progression. The Cohesin complex plays a key role in the repair of DNA double strand breaks, though the exact mechanism of how Cohesin contributes to this repair is not well understood. Understanding this role has been hindered by the many cellular functions performed by Cohesin, with roles in cell division, transcription, and DNA replication, where disruption to Cohesin leads to broad and indistinguishable phenotypes. Together, this has left an essential gap in our knowledge of how Cohesin is regulated at DNA damage sites and its contribution to disease. Recently, we identified the Cohesin regulator PRR12 that specifically regulates the population of Cohesin at DNA damage sites, however, the mechanisms of this regulation remain to be defined. Understanding the role of PRR12 provides a unique opportunity to specifically target the population of Cohesin at DNA breaks while leaving its other functions intact, an approach that will allow us to specifically address the role of Cohesin in DNA repair for the first time. Additionally, defining the function of PRR12 is critical as patients with mutations in PRR12 phenocopy cohesinopathies, severe developmental and neurological disorders that result from altered Cohesin function. In this proposal, I will define how PRR12 regulates the localization of Cohesin to DNA damage sites and determine the role of the Cohesin complex in efficient DNA repair. To identify how PRR12 interacts with the Cohesin complex and localizes it to DNA lesions I will first perform a structure function analysis of PRR12. Using biochemistry and genetic tools I will determine if this interaction is direct and test its role in Cohesin stabilization. Next, I will determine if Cohesin regulates DNA architecture surrounding DNA breaks using a chromosome conformation capture technique. Last, I will test if PRR12 regulates Cohesin function in two independent DNA repair pathways using a quantitative fluorescent reporter. The work proposed here will be the first to separate the DNA damage role of Cohesin from its various functions throughout the cell cycle and begin to shed light on how misregulation of this process may contribute to genome instability in disease. This training will take place on the CU Medical School campus, where I have access to a wide variety of core resources and opportunities to interact with cell biologist and biochemists in the genome integrity field that will set me up for the successful completion of this proposal. My training plan will expand my experimental toolkit with training in biochemistry and genome organization techniques that will compliment my current expertise in cell biology and microscopy. In addition, I will prioritize gaining the professional development skills, mentorship experience, and communication skills that I will need to transition into an independent research position.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY. Alzheimer's disease (AD) is characterized not only by progressive memory loss but also by a range of non- cognitive deficits, including sleep disturbances and autonomic dysfunction. Emerging evidence implicates herpes simplex virus type 1 (HSV-1) as a critical environmental trigger that accelerates AD pathology. Our preliminary data demonstrates that HSV-1 preferentially infects the locus coeruleus (LC) and paraventricular nucleus of the hypothalamus (PVN) in both wild-type (WT) and AD mouse model mice—key regulators of non- cognitive functions—to induce early amyloid deposition, tau hyperphosphorylation, and neuroinflammatory responses, ultimately exacerbating AD progression. Furthermore, HSV-1 exacerbates microglia dysfunction and amyloid accumulation in AD mice. These observations raise a critical question: does HSV-1 infection initiate early transcriptional and post-translational changes in the LC and PVN that accelerate physiological and behavioral deficits? In this proposal, we hypothesize that HSV-1 induces Aβ and NFT formation in the LC and PVN, triggering a hyperinflammatory response prior to hippocampal involvement. To test this hypothesis, we will employ an integrated, multidisciplinary approach using advanced spatial transcriptomics and proteomics (via the NanoString GeoMx DSP platform) alongside in vivo electrophysiological (EEG/LFP) and behavioral assays (using FED3 feeding devices). Aim 1 will delineate the spatial and temporal molecular alterations in the LC and PVN following intranasal HSV-1 infection in 3xTg AD mouse models and WT controls. This analysis will focus on the regional accumulation of amyloid and tau pathologies, microglial activation, and associated gene expression changes that precede hippocampal involvement. In Aim 2, we will link these molecular changes to functional outcomes by monitoring disruptions in LC activity, sleep-wake cycles, EEG rhythms, and feeding behavior. This study is innovative in its use of state-of-the-art spatial omics combined with rigorous neurophysiological and behavioral assessments to bridge the gap between molecular pathology and functional deficits in AD. The outcomes are expected to provide critical insights into HSV-1's role in triggering early AD pathogenesis, particularly in non-cognitive domains, and may identify novel targets for early intervention. Ultimately, this research will help reshape our understanding of viral contributions to neurodegenerative processes and inform the development of therapeutic strategies aimed at mitigating both cognitive and non-cognitive symptoms of AD.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Unraveling the basic functional properties of individual HIV-1 proteins could provide important clues relevant towards novel therapies and cure strategies. The functional properties of most HIV-1 proteins had been dissected in great detail, but among the viral `accessory' proteins, HIV-1 Vpr remains enigmatic. HIV-1 Vpr has been linked to diverse phenotypes that include significant effects on apoptosis, cell-cycle arrest, innate immune regulation and latency reactivation by interacting with a multitude of host proteins. Interestingly, Vpr-associated replication phenotypes were most consistent in myeloid cells such as macrophages and dendritic cells, but not in CD4 T cells. These data are puzzling, as in persons with HIV-1 infection (PWH), macrophage-tropic viruses typically do not emerge until later clinical stages. As a highly conserved virion-associated protein, HIV-1 Vpr is expected to exert its effects very early on, when mucosal CD4+ T cells serve as critical cellular infection targets. Specifically, during acute HIV-1 infection, high levels of HIV-1 replication and CD4 T cell depletion in the gastrointestinal (GI) tract contributes to a dysregulated epithelial barrier. The subsequent translocation of bacteria and/or bacterial products from the gut lumen to the underlying lamina propria and systemic circulation leads to persistent inflammation and chronic immune activation that does not resolve with antiretroviral therapy. Recently, HIV-1 Vpr was reported to alter the transcriptome and/or proteome of CD4 T cell lines and mitogen-activated blood CD4 T cells, but without a significant effect on virus replication. We suspect that inconsistencies reported for HIV-1 Vpr function could be due to the use of infection models that may not capture fundamental attributes of early HIV-1 replication in vivo. Previously, we established the Lamina Propria Aggregate Culture (LPAC) model to study the biology of clinically relevant HIV-1 strains in primary immune cell types derived from the GI tract. Using the LPAC model, we observed that Vpr in the context of transmitted/founder HIV-1 had a consistent defect in (Aim 1) replication and (Aim 2) depletion of primary gut CD4 T cells. To begin to decipher the underlying molecular mechanisms, we propose to evaluate critical virological determinants linked to various Vpr functional attributes. Linking unbiased proteomic and transcriptomic approaches with focused strategies to track the replication block, we will pinpoint candidate pathways and molecular partners in gut CD4 T cells for subsequent in-depth analyses. Altogether, this exploratory study promises to expand our understanding of HIV-1 Vpr biology in CD4 T cells, the main cellular targets of HIV-1, and in the process, enrich our understanding of HIV-1 mucosal pathogenesis.

NIH Research Projects · FY 2026 · 2026-05

Abstract Allergic diseases including food allergies and allergic asthma represent a substantial health and economic burden, with the US Centers for Disease Control (CDC) estimating more than 50 million people within the US suffering from some form of allergic disease. Their natural history reveals a natural progression of co-morbid allergic diseases along the skin – gut – lung axis within the same individual commonly referred to as the “allergic march”. Systemic mechanisms that underscore allergic march progressions remain poorly understood, representing a critical knowledge gap. In prior work we demonstrated mouse models of food allergy activate small intestinal cellular and molecular circuits that coordinately disseminate an intestinal type 2 immune response and exacerbate allergic susceptibility of remote (allergen non-exposed) airways via dysregulation of lung tissue eosinophils. Strikingly, we found different functional phenotypes of tissue eosinophils, shaped by their local tissue microenvironments, to differentially influence intestine- and lung-localized aspects of this type 2 immune gut – lung axis. Based on these findings, this proposal will explore novel contributions of intestinal and lung tissue eosinophils to allergic march progressions along the gut – lung axis through two specific aims. Aim 1 will leverage new mouse lines exhibiting eosinophil-targeted deletion of key receptors and signaling molecules and allergen- dependent and -independent in vivo models to unravel the mechanistic underpinnings of an observed negative regulation of type 2 immune dissemination mediated by a subset of intestine-adapted, resident eosinophils. Aim 2 will apply pulse chase and lineage tracing approaches to determine the origin, phenotype, and tissue retention behavior of a subset of food allergen-elicited, remote lung-infiltrating eosinophils with putative type 2 exacerbating functions. In parallel translational subaims embedded within both aims 1 & 2 we will complement the manipulatable in vivo mouse models with analysis of cellular and molecular markers from duodenal biopsies and blood samples from patients with or without food allergies seen in our gastrointestinal eosinophilic diseases program (GEDP) clinic. Together these studies will provide new insights into the cellular and molecular circuitry that underscores enhanced vulnerability of some allergic patients to allergic march progressions and reveal homeostatic and pathologic contributions of tissue eosinophils to the systemic dissemination of type 2 immunity. In addition to mechanistic insights to instruct the development of novel therapeutic strategies aimed at interrupting the allergic march, these studies hold important considerations related to potential impacts of long-term use of anti- IL-5 biologics in allergic patients that aim to globally delete eosinophils.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Lymph nodes (LNs) are essential for the induction of adaptive immune responses. The organization and environment of LNs is coordinated by lymph node stromal cells (LNSCs), which include heterogenous populations of fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (LECs). These cells provide a physical scaffold for immune cell migration and produce numerous signals to regulate migration, adhesion, localization, function, and survival of hematopoietic cells. Moreover, we discovered that foreign protein antigens are acquired and retained by LN LECs which enhances CD8+ T cell memory and protection against rechallenge, a process we termed antigen archiving. LNs also limit pathogen dissemination via the capture of viral particles by macrophages lining the subcapsular sinus. Remarkably, for several mosquito-transmitted RNA alphaviruses, including chikungunya virus (CHIKV), we found instead that this function is mediated by the scavenger receptor MARCO expressed by distinct subsets of LECs. Although LEC-mediated capture of lymph-borne alphavirus particles limits viral dissemination, this viral capture is associated with profound LN inflammation, interferon responses, and disorganization that impairs germinal center formation and the capacity of LECs to acquire and archive foreign antigen. The primary goals of this collaborative and interdisciplinary project are to define mechanistically how discrete LNSCs regulate viral dissemination to distal tissues and contribute to the development of antiviral immune responses. In addition, we will determine how alterations to specific LNSCs during viral infection influence protective immunity from both previous and subsequent antigenic challenges. A better understanding of the role of distinct LNSCs in the development of immune responses, and how viral infection alters these responses, could identify new ways to rationally tune immune responses in health and disease. In Specific Aim 1, we will use mice with genetic deficiencies in key CHIKV cell entry molecules, the type I IFN receptor, or Irf5 in specific LECs or FRCs, and single-cell RNA analyses, to define how viral interactions with discrete LNSCs, and LNSC responses to viral infection, limit viral spread in the LN and to distal sites. In addition, we will determine how viral interactions with discrete LNSCs regulate the development of antiviral B and T cell responses including the activation and differentiation of B cells, the avidity, neutralization capacity, and durability of the polyclonal anti-viral Ab response, and the priming, proliferation, and differentiation of virus- specific T cells. In Specific Aim 2, we will define how virus-specific interactions with LECs, MARCO, and virus- specific inflammatory responses impact antigen trafficking, acquisition, and archiving in vivo and in human LECs and LN explants in vitro. We also will elucidate how viral targeting of LNSCs alters responses to previously archived antigen and archiving of exogenous antigen post-infection. These innovative molecular, genetic, immunological, and in vivo approaches will provide new mechanistic insight into how LNSCs respond to viral infection and regulate immunity.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT Generalized joint hypermobility (GJH), widespread excessive joint range of motion, is present in 1/3 of young women. While many with GJH are asymptomatic, GJH is associated with a higher risk of chronic joint pain (symptomatic GJH; s-GJH). Chronic neck pain is particularly prevalent, affecting nearly 25% of young women with GJH. It is theorized that hypermobility is associated with joint instability, which causes joint injury, degeneration, and pain. However, the relationship between joint instability and pain in GJH has not been confirmed. The lack of a mechanistic understanding of pain in GJH is a major barrier to the development of evidence-based guidelines for clinical management and contributes to poor clinical outcomes. Therefore, the overall objective of this proposal is to investigate the biomechanisms underlying chronic joint pain in s-GJH. Dynamic joint stability depends on 3 subsystems: 1) passive (connective tissue; range of motion and laxity), 2) active (muscle; strength and endurance), and 3) neural (sensorimotor control; proprioception and motor control). However, GJH is categorized based on the passive subsystem alone. Deficits in strength, endurance, and proprioception have been identified in s-GJH, but it is unclear whether these deficits are also present in asymptomatic GJH (a-GJH). Central sensitization has also been reported in s-GJH, which is known to influence sensorimotor control. Our central hypothesis is that chronic joint pain in GJH is associated with poor dynamic joint stability and central sensitization. Furthermore, asymptomatic individuals with GJH avoid pain by compensating for poor passive stability with better active and neural performance. The proposed study aims to 1) characterize the performance of the passive, active, and neural subsystems of neck dynamic joint stability, and 2) determine the extent to which central sensitization is associated with poor dynamic joint stability in 3 groups (n=40 each): 1) symptomatic GJH with chronic neck pain, 2) asymptomatic GJH, and 3) non-GJH controls. The comprehensive assessment of neck dynamic joint stability includes multiple clinical measures for each subsystem. Central sensitization will be assessed using dynamic quantitative sensory testing. This study is innovative in that it will be the first to comprehensively quantify the contributors to dynamic joint stability in individuals with GJH and to investigate the role of central sensitization in dynamic joint stability. The findings will be significant because they will provide a mechanistic foundation and potential biomarker for joint protection, overcoming a major barrier to the development of effective interventions. The comprehensive career development plan, which includes training, coursework, and mentorship in clinical trial design, quantitative sensory testing, and biostatistics, is vital to the PI’s career goal to be an independent investigator in translational rehabilitation research. The completion of these aims will lead directly to an R01 clinical trial proposal for a mechanistically informed physical therapy intervention for chronic pain in s-GJH.

NIH Research Projects · FY 2026 · 2026-05

Pancreatic beta-cells are specialized to carry out high capacity mRNA translation that is tightly regulated by the nutrient environment. However, these features expose beta-cells to several vulnerabilities, including deleterious endoplasmic reticulum stress and translation errors that can can result in production of defective ribosome products (DRIPs) that have been implicated in autoimmunity in type 1 diabetes. Whereas, acute glucose exposure robustly increases translation of insulin and other secretory granule proteins, chronic high glucose decreases insulin translation and secretion even prior to impact on global translation or upregulation of endoplasmic reticulum stress. To determine the extent of translational changes at this early stage of beta-cell dysfunction, I used ribosome profiling and nascent proteomics in MIN6 insulinoma cells to elucidate the genome-wide impact of sustained high glucose on beta-cell mRNA translation. Sustained high glucose conditions that suppressed insulin secretion downregulated translation of insulin and proteins, such as SCGN, IDH2, VPS41, SLC2A2, IGF2, SLC30A8 and PFKFB3, which are involved in insulin secretory granule formation, exocytosis, and metabolism-coupled insulin secretion. Translation of these mRNAs was also downregulated in primary rat and human islets following ex-vivo incubation with chronic high glucose, and in an in vivo partial pancreatectomy model of chronic hyperglycemia. Translational downregulation decreased cellular abundance of these proteins. Subsequent analysis of actively translating ribosomes and pathways that regulate mRNA quality during translation showed that sustained high glucose changes the protein composition of translating ribosomes and suppresses nonsense mediated RNA decay (NMD). Altered ribosome composition and activity of RNA decay pathways could result in changes in the abundance and fidelity of the proteins produced. I hypothesize that hyperglycemia-induced remodeling of ribosomes and suppression of NMD alter expression of key beta-cell genes and increase neo-antigen production. In this proposal I will investigate the extent to which sustained high glucose-remodeled ribosomes regulate translation in beta-cells and determine the impact of reduced RNA surveillance and altered translation on neoantigen production and autoimmunity in T1D. These studies could uncover novel therapeutic targets for prevention of progressive beta-cell failure in T1D and for optimizing functionality of ex vivo generated beta-cells for cell replacement therapy.

NIH Research Projects · FY 2026 · 2026-05

Heterosynaptic mechanisms driving elevated synaptic inhibition and plasticity impairments following cardiac arrest GABAergic inhibitory synapses innervate pyramidal neurons and are crucial for controlling neuronal firing and excitability. Synaptic inhibition profoundly influences the efficacy of excitatory synaptic transmission, by regulating synaptic plasticity, dendritic Ca2+-transients and dendritic integration. Upscaling of inhibitory synapses is a homeostatic mechanism that occurs in response to persistent increases in neuronal excitability. Ischemia drives excitotoxic increases glutamatergic transmission that can result in CA1 pyramidal cell loss and long-term impairments in long-term potentiation. We have recently published that at chronic timepoints that there is a upscaling of GABAergic inhibitory synapses in surviving neurons through postsynaptic clustering of GABAA receptors and their scaffold, gephyrin. We hypothesize that ischemia engages increases GABAA postsynaptic structure and function that is mediated by CAMKII and results in increased inhibition relative to excitation. We also hypothesize that GABAergic upscaling is maladaptive and ultimately contributes to impaired excitatory synaptic. In this project, we will explore the mechanisms that mediate strengthening of GABAergic synapses and whether increased inhibition dampens glutamatergic synaptic transmission and plasticity. To evaluate this hypothesis, we will use an in vivo rodent model of cardiac arrest to induce global cerebral ischemia and perform electrophysiology, imaging and biochemistry to evaluate changes in inhibitory and excitatory synapse structure and function. We will use pharmacological, genetic and optogenetic manipulations of synaptic receptors and intracellular signaling pathways to target changes in synaptic function. These studies will elucidate mechanisms of cognitive impairment following cerebrovascular injury.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Small Vessel Disease (SVD), characterized by dysfunctional microvessels in the brain, is a leading contributor to stroke and dementia worldwide, with up to 40% of dementias developing with a vascular component. While microvascular deficits often arise years prior to neuronal damage, treatments targeting microvascular function to preserve brain health are limited. Hypertension is the leading modifiable risk factor for vascular or mixed dementias and affects nearly half of the adult population in the United States, according to the American Heart Association. As little is known of how capillaries sense and respond to changes in luminal pressure, treatments to protect capillary blood flow to preserve cognitive health are not available. Pericytes are a heterogenous population of contractile cells that wrap around the basement membrane of capillaries. Due to their fast on/off contractile kinetics, pericytes in the arteriole-capillary transition (ACT) zone have emerged as integral regulators of capillary blood flow. However, the signaling processes that trigger pericyte contraction are largely unknown. My preliminary work has identified the TRPC3 channel as a key regulator of pericyte membrane depolarization in response to increased capillary luminal pressure. My next inquiry, at the core of this proposal, is then to investigate the upstream signaling activates the TRPC3 channel. G-Protein Coupled Receptors, including the Angiotensin Type 1 Receptor (AT1R), have garnered substantial attention in pressure-induced signaling as potential mechanosensitive receptors. My preliminary work demonstrates that ligand activation of AT1R also contracts ACT pericytes, and interestingly, in a TRPC3 channel dependent manner. To investigate this AT1R to TRPC3 channel signaling cascade, Aim 1 focuses on AT1R- generated ligand activation of the TRPC3 channel in native capillary pericytes using a whole cell patch clamp electrophysiology approach. Aim 2 investigates the mechanosensitivity and engagement of AT1R in pericyte pressure-induced constriction through a multimodal approach, including whole cell patch clamp electrophysiology, ex-vivo pressure myography diameter measurements, sharp microelectrode electrophysiology, and in vivo vessel network interrogation with two photon scanning laser microscopy. Completion of this proposal will fill a significant knowledge gap in mechanistic signaling processes in pericyte contractility. With a greater understanding of pericyte reactivity, the pericyte control of capillary blood flow can be more specifically targeted to prevent hypoperfusion of cerebral tissue. Focusing on preserving capillary blood flow in diseases such hypertension can provide a novel approach to preserve cognitive health in an effort to delay the devastating and irreversible effects of dementia.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Restrictive eating disorders (EDs) most commonly affect female adolescents and can lead to low bone mineral density (BMD) and impaired bone microarchitecture. Peak bone accrual occurs during adolescence, and the presence of a restrictive ED at this time can increase the risk of osteoporosis into adulthood. Weight-bearing physical activity can promote bone accrual, but the bone health benefits may be reduced with an ED. Physical activity participation is often restricted during ED treatment due to concerns for compulsive exercise (i.e. rigid and highly-driven exercise behaviors) and interference with weight restoration. Data is lacking regarding if, when, and how patients return to physical activity and the associations with compulsive exercise and eating disorder behaviors during ED recovery. Additionally, the changes in BMD and bone microarchitecture, and the impact of weight-bearing physical activity on bone health in female adolescents as they recover from a restrictive ED are unknown. Addressing these knowledge gaps is essential to inform the clinical approach to physical activity integration and optimization of bone health during ED recovery among female adolescents. Dr. Aubrey Armento will conduct a prospective longitudinal clinical study of female adolescents admitted to the Children’s Hospital Colorado Eating Disorder Program (CHCO-EDP) over 1 year of treatment/recovery, compared to a healthy, physically active control group. The specific aims include: 1) examine physical activity participation (as measured by a wearable activity monitor) and its association with compulsive exercise and eating disorder behaviors, and 2) determine changes in BMD and bone microarchitecture and estimated strength (as measured by high resolution peripheral quantitative computed tomography; HR-pQCT) and the impact of weight-bearing physical activity on these bone outcomes. The findings of this study could shift current clinical paradigms to improve the health and well-being of female adolescents with restrictive EDs. In addition to obtaining valuable experiential training through completion of the proposed study, Dr. Armento will complete a career development plan designed to develop proficiency and expertise in conducting longitudinal clinical studies, analyzing and interpreting HR-pQCT data, and physical activity monitoring using wearable technology. During her time as a K12 scholar, Dr. Armento has established a productive working relationship with the CHCO-EDP, demonstrated feasibility of recruiting this study population, and collected pilot data. The additional time offered through the K23 award is essential to address her persisting training gaps and collect foundational data for a future R01 proposal. With ongoing support from her expert multidisciplinary team and the robust research and education infrastructure offered through the University of Colorado, Dr. Armento is well-equipped to develop into a successful independent investigator of the bone health consequences of EDs in female adolescents and the potential therapeutic benefits of physical activity.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Craniofacial development is a complex morphogenetic process, disruptions in which result in prevalent human birth differences. Signaling through the platelet-derived growth factor receptor (PDGFR) family of receptor tyrosine kinases (RTKs) plays critical roles in this process in humans and mice. Pdgfra mutant mouse models display midline clefting, subepidermal blebbing and hemorrhaging, due to aberrant cranial neural crest cell (NCC) migration and defective proliferation of the NCC-derived craniofacial mesenchyme at mid-gestation. Alternatively, conditional ablation of Pdgfrb in the NCC lineage results in increased nasal septum width, delayed palatal shelf development and subepidermal blebbing, primarily due to decreased proliferation of the craniofacial mesenchyme past mid-gestation. Use of a novel bimolecular fluorescence complementation approach enabled visualization and purification of individual PDGFR dimers both in vitro and in vivo, revealing differences in the timing and extent of dimer activation, signal molecule binding, internalization, trafficking and downstream signaling. These differences in PDGFR dimer-specific dynamics translated into changes in migration and cell proliferation. Further preliminary results suggest that these receptors signal at sites other than the plasma membrane and require internalization to maximally activate downstream signaling. Combined, these findings have shifted the paradigm on how biological specificity is achieved to generate unique responses downstream of PDGFR engagement. The goal of this proposal is to test the hypothesis that the differential internalization and trafficking dynamics of the various PDGFR dimers underlie differences in downstream intracellular signaling and cellular behavior during craniofacial development. First, the internalization dynamics of ligand-receptor complexes for the various PDGFR dimers will be quantified via flow cytometry to determine how ligand concentration affects receptor internalization. Separately, CITE-seq will be combined with spatial transcriptomics to quantify individual PDGFR dimer formation in the murine craniofacial mesenchyme and correlate this metric with gene expression changes and distance from the ectodermal PDGF ligand source. Second, Myo1d, a novel protein involved in trafficking shown to differentially interact with the various PDGFR dimers, will be knocked out and the effects on PDGFR localization, downstream signaling, proliferation and craniofacial development examined. Finally, the requirement for formation of various endosomal compartments on PDGFR activation and downstream signaling will be analyzed to identify the subcellular compartment(s) that serves as the major signaling platform for the various PDGFR dimers, and the effects of craniofacial disease-associated PDGFRA and PDGFRB variants on receptor trafficking will be characterized. These studies will employ innovative techniques to provide significant insight into what are likely broadly applicable mechanisms underlying the temporal and spatial regulation of RTK signaling during mammalian craniofacial development.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Type2 diabetes mellitus (T2DM) is caused by a failure of insulin-secreting 13-cells to secrete sufficient insulin following increased insulin resistance under metabolic stress. During increased insulin demand under metabolic stress 13-cells show adaptation to increase insulin release, which includes increasing the insulin release by each 13-cell. However, the mechanisms underlying this 13-cell adaptation and its failure in T2DM are poorly understood. It has long been known that 13-cells are heterogenous in their capacity to secrete insulin. We previously demonstrated mechanistically how distinct sub-populations of 13-cells with differing patterns of electrical activity can influence the dynamics and glucose-regulation of islet electrical activity and insulin secretion. However, it is unclear how sub-populations of 13-cells influence islet adaptation under metabolic stress, and whether these subpopulations are more susceptible to dysfunction during T2DM development In part this has been due to a lack of tools to genetically mark and track these sub-populations of 13-cells. We have developed an overall hypothesis: that 'functionally adapted' B-cells exist in small numbers within the healthy islet that influence islet function, where this subset is increased in number under metabolic stress but is susceptible to progressing to a dysfunctional state and thus contributing to islet dysfunction during T2DM. To test this overall hypothesis, we will conduct the following specific aims: 1 ): Characterize the molecular properties underlying heterogeneous 13-cell glucose responses within the islet, by using a novel CAMPARI activity reporter to mark active cells and perform detailed functional and molecular analysis. 2): Determine the fate of 13-cells with heterogeneous glucose responses under metabolic stress, by using a novel genetic reporter for basal-active cells together with intravital imaging and longitudinal Ca2' imaging. 3): Determine the role of activity-responsive genes in maintaining 13-cell heterogeneity, by tracking active cells in the presence and absence of cFos activity and characterizing their response to metabolic stress. By understanding the characteristics of heterogenous 13-cell populations within the islet, we will gain fundamental understanding how islet function is regulated in both healthy conditions and under metabolic stress. Thus, therapeutic agents that can target a specific population of 'functionally adapted' 13-cells, including targets we will identify in this project, may provide new ways to control the islet under pathogenic conditions.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by trinucleotide ‘premutation’ repeat expansions at the FMR1 locus, presents with late-onset tremor, ataxia, neuropsychiatric symptoms, and cognitive decline. One challenge in addressing FXTAS is the significant clinical heterogeneity, but the source of this remains unresolved. In many ways, variability in the repeat expansion itself could also hold the key to unlocking innovative new therapeutic strategies. However, historical challenges in parsing repetitive genomic regions in heterogeneous brain tissue have stymied understanding of the underlying physiology. Furthermore, fundamental differences in the biology in animal model systems limit their utility in unraveling endogenous mechanisms of trinucleotide pathogenicity. Thus, there are no therapeutic interventions currently available to treat FXTAS, or any of the Fragile X-related conditions for that matter. Given the relatively high prevalence of the FMR1 premutation in the general population, there is a critical unmet need to better understand FMR1 repeat variability. Specifically, we will apply cutting edge sequencing and analytic approaches, that will allow us to interrogate the neurogenetic mechanisms of FMR1 regulation directly in the human condition. This work is innovative in integrating cutting edge approaches to answer long-standing questions about FXTAS, with broader relevance not just for FXTAS and Fragile X-related conditions but neurologic repeat expansion disorders as well. We expect this project will elucidate the genetic and cellular mechanisms mediating FMR1 repeat instability, which in turn will accelerate therapeutic development and improve clinical care.

NIH Research Projects · FY 2026 · 2026-05

F.220: 7. PROJECT SUMMARY / ABSTRACT The olfactory epithelium (OE) is a pseudostratified tissue deep within the nasal cavity, near the cribriform palate. It primarily contains olfactory sensory neurons (OSNs) that are responsible for transmitting odor- detecting signals to the olfactory neural pathway, as well as basal progenitor cells and supporting cells1,2. Anosmia (the loss of the sense of smell) arises from conditions where OSN regeneration is diminished, leaving behind depleted regions without OSNs3,4. This can happen due to normal aging, neurodegenerative diseases, viral infections, congenital disorders, and exposure to external toxins3,5,6. More than half of people aged 65 or older will experience some degree of anosmia5. When a patient presents with anosmia, clinical evaluation involves a combination of the patient's medical history and functional tests. These tests have been shown to be subjective due to cultural and environmental factors5, and they do not discern whether the problem lies with OSNs and their transmission or elsewhere in the olfactory neural pathway. Biopsies are reserved for extreme cases since they carry a risk of damaging the already scarce OE tissues, offer extremely limited sampling, and require significant time and expertise5,7. There is currently no endoscopic tool that can reliably identify and image the olfactory epithelium in humans in real time with high spatial and temporal resolution. This type of imaging has been difficult to achieve due to anatomical complexity, inability to differentiate between cell types, and optical limitations. The OE is located deep within the nasal cavity, behind bony structures and cartilage, requiring careful and precise navigation to access1. Even when reached, the OE exists as scattered patches that constitute only ~10% of the nasal epithelia1. These patches have no clear macroscopic boundaries and are nearly indistinguishable from their surrounding RE without the aid of external markers1,8. Furthermore, these patches shrink with age and disease progression3,5,9,10, making identification even more difficult. In this proposal, I aim to develop a nasal endoscope tool that can reliably distinguish between OE and RE while also providing real-time imaging of the OE at high spatial and temporal resolution. This device would be designed for use by clinicians in outpatient settings to enable direct assessment of the OE in patients. The proposed tool would significantly advance both biomedical research and clinical practice. By enabling direct visualization of the spatial distribution of OSNs, this technology would allow researchers and clinicians to visually assess the size, uniformity, and patchiness of the OE. Because these features change with aging and disease, they can offer valuable insights into the underlying biology of olfactory dysfunction. This tool will enable longitudinal studies of OE regeneration and response to therapies, informing the development of targeted treatments. Clinically, this tool would provide a more objective assessment of anosmia than current smell tests, allow for the monitoring of OE changes over time, and significantly improve diagnostic accuracy.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Of the >280,000 women diagnosed with breast cancer (BrCa) in 2024, the majority will have estrogen receptor (ER) positive disease and will be treated with endocrine therapies (ET) for up to 10 years. Unfortunately, endocrine therapy resistance (ETR) develops over time in up to 30% of these women which is incurable and eventually leads to mortality despite additional targeted drugs and chemotherapy. Thus, there is an unmet need to discover modifiable factors that both prevent the development of ETR and/or impede disease progression. Environmental factors play a significant role in the development and progression of ETR. Among these, dietary n-3 polyunsaturated fatty acids (PUFAs) have a long yet controversial history of impacting breast cancer etiology. In particular, there is some discrepancy about the putative effects of “plant-based” n-3 PUFAs (alpha linolenic acid, ALA) and “marine based” n-3 PUFAs (eicosapentanoic acid, EPA; and docosahexanoic, DHA). ALA is converted to EPA/DHA in cells through a series of elongation and desaturation events catalyzed by fatty acid desaturases (FADS). Overabundance of PUFAs leads to their oxidation in the cell membrane and is a precursor for cellular damage and cell death. While preclinical and clinical studies demonstrate both types of n-3 PUFAs are associated with improved BrCa outcomes, the evidence is stronger with the marine-based n-3 PUFAs. We have generated a series of breast cancer cell lines resistant to common forms of ET. Studies in these cells have revealed a persistent ETR metabolic phenotype that includes: 1)  expression of a FADS2 isoform with high enzymatic activity; 2)  intracellular n-3 polyunsaturated fatty acids; 3)  cytoplasmic neutral lipid droplets (LDs); and 4)  lipid peroxidation /  antioxidant capacity. Our working hypothesis is that ETR BrCa cells leverage endogenous FADS2-dependent conversion of ALA to EPA and DHA (endogenous production) to support the macromolecular and energetic needs of growth and progression, while protecting the cells against the anti-tumor effects of EPA and DHA via preferential sequestering into LDs. In contrast, exogenous EPA and DHA exposure has anti-tumor effects via suppression of extracellular growth factor receptors, the suppression of BrCa FADS2 expression, and increasing fatty acid oxidation, production of reactive oxygen species (ROS), and lipid peroxidation. This proposal merges expertise in diet and nutrition, breast cancer endocrine resistance, and medical oncology to: 1) assess the impact of ALA and EPA+DHA on the growth and progression of ETR BrCa cells and tumors; and 2) determine the role of FADS2 in both the development and maintenance of the ETR phenotype. These studies will advance our understanding of how dietary plant-based and marine-based PUFAs differentially affect the development and maintenance of ETR breast cancer. They have the potential to inform specific nutritional and pharmacological interventions for improving disease outcomes in the large population of women at risk for or living with ETR BrCa.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Myelin facilitates rapid and efficient conduction of action potentials and promotes the long-term health of axons. The absence or loss of myelin consequently has tremendous effects on nervous system function as seen in neurodegenerative diseases. Notably, myelin pathology and microglia activation often are coupled in neurological diseases. Knowing how microglia activation alters myelin and how this affects brain development and function would significantly improve our understanding of human health. A major unanswered question is how specific amounts of myelin are targeted only to select axons in development. Myelination is highly selective and plastic; not all axons are myelinated. Neuronal activity can influence oligodendrocyte differentiation, the probability of axon selection for myelination, the number, length and thickness of myelin internodes produced by oligodendrocytes and the total myelin coverage on axons. Furthermore, under normal circumstances, myelin forms mostly on axons of the dorsal and ventral tracks of the spinal cord, with very little myelination occurring in the axons of the region in between. What mechanisms account for this remarkable specificity and plasticity? In vivo imaging studies using zebrafish revealed that a substantial number of nascent myelin sheaths are removed from axons, raising the possibility that selective myelin sheath removal contributes to plasticity and target specificity. Microglia remove myelin in disease and injury. Recent work by our lab uncovered they also remove myelin in normal development to refine the amount and placement of myelin on specific neural circuits, but the molecular cues and mechanisms for microglial regulation of myelin are still unknown. How do microglia target myelin for phagocytosis and can dysregulated microglia activity contribute to neurodegenerative diseases? Developmental myelination is a dynamic process engaging precise multicellular interactions, but most experimental models do not permit direct and simultaneous observation of oligodendrocytes, their myelinating targets and microglia in living animals. Thus, we do not know how microglia engage with myelin as it forms. Consequently, we lack insight to how microglia selectively remove myelin under non-pathological conditions. By establishing methods for imaging oligodendrocytes, microglia and axons in living zebrafish, we have created powerful assays to test the mechanistic basis of myelin refinement. By harnessing genetic, and pharmacogenetic tools, we have the ability to precisely test hypotheses aimed at uncovering the mechanisms that mediate myelin surveillance and refinement by microglia. Altogether, we now have the conceptual framework, experimental tools and expertise to significantly advance our understanding of developmental myelination. Our experimental plan is designed to investigate the mechanistic basis of myelin refinement in development, with a particular focus on how microglia contribute to myelin plasticity and myelin integrity.

NIH Research Projects · FY 2026 · 2026-05

Abstract Telomere entanglements: formation, disentanglement, and impact of failed disentanglement on genome stability To preserve genome stability, replicated sister chromatids must be disentangled and cleanly separated at mitosis. Telomeres safeguard this process by protecting chromosome ends from degradation and end-joining reactions that generate dicentric chromosomes and rampant chromosome instability. In most human somatic cells, however, telomerase is inactive, leading to progressive telomere erosion over time. This raises a fundamental question: what protective functions are lost as telomeres shorten and become dysfunctional? Telomeres are well known for preventing end fusions, but we have uncovered an additional threat: telomere entanglements. These arise when stalled replication forks at dysfunctional telomeres fail to restart and engage in aberrant interactions, leading to persistent DNA bridges during mitosis. The fission yeast telomere-binding protein Taz1, and its mammalian ortholog TRF1, promote replication fork progression through telomeres and prevent such entanglements. Loss of Taz1 causes stalled telomeric forks that generate anaphase-spanning DNA bridges. We find that resolution of these structures depends on the timing of anaphase midregion nuclear envelope breakdown, which exposes the entanglements to the cytoplasm, an unexpected but essential step for entanglement resolution. This proposal dissects the mechanisms governing telomere entanglement formation and resolution. We hypothesize that the most problematic entanglements stem from strand invasions between stalled forks on different chromosomes, forming non-sister telomere entanglements. We will define their molecular structure and investigate how long noncoding telomeric RNAs and RecQ helicases contribute to their formation. We further show that resolution involves a noncanonical function of Topoisomerase II, likely modulated by the condensation state of Top2- DNA complexes, a novel concept with broad implications. While these discoveries emerged from studies in S. pombe, our preliminary findings reveal similar entanglement phenotypes in mammalian cells, particularly in response to telomeric replication stress. We will extend these studies to human cells undergoing telomere-driven replicative aging, to assess whether telomere entanglements contribute to the genomic instability associated with aging. Together, this work defines a previously unrecognized consequence of telomere dysfunction and illuminates the molecular handoff between stalled replication and chromosome segregation at the critical final act of mitosis, the moment of truth when euploidy is either preserved or lost.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY / ABSTRACT Chronic, low-grade inflammation is a hallmark of aging and a key driver of multiple age-related diseases. Accumulated senescent cells in aged tissues contribute to local and systemic inflammation by releasing a range of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP). Accordingly, there is growing interest in developing pharmacologic strategies to eliminate senescent cells and promote healthy aging. While senolytic drugs show promise, their off-target effects and dose-limiting toxicities constrain clinical use. An emerging alternative is the development of senomorphic therapies that suppress the SASP without inducing senescent cell clearance. However, progress has been hampered by an incomplete understanding of the regulatory mechanisms—particularly persistent NF-κB activation—that sustain SASP expression. Our recent work has uncovered a novel, spatially encoded mechanism underlying chronic inflammatory signaling in senescent cells. We identified a previously unrecognized class of lysosome–Golgi membrane contact sites (LG-MCSs) that form de novo during senescence and appear to act as structural scaffolds for the STING signalosome—a complex comprising the adaptor STING and the kinases TBK1 and IKKε, which together activate NF-κB. Unlike in canonical immune signaling, where STING is rapidly degraded via lysosomal routing after activation, we propose that senescent cells reorganize their organelle architecture to stabilize STING at LG-MCSs, shielding it from degradation and maintaining persistent signalosome activity. This R21 project will define the molecular architecture and functional role of LG-MCSs in sustaining chronic STING– NF-κB signaling. In Aim 1, we will use split-TurboID proximity labeling and quantitative mass spectrometry to generate a proteomic blueprint of LG-MCSs in senescent cells, identifying key tethering and signaling proteins. In Aim 2, we will employ CRISPR-based gene editing and the light-inducible OptoPBer system to manipulate LG-MCS formation in live cells and assess downstream effects on STING localization, NF-κB activation, and SASP gene expression. In addition to in vitro models of replicative and oncogene-induced senescence in normal human fibroblasts and epithelial cells, we will validate key findings in primary cells from aged donors and from individuals with Hutchinson-Gilford Progeria and Werner Syndromes—capturing both physiological and pathological contexts of aging. By establishing a new spatial framework for chronic inflammatory signaling in senescence, this project will generate foundational proof-of-concept data for a novel class of organelle-targeted senomorphic therapies. Aligned with the high-risk, high-reward mission of the R21 mechanism, these studies will lay the groundwork for future R01 research programs aimed at mitigating age-associated inflammation and promoting healthy aging through next-generation, organelle-based interventions.

NIH Research Projects · FY 2026 · 2026-04

Project Summary This project aims to uncover the transcriptional and metabolic mechanisms that govern the identity, function, and therapeutic potential of mucosal-associated invariant T (MAIT) cells, a non-MHC-restricted, innate-like T cell subset with growing relevance in cancer and infectious disease immunotherapy. By leveraging two clinically relevant molecular glues—CC-647 and DKY-709—that selectively degrade the transcription factors PLZF and Helios, we will precisely manipulate the transcriptional programs of MAIT cells and related innate-like lymphocytes ( T and NK cells) in primary human samples. Using integrated transcriptomic, epigenomic, metabolic, and functional profiling, this study will define how PLZF and Helios sustain MAIT cell effector poise, tissue-homing capacity, and metabolic restraint. The outcomes will enable the rational design of engineered MAIT cells with optimized persistence and functionality for off-the-shelf immunotherapies.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The rise in cannabis use and its legalization in the US have increased concerns about impaired driving and public safety. Current approaches to detect recent cannabis use, such as biomarkers in blood or urine, are invasive and fail to reliably indicate recent use. Since peak drug impairment lasts for several hours after cannabis use, there is a need for objective, non-invasive, and portable detection methods within this timeframe. This study explores two promising approaches for detecting recent cannabis use: (1) breath sampling and (2) pupil dynamics. These methods are objective, non-invasive, portable. Furthermore, emerging evidence suggests these detect recent cannabis use during the window of acute impairment. Several devices using these approaches are nearly or already commercially available, yet independent validation of their uncertainty, reliability, and predictive validity is limited. This study will rigorously assess the performance of two breath sampling devices and two ocular devices. Using a within-subjects observational design, we will recruit 45 participants to compare device performance pre- and post-cannabis use. Over two years, we will address the following aims: (1) Test the repeatability of findings within and between detection methods. We will compare repeat measures of cannabinoids in breath, and pupil size and dynamics in response to light; (2) Determine the duration of detectable acute cannabis effects, using post-use assessments over 4.5 hours; (3) Evaluate the joint predictive validity of both detection methods. This study builds on preliminary data to refine detection protocols and inform industry standards. The overall goal of our program of research is to develop objective approaches to detect cannabis use and impairment to prevent injuries and promote public safety. This work builds on preliminary data, addresses a critical gap in the ability to detect cannabis-related impairment with real-time, non-invasive, and objective approaches. Validation of breath-sampling and pupil measurement approaches will provide actionable insights for law enforcement, public health, and transportation safety professionals in identifying and preventing cannabis impaired driving.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Measuring the functional connectivity between cortical neurons in the primary visual cortex (V1) remains a pivotal challenge in neuroscience, particularly in understanding how selective visual responses emerge from myriad synaptic inputs. This proposal aims to identify the principles of functional connectivity within layer 2/3 of ferret V1, building upon previous work in mouse and classical work in carnivores and primates. Our central hypothesis posits that inter-columnar connections, following the functional similarity principles observed in mouse V1, are essential for feature selectivity. We propose two main aims. First, using all-optical interrogation, we will perturb and map excitatory and inhibitory neuronal interactions within and between orientation columns, testing hypotheses about the spatial profile of excitatory connectivity, the functional specificity of inhibitory interneurons, and the dynamic recruitment of functional connections. Second, we will employ two-photon calcium imaging to map and analyze the organization and integration of synaptic inputs on the dendritic tree during diverse visual stimuli presentations. These studies will assess the functional similarity of long-range excitatory inputs and their preferential location on distal dendritic tufts, as well as the dynamic recruitment of inputs in shaping somatic responses. Through these approaches, our research aims to uncover novel computational circuit motifs in ferret V1, advancing our understanding of cortical circuits and informing the development of brain-inspired artificial intelligence.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Cardiovascular diseases (CVD) are major chronic diseases and the leading cause of death in the United States and worldwide. Coronary artery disease (CAD), the most prevalent form of CVD, affects approximately 1 in 20 adults over 20 years old. Current treatments help manage risk factors but do not address thrombosis or restenosis comprehensively. Drug-eluting stents (DES) have improved restenosis rates but rely primarily on timed drug release, which fails to fully accommodate the multi-phase nature of vascular injury and repair. FDA approved DES effectively limit vascular smooth muscle cell (SMC) proliferation but also block endothelial growth required for vascular repair and has no effect on inflammation or chronic vascular remodeling resulting in incomplete healing, late stent thrombosis, and suboptimal long-term outcomes. PTEN is a key regulator of SMC function. Vascular SMCs are major contributors to pathological vascular remodeling through functional phenotypic modulation that plays a critical role in vascular disease progression. Our published and preliminary studies indicate that genetic and pharmacological upregulation/maintenance of PTEN levels actively preserves SMC phenotype, blocks inflammation, and prevents vascular disease progression in PTEN phosphatase- dependent and PTEN nuclear transcriptional-dependent manners. In contrast, SMC-specific depletion of PTEN exacerbates atherosclerotic lesion formation, injury-mediated restenosis, and hypertension-associated vascular remodeling making PTEN an essential and causal vascular protective target, which represents a novel concept for the treatment of cardiovascular disease. Unlike traditional DES, PTEN has been shown to directly target SMCs and block the major adverse events thereby mitigating neointimal hyperplasia, which is a major contributor to restenosis. Polymer poly-lactic-co-glycolic acid (PLGA) can be used as a promising delivery system due to their FDA approval, biodegradability, controlled drug release properties, cost-effectiveness, and commercial availability. These characteristics make PLGA polymers ideal for synthesizing PTEN encapsulated nanoparticles. For the current proposal, we hypothesize that engineered PTEN-PLGA nanoparticles will restore the contractile phenotype of SMCs, reducing proliferation, migration, and inflammation associated with restenosis. This approach has the potential to address critical gaps in current CAD treatment by offering a more precise and sustained intervention. As CVD cases continue to rise, developing a targeted therapeutic strategy is essential. A PTEN-PLGA nanoparticle system could transform restenosis prevention and provide a long-term solution to one of the biggest challenges in cardiovascular medicine. We propose that SMC targeted nanoparticle PTEN mRNA delivery will prevent SMC phenotypic modulation through PTEN-dependent maintenance of the contractile, differentiated VSMC phenotype and thereby inhibit in-stent restenosis. Two Aims are proposed to test engineered SMC-targeted PTEN-encapsulated PLGA nanoparticles in in vitro human SMC culture models and in vivo genetic mouse whole body delivery and rat stent-based delivery.