Utah State Higher Education System--University Of Utah

NIH Research Projects · FY 2025 · 2025-04

PROJECT SUMMARY Immunosuppression is essential for treating various medical conditions, but current treatments often suffer from suboptimal effects and long-term lymphopenia and immune deficiency. Targeted depletion of programmed death-1-positive (PD-1+) cells presents a promising solution to these limitations. PD-1+ cells play a critical role in sustaining immune responses in contexts such as autoimmune diseases and organ transplantation. Consequently, depleting PD-1+ cells has been shown to effectively suppress immune responses. This strategy offers two key advantages: it is likely more potent because it targets both B and T effector cells, and it spares naïve cells (PD-1-) and lymphocyte repertoires, avoiding long-term immune deficiency and preserving immune protection. Therefore, developing suitable agents for PD-1+ cell depletion in clinical settings is a warranted effort. Previously, immunosuppression through PD-1+ cell depletion was achieved using immunotoxins, which are not ideal for chronic conditions requiring sustained immunosuppression. In our efforts to develop suitable agents, we engineered PD-1-specific antibody-drug conjugates (ADC) and depleting antibodies. Although effective in depleting PD-1+ cells, these agents failed to suppress autoimmunity in a type 1 diabetes (T1D) model, instead exacerbating auto-attacks and the progression of hyperglycemia. This paradoxical result may be attributed to the Fc component within the ADC and the depleting antibody, which can elicit proinflammatory, effector responses. Indeed, previous studies have shown that antibodies or ADCs designed for immunosuppression need have their Fc mutated or modified to minimize proinflammatory responses. Therefore, we posti that an Fc- devoid, PD-1-specific depleting agent might be ideal for achieving immunosuppression. Specifically, we suggest that a PD-1-specific Albumin-Amended Antibody Drug Conjugate (A3DC), with its Fc replaced by albumin, could effectively deplete PD-1+ cells. The PD-1 A3DC is built upon a scaffold protein comprising the single-chain variable fragment (scFv) of an anti-PD-1 antibody and albumin. The goal of this project is to generate PD-1 A3DCs and confirm their selective toxicity to PD-1+ cells and their immunosuppressive capability. Through preliminary studies, we have developed three scaffold proteins with varied domain configurations and demonstrated their binding and internalization by PD-1+ cells. Building on this progress, we aim to achieve our objectives through the following two aims: Aim 1: Determine and compare the toxicity of PD-1 A3DCs to PD-1+ cells. We plan to generate a library of 24 A3DCs and select three A3DCs from the library to be used in Aim 2, based on their binding with the neonatal Fc receptor and toxicity to PD-1+ cells. Aim 2: Determine and compare the immunosuppressive effect of PD-1 A3DCs in a mouse T1D model. The ultimate deliverable aim is to identify one or more A3DCs that deplete PD-1+ cells and suppress autoimmunity.

NIH Research Projects · FY 2026 · 2025-04

Project Summary This research project aims to study the neural basis of the precedence-type sound localization processes, including the Franssen effect. This central computation is key to understanding the normal function of auditory perception and is a priority area in NIH's hearing research. The precedence phenomena play a critical role in speech-in-noise, dichotic, and temporal processing, in addition to source location and echo identification. Illusions such as these are distortions in perception that provide insights into the workings of the auditory system. The basic precedence effect consists of two ‘identical’ tone bursts are presented with various timing relations from separate loudspeakers situated on either side; the listener perceives a single ‘fused’ sound as coming from the speaker that broadcasted the leading sound. The Franssen effect is an illusion where the listener incorrectly perceives the sound as coming from a loudspeaker that broadcasts a leading short-duration sound pulse with a fast amplitude rise and slow decay. This happens despite most of the sound originating from a contralaterally placed lagging loudspeaker producing long-duration sound with a slow onset. The proposed research takes advantage of the natural preference of a species of gray treefrogs (Hyla versicolor) for slow-rise, long-duration (SR-LD) sound pulses that represent those used to elicit FE illusions. In choice tests, H. versicolor females strongly prefer SR-LD sound pulses over the fast-rise, short-duration (FR-SD) pulses of their sister species Hyla chrysoscelis and approach the transducer broadcasting the former. In aim 1, we plan to conduct behavioral experiments that take advantage of this natural preference. We hypothesize that subjects will erroneously approach a loudspeaker broadcasting FR-SD pulses when they precede SR-LD pulses form an orthogonally placed loudspeaker. In aim 2, we propose to make extracellular recordings from single neurons in the anuran inferior colliculus (ICan) to stimuli that elicit FE. We hypothesize that FR-SD pulses from a contralateral loudspeaker suppress neurons selective to SR-LD stimuli. To understand the temporal integration of binaural excitatory and inhibitory inputs to the ICan, we propose, in aim 3, to examine the role of inhibition in FE. We seek to utilize a constellation of techniques, including in vivo whole-cell recordings and analytical methods for estimating inhibition elicited in SR-LD selective neurons by preceding ipsilateral FR-SD stimulus.

NIH Research Projects · FY 2026 · 2025-04

Project Summary Understanding how sensory receptors respond to a range of stimuli is essential for delineating how sensory information is encoded, but neuronal response features are not determined solely by the interaction between stimuli and receptors. Inhibitory circuits play a fundamental role in shaping response features to sensory stimuli, therefore impacting the information that is relayed to higher levels of processing. Within the olfactory system, responses are influenced by a diversity of inhibitory circuits but we still lack an understanding of the functional organization of these circuits. Are inhibitory connections randomly organized or is there structure that reflects receptor domains and chemical space? It remains challenging to map responses from the receptor level to their principal output neurons and quantify inhibitory responses of the same neurons across individuals. The proposed project overcomes this challenge by taking advantage of three receptor-tagged mouse lines to delineate how inhibition is functionally organized in the olfactory bulb and how inhibitory responses manifest in postsynaptic neurons. In Aim 1, I will test alternate models of lateral inhibitory organization and ask how inhibition is organized relative to existing structure in the olfactory bulb. While it is known that lateral inhibition is odor-defined and selective, little is known regarding how this selectivity is organized within and across individuals. In Aim 2, I will then ask how inhibition manifests in postsynaptic cells that transmit sensory information to cortical regions. Previous work suggests that the two types of postsynaptic output neurons in the olfactory bulb are differentially influenced by inhibition, but there is conflicting evidence regarding whether sister cells receiving the same receptor-defined inputs are homogenously modulated by inhibition. To test these questions, I will characterize pre- and postsynaptic excitatory and suppressive tuning in vivo using olfactory receptor-defined neurons and the most up-to-date optical reporters to image neuronal responses in awake, head-fixed mice. I will also image from the soma of postsynaptic olfactory receptor-defined neurons by using a diagnostic ligand. This project will identify novel principles underlying inhibitory circuit organization, which has implications for sensory processing across modalities and will broaden our insight into the relationship between sensory receptors, stimulus identity, and the organization of sensory circuits. The proposed project will provide me with training in the technical skills and conceptual knowledge needed for my future career goal of becoming a tenure-track researcher investigating how developmental deviations impact the evolution and function of chemosensory systems. This research will take place in my sponsor’s lab at the University of Utah, but I will spend a month in Spring 2025 in my co-sponsor’s lab at Duke University learning in vitro techniques to assay odorant receptor activation. Both institutions have collaborative research environments that will provide me with the necessary resources to complete my research training goals.

NIH Research Projects · FY 2026 · 2025-04

Project Summary. Our overall goal is to improve the differential diagnosis and treatment of complex multi-canal benign paroxysmal positional vertigo (BPPV) and related disorders of the labyrinth. We will achieve this goal using an array of morphological, computational and experimental methods focused on semicircular canal biomechanics in health and disease. The project has 5 Specific Aims: Aim 1 will apply statistical shape modeling and principal component analysis to quantify inter-subject variance in human membranous labyrinth morphology, which is essential to design of robust canalith repositioning maneuvers (CRMs). Aim 2 will construct and validate computational and physical models to easily simulate all forms of BPPV, diagnostic tests, and candidate CRMs across a diverse range of labyrinth morphologies. Aim 3 will develop and test "universal" CRMs that are robust to morphological variability and designed to clear all 3 ipisilateral canals of otoconial debris in a single movement sequence. Aim 4 will experimentally evaluate the head impulse tests (HIT) as part of the test battery for differential diagnosis of canalithiasis, cupulolithiasis, cupuloperfluo and canal jam. Aim 5 will determine if short-arm posterior canalithiasis and cupulolithiasis can account for type 2 BPPV and characteristics of nystagmus. We expect results to quantify sensitivity of standard of care CRMs to morphological diversity, determine if HITs are useful in differential diagnosis of BPPV and related conditions, and introduce a robust universal CRM.

NIH Research Projects · FY 2025 · 2025-04

This application for a K24 Midcareer Investigator Award will promote Dr. Alayne Markland’s mentoring and career development in patient-oriented research on lower urinary tract symptoms and urinary incontinence at the University of Utah (U). Dr. Markland is a geriatrician and clinician investigator dedicated to advancing evidence on the prevention, evaluation, and treatment of bladder and bowel symptoms for older women and men. With funding from the National Institute on Aging, the National Institute on Diabetes, Digestive, and Kidney Diseases, and the Agency for Healthcare Research and Quality, she leads a nationally recognized, patient-oriented research program that emphasizes improving access to care models, as well as improving knowledge on shared risk factors underlying aging-associated genitourinary dysfunction. Her work focuses on the intersection of common aging syndromes, such as multi-morbidity, cognition, and functional status, with lower urinary tract symptoms and incontinence. To date, she has created new models of care, improved patient-reported outcome measures used in clinical care and research, and provided evidence to guide national and international guidelines on the treatment of lower urinary tract symptoms and incontinence. She has also emerged as a successful mentor of early-stage clinical investigators who have published high-impact research, obtained NIH and VA-funded awards, and improved patient-oriented research focused on behavioral interventions. With award support and a career move, Dr. Markland plans to expand and refine her mentoring skills through didactics and focused training, and to continue mentoring her current early-stage trainees and recruit new trainees. All trainees will be provided with educational and research experiences tailored to their career stage and interests. With award support, Dr. Markland’s research program will be augmented through a funded clinical trial addressing the use of mobile health platforms to deliver behavioral treatments for lower urinary tract symptoms and incontinence care, which will provide new opportunities for mentoring trainees, collaborations, and future funding. The Aim of New Study 1 is: Identify mechanisms by which behaviorally based mobile health platforms improve lower urinary tract symptoms and incontinence severity. The Aim of New Study 2 is: Define barriers and facilitators for using mobile health technology for improving lower urinary tract symptoms and incontinence severity. The Aim of New Study 3 is: Determine effective, feasible candidate components for future mobile health interventions. The long-term goal of Dr. Markland’s research and career is two-fold: 1) to become a leader of behaviorally-based treatment interventions with digital health platforms, and 2) to enhance skills as a mentor of patient-oriented research. Through this award and the new research studied proposed, Dr. Markland will support high-quality mentees with the potential to become leaders in patient-oriented research related to aging and lower urinary tract symptoms/incontinence.

NIH Research Projects · FY 2026 · 2025-03

ABSTRACT Obesity affects 2 out of 5 American adults and leads to high individual and societal costs. Behavioral interventions focusing on diet and exercise can yield clinically significant weight loss of at least 5%. However, the proportion of people who achieve this benchmark in behavioral weight loss trials is limited due to variable and waning intervention adherence. One strategy to improve intervention adherence and weight loss is to provide small monetary incentives for behaviors such as calorie logging or outcomes such as interim weight loss. Current intervention structures are uniform, providing the same incentive timing and amount to all people. Thus, some receive incentives even though they do not need them, while others do not receive enough incentives to change their behavior. This uniform structure taxes limited budgets available for incentives. There is an urgent need for a precision medicine approach that distributes incentives to people who respond to them. To address this need, we apply reinforcement learning, a machine learning method, to create a precision medicine intervention whereby each participant receives an individualized sequence of incentives to increase the probability they achieve clinically significant weight loss. This novel approach takes data from cellular scales and a dietary logging application to inform the prediction of participant behavior in response to incentive amount. Using data from a previous incentives trial, we developed an algorithm with high predictive accuracy. We plan to conduct a future randomized trial comparing the efficacy of this precision approach to a uniform approach on weight loss. To prepare for the future trial, we will conduct a planning study with three aims: 1) Develop a digital health platform to incorporate an existing commercial mathematical optimization modeling software for prescriptive analytics to implement our algorithm. The platform will provide real-time analytics and deliver a weekly incentive based on past behavior. We will develop a manual of procedures for detecting and resolving errors for real-time data capture and processing. 2) Evaluate the feasibility of applying the algorithm prospectively in a clinical trial. We will enroll two successive cohorts of adults with obesity in a single-arm feasibility study and implement the personalized incentives intervention over six months. We will establish logistical feasibility of executing the protocol and provide estimates of screening-to-enrollment, retention, and incentives intervention response rates. 3) Characterize participant intervention acceptability as indicated by intervention adherence rates, safety criteria, and feedback from qualitative interviews. Our findings will be used to support a future, adequately powered randomized trial. If efficacious, our personalized intervention could maximize return on investment for healthcare payers by optimally distributing a preset budget across a population to maximize long-term, population-level weight loss in real-world settings.

NIH Research Projects · FY 2026 · 2025-03

Summary Myocardial fibrosis serves to define various cardiac diseases, and is very useful as an early marker of cardiovascular disease and its progression. Some myocardial fibrosis is reversible and can be surveilled to determine response to treatment. Late gadolinium enhancement (LGE) MRI is a robust method for sizing scar (focal fibrosis) regions. Diffuse fibrosis and hemorrhagic infarctions can be more difficult to assess well. A relatively new MRI method, spin locking or T1rho imaging, is thought to provide valuable information regarding myocardial fibrosis. However, many problems including a variety of implementations with wide-ranging T1rho values, challenging artifacts, possibly different values by sex and age, and a lack of gold standards has impeded the potential value of cardiac T1rho. Here we seek to improve and better understand the factors that influence spin locking cardiac MRI. This project will also enable improved understanding of the utility of non-contrast MRI methods that include T1rho for assessing myocardial fibrosis. We propose to develop and test new combination MRI methods to predict myocardial fibrosis without gadolinium. The aims and methods of this project are to (1) study the value of different T1rho methods and more conventional MRI techniques in preclinical models. The models will have either diffuse fibrosis from rapid pacing, or focal fibrosis from coronary injection of ethanol. Half of the studies will also include focal fibrosis from radiofrequency ablation lesions placed on the LV endocardium. Histology of these models will inform their utility in translational studies. (2) To develop and compare new combined multi- parametric cardiac MRI methods for quantitative fibrosis measurements. This includes validating the methods in the preclinical model of aim 1. (3) We will characterize the repeatability of the T1rho and other MRI methods, in patients with cardiac disease. The new gadolinium-free methods will also be evaluated for their ability to predict extracellular volume (ECV) maps. The relevance to public health is that myocardial fibrosis causes disability and death and current treatments are inadequate. The development and use of more accurate and repeatable measurements of myocardial fibrosis will improve diagnosis and evaluation of therapies. As well, validated MRI methods that do not use gadolinium contrast will lead to accelerated evaluation of clinical therapies, in particular therapies in patients with severe kidney disease where administering gadolinium is contraindicated for research.

NIH Research Projects · FY 2026 · 2025-03

Project Summary The role of the basal body (BB) and daughter centriole (DC) linkage in photoreceptor biology and pathophysiology has not been explored, while the mother centriole (MC) and DC linkage in cultured mammalian cells is important for cell cycle progression and genome stability. The MC and DC linkage is mediated by ciliary rootlets, which are recruited to the proximal ends of centrioles by CNAP1 (Centrosomal NEK2-Associated Protein 1). NEK2 (NIMA-related kinase 2) phosphorylates CNAP1 and several ciliary rootlet component proteins to regulate the centriole linkage, and CEP78 is known to interact with CNAP1. Genes encoding CNAP1 (CEP250), NEK2 (NEK2), and CEP78 (CEP78) have been identified in patients with retinitis pigmentosa (RP) and combined cone-rod dystrophy and hearing loss (CRDHL). The latter is also considered an atypical type of the most common genetic deaf-blindness disease, Usher syndrome (USH). To understand the disease mechanism underlying the mutations in these genes and the role of the BB and DC linkage, this application focuses on the CEP250 gene. In the preliminary study, new Cep250 mutant mice with both vision and hearing impairments were generated. In the mutant photoreceptors, the BB and DC were disconnected and detached from the ciliary rootlets; DC and axoneme marker proteins were mislocalized; and many proteins in the centriole, connecting cilium, and outer segment were downregulated. The three USH type 2 (USH2) proteins were also reduced, and CNAP1 was found to interact with the USH2 scaffold protein WHRN in vitro, suggesting a mechanistic link between CNAP1 and USH2. Additionally, multiple CNAP1 isoforms were discovered in mouse retinas, which may explain the different phenotypes in our Cep250 mutant mice and the previously reported Cep250R187* mice as well as the different phenotypic manifestations in CEP250 patients. Based on these findings, the following hypothesis will be tested that two functionally important CNAP1 isoforms contribute collectively to the BB and DC linkage and the maintenance of the ciliary structure and USH2 protein complex in photoreceptors and hair cells. In Aim 1, the role of CNAP1 and the BB and DC linkage in the ciliary structure and function will be determined in our Cep250 mutant photoreceptors. In Aim 2, the functional relationship between CNAP1 and the USH2 protein complex will be explored in photoreceptors and hair cells. In Aim 3, the vision and hearing phenotypes of two Cep250 mutant mice, which represent different CEP250 mutation groups and presumably have different CNAP1 isoform disruptions, will be compared. This study will reveal the role of the BB and DC linkage in photoreceptors, understand the vision and hearing pathogenesis caused by different mutations in CEP250 and related genes, uncover the mechanistic connection between CRDHL and USH, and provide new insight and animal models for future therapeutic studies.

NIH Research Projects · FY 2026 · 2025-02

Abstract The focus of the research in the Lamb lab is to determine mechanisms of the immunopathogenesis of malaria. The long-term goal of the proposed work is to determine the molecular mechanisms of vascular leak in malaria. It is estimated that annually more than ~250 million people develop malaria worldwide resulting in over 600,000 deaths[1]. Malaria-associated respiratory distress syndrome (MA-ARDS) and malaria-associated acute lung injury (MA-ALI) are features of adult malaria where infection is caused by the species Plasmodium knowlesi and Plasmodium vivax. Despite the poor prognosis of this syndrome in malaria, very little is understood about the molecular players that mediate pulmonary vascular leak in MA-ARDS / MA-ALI. As such it is difficult to design new adjunct therapeutic strategies for this condition. CD8 T cell responses against the Plasmodium parasites that cause malaria are responsible for the pathogenesis of infection and are required for pulmonary vascular leak. Here we investigate our fascinating finding that co-infection of influenza with P. berghei NK65e prevents MA-ARDS / MA-ALI in mice. The proposed work will capitalize on this finding to establish the mechanisms by which protection occurs. Our published and preliminary data leads us to test the working hypothesis of this study that influenza modifies pulmonary vascular endothelial cells (PMVECs) and induces arginase 1 (Arg1)-producing monocytes as key protective mechanisms against CD8-mediated MA- ARDS / MA-ALI. Staggering of influenza A/X31 co-infection reveals protection only occurs when X31 infects at the same time as P. berghei NK65e suggesting an innate immune mechanism at play. We show that influenza A/X31 recruits a large number of Arg1-producing monocytes which are capable of suppressing the proliferation of polyclonally stimulated CD8 T cells. The rationale for the proposed work is that CD8 T cell responses are central to pulmonary vascular leak associated with malaria, and a more comprehensive understanding of how influenza prevents this damaging response will provide key information for the rational design of novel interventions to reverse pulmonary vascular leak in MA-ARDS / MA-ALI. We plan to test our central hypothesis and thereby accomplish the objective of this application by pursuing the following two specific aims: Aim 1: Determine whether influenza co-infection can suppress the pathogenic response of Plasmodium-reactive CD8 T cells directly or indirectly. Aim 2: Test the hypothesis that influenza-induced Arg1+ monocytes protect NK65e-infected mice from vascular leak.

NIH Research Projects · FY 2026 · 2025-02

Depression is a debilitating nonmotor symptom of Parkinson’s disease (PD) that affects approximately 40% of patients and contributes to worsened quality of life. Despite its prevalence and burden, depression in PD is often inadequately treated with current therapies. Growing evidence indicates depression is likely linked to PD pathophysiology involving the basal ganglia, rather than just a reaction to general illness. Deep brain stimulation (DBS) therapy, targeted to the basal ganglia in either the globus pallidus internus (GPi) or the subthalamic nucleus (STN), is effective for improving PD motor symptoms. However, the effects of DBS on depression in PD vary across patients, from meaningful improvements to detrimental worsening. This variability is partly because the basal ganglia pathophysiology of depression is unclear, and it is unknown which brain signals and networks to modulate with DBS to improve depression in PD. The objective of this proposal is to identify basal ganglia neural activity associated with depression in PD and identify brain regions and networks associated with depression improvement with DBS in PD. My central hypothesis is that PD patients with depression exhibit altered neural activity compared to patients without depression, and these alterations (1) are localized to specific brain regions and networks, and (2) are similar across the GPi and STN, pointing to a common basal ganglia network associated with depression in PD. To investigate, I will use multimodal approaches combining neural recordings in patients who underwent GPi DBS or STN DBS for PD (N=199 patients, 291 hemispheres), neuroimaging to map brain regions and networks, and computational models to evaluate the effects of DBS. In Aim 1, I will identify basal ganglia neural activity associated with depression in PD using machine learning techniques. In Aim 2, I will determine the local and network topography of basal ganglia neural activity to identify physiological brain networks showing alterations in PD patients with versus without depression. In Aim 3, I will identify “hotspots” and brain networks associated with depression improvement with DBS for PD. During the K99 phase, I will receive training in human neurophysiology and clinical research in psychiatry, facilitated by Dr. Coralie de Hemptinne (expert in human neurophysiology), Dr. Gregory Pontone (expert in neuropsychiatry in PD), and a team of interdisciplinary advisors. After securing an independent faculty position, I will transition into the R00 phase and build on my K99 research in Aim 4 to prospectively evaluate neural activity and neuroimaging- based markers of depression in PD in a novel cohort (N=20 patients) using a DBS device capable of chronic neural recordings to test whether they correlate with longitudinal depression symptoms in the patients’ naturalistic environment and evaluate the effects of DBS and dopaminergic medication. Collectively, this K99/R00 award will enable me to pursue the technical and career development training necessary to prepare me to lead an independent research lab focused on understanding the pathophysiology of neurological and psychiatric disorders and establishing neurophysiological and network-guided neuromodulation therapies.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY/ABSTRACT Sulfur is an important heteroatom in pharmaceuticals, with 30% of the top-grossing small- molecule drugs in 2022 containing sulfur. Highly oxidized sulfur functional groups, such as sulfonamides, are particularly common. Sulfondiimines are a type of high oxidation state sulfur compound that can be chiral, which is an important property in drug molecules. However, synthesis of sulfondiimines, especially with high selectivity for one enantiomer, can be challenging and exhibit poor safety profiles. It is clear that the development of improved methods for sulfondiimine synthesis would be beneficial. One approach to method development is using data science, which can expedite the optimization process by allowing for in silico screening. Data science models have the potential to give insight into mechanistic details of reactions when applied in tandem with computational chemistry tools and careful data generation. A challenge within this method development is to identify general conditions that work for many compounds of a general synthetic goal. One approach to develop a generalizable reaction is by optimizing conditions around several compounds rather than a single model substrate. Thus, the primary aim of this proposal is to develop generalizable novel synthetic methods for sulfondiimines using data science. This goal will be achieved by applying a generality-oriented, data science-driven reaction development approach to two specific aims: (1) a desymmetrization of sulfondiimines and (2) selective addition to fluoro-λ6-sulfanenitriles. The separate synthetic strategies could allow for access to a broader range of sulfondiimines, as each may exhibit different reactivity profiles for various compounds. These methods will be showcased through broad substrate scopes featuring syntheses of sulfondiimine analogues for known sulfonamide-containing cancer drugs. A long- term application of this proposal is the synthesis of a library of sulfondiimine analogues of known drug targets for analysis as potential therapeutics.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY Microglia, the resident innate immune cells of the CNS, play essential roles in CNS development and homeostasis, and are key responders to neuronal stress, injury and disease, including in retina. While retinal microglia have been well characterized in rodent models, much less is known about the properties and responses of human retinal microglia, particularly in an in vivo context. To address this, we seek to establish a model to study human microglia in vivo in the context of the retina. Here we will introduce human induced pluripotent stem cell derived hematopoietic progenitor cells (iHPCs) into the newborn murine brain and assess engraftment of the resulting human xenotransplanted microglia (xMGs) in the retina. In the first aim, we will characterize the engraftment, including density and distribution, of xMGs into mouse retina and optic nerve, and will determine the impact on host retinal cells and tissue organization. In the second aim we will use single cell RNA sequencing to define the human xMG transcriptome, will compare gene expression to endogenous human microglia, and finally will analyze xMG responses via transcriptional changes to optic nerve crush, a well characterized axon injury model resulting in retinal ganglion cell degeneration. This study will provide critical foundational insight into the properties of human xMGs integrated into the mouse retina and test their responses to retinal ganglion cell injury, providing a potentially powerful resource for studying in vivo human retinal microglia responses to injury, disease or neurodegeneration.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM) is the most common and most aggressive adult primary brain tumor. Regardless of therapy, the median survival time is less than 15 months as GBM nearly always recurs. Diagnosing GBM currently depends on acquiring tumor tissue for histologic examination to differentiate GBM from other types of brain lesions with a similar imaging appearance. Detecting GBM recurrence is also challenging as treatment effects such as pseudoprogression and radiation necrosis mimic recurrent disease. Thus, risk-associated diagnostic invasive procedures remain a critical aspect of GBM patient care even though surgically acquired neurologic deficits may reduce an already short survival time. Therefore, a non-invasive approach to diagnose GBM and identify true recurrence has the potential to directly impact patient care throughout the entire disease course. DNA released from cells during programmed cell death, termed cell-free DNA, is an emerging biomarker for diagnosing human cancers and monitoring response to therapy. Detection of tumor-derived cell- free DNA in plasma, also known as circulating tumor DNA (ctDNA), has previously been largely unsuccessful in humans with GBM due to an inability to find the ctDNA amongst the abundant background of normally occurring cell-free DNA. The large intra- and inter-tumor genetic heterogeneity of GBM has hindered searches for specific tumor variants in cell-free DNA, while the rarity of GBM to metastasize beyond the central nervous system has considerably restricted the quantity of ctDNA present. However, our uncovering of ctDNA in a xenograft brain tumor model using human GBM stem-like cells strongly supports the feasibility of detecting GBM-derived ctDNA in humans. Moreover, our previous success in the animal model provides direction for the human translation – reducing or eliminating noise associated with next-generation sequencing (NGS) that interferes with the detection of very low frequency variants is necessary to allow searches for ctDNA that are not dependent on a priori knowledge of solid tumor variants. In this proposal, we attenuate NGS-related noise and demonstrate the unbiased detection of GBM-derived ctDNA at time of initial diagnosis and at recurrence. We also show that identification of GBM solid tumor DNA variants in ctDNA is enhanced by reducing errors associated with NGS to improve sampling of the solid tumor genetic heterogeneity typical of GBM. Therefore, this proposal seeks to translate plasma cell-free DNA as a biomarker to detect GBM in humans by suppressing errors associated with NGS to improve variant detection at very low allele frequencies. The successful application of ctDNA biomarkers to non-invasively assess GBM will directly affect patient care by enabling the optimization of clinical management prior to or instead of risk-associated invasive diagnostic procedures.

NIH Research Projects · FY 2026 · 2025-02

Cellular heterogeneity in cancer represents a major challenge to the development of curative therapies, as even small subsets of cells can fuel relapse, dormancy, treatment failure, and metastasis. Cellular plasticity i.e. reversible state change, likely provides a key contributing mechanism. However, clinical approaches that specifically target molecular mediators of cellular plasticity are lacking. This proposal investigates the CR1 pathway as a critical plasticity mediator in breast cancer progression. CR1 is a cell surface/secreted stem cell factor and oncofetal protein that promotes proliferation, migration and epithelial-mesenchymal transition in human mammary epithelial cells in vitro and stem cell maintenance in primary mouse mammary epithelial cells cultured ex vivo. Recently, we showed that inhibition of CR1 with a candidate, engineered, peptide therapeutic (ALK4L75A-Fc a.k.a. A4Fc) reduced growth of human breast cancer cells under nutrient stress, and blocked metastasis when these were transplanted into mice. CR1 blockade in these tumor models is associated with reduced fibrosis -- consistent with the discovery of CR1 as a key regulator of fibrosis in wounding. We now seek to understand molecular mechanisms of CR1’s sensitivity to microenvironmental or therapy associated stress, to determine the role of novel signal mediators, and to uncover targetable molecular underpinnings of the reprogramming that CR1 coordinates between cancer cells and their neighbors during breast cancer progression. To this end in Aim 1, we utilize a series of mouse transplant models (including patient derived breast cancer cells) and bioengineered systems to examine CR1 dependent cell state change at different stages of metastasis, and to test the effect of blocking CR1 on aggressive breast cancer phenotypes. In Aim 2, we will use multicellular culture systems to uncover the mechanics of CR1 signaling including its dependence on stress related upstream and downstream mediators, and cellular cross-talk. Both aims leverage our experience in single cell RNA-sequencing to elucidate cell state change at high resolution. Impact: This work will not only bring new understanding to the molecular biology of breast cancer cell plasticity and heterogeneity, but will also set the stage for clinical translational studies of CR1 blocking agents with newly defined targets, readouts and biomarkers at single cell resolution.

NIH Research Projects · FY 2026 · 2025-02

Project Summary/Abstract: Myelofibrosis (MF) is a type of myeloproliferative neoplasm (MPN) that results in progressive scarring of the bone marrow, leading to constitutional symptoms, decreased hematopoiesis, and increased risk of acute leukemia. Symptomatology and disease progression are driven by constitutive genetic activation of the JAK/STAT pathway. Current treatments target JAK/STAT signaling and alleviate symptoms but fail to alter the natural progression of disease. Hyperactive cytokine signaling though JAK/STAT promotes disease progression by stimulating pro-fibrotic signals, such as TGF-β, which converts mesenchymal stromal cells (MSCs) into myofibroblasts. Myofibroblasts deposit extracellular matrix, which perpetuates fibrosis. One treatment goal is to prevent/reverse fibrosis and allow for expansion of normal hematopoietic stem cells (HSCs). However, there are currently no treatments that reproducibly inhibit progression of fibrotic diseases, and new treatment strategies are needed in this field. Lactate, which was canonically considered a waste product of glycolytic metabolism, has recently been shown to play a role in several diseases. Interestingly, fibroblasts increase glycolysis and lactate production when they convert to myofibroblasts. In line with these previous observations, my preliminary data suggests that inhibiting lactate export from fibroblasts by pharmacologically blocking monocarboxylate transporter 4 (MCT4) prevents TGF-β mediated myofibroblast differentiation in a cell autonomous manner. I also demonstrate that MCT4 is dramatically increased in bone marrow samples from myelofibrosis patients compared to non-fibrotic bone marrow samples. Together, these findings led me to hypothesize that lactate export through MCT4 is necessary for TGF-β mediated MSC-to- myofibroblast differentiation and disease progression in MF. To test this hypothesis, I propose three specific aims. First, I will determine the necessity of MCT4 for bone marrow MSC-to-myofibroblast differentiation. This will include pharmacologically manipulating the fate of pyruvate under different nutrient conditions to mechanistically understand how pyruvate-lactate metabolic axis alters MSC and myofibroblast phenotype. Second, I will test the relevance of MCT4 levels and function to MF pathophysiology in vivo. To do this, I will utilize human samples from pre-fibrotic MPN patients and compare them to patients with MF, to test the hypothesis that increased MCT4 expression correlates with fibrotic disease progression. Using a well characterized mouse model of MF, I will test whether MCT4 inhibition alleviates disease and prolongs survival. In my third aim, I will use unbiased single cell RNA-sequencing and 13C-glucose tracing to understand how different signals, such as TGF-β and mechanical tension, alter metabolism and lead to myofibroblast differentiation. This research proposal will determine whether MCT4 is a viable clinical target for myelofibrosis and given the recent development of selective MCT4 inhibitors, there is an opportunity for translation to the clinic and direct impact on patient care.

NIH Research Projects · FY 2025 · 2025-01

PROJECT SUMMARY With growing concerns regarding the environment and sustainability, there is an increasing demand for integrating green chemistry and green engineering into the pharmaceutical industry. Electrochemical organic synthesis represents a green and advantageous alternative to traditional synthetic methods because it directly uses electrons from a power source to complete the redox transformations, which can cut down on the usage of chemicals, reduce waste, and offer improvements in cost, safety, and sustainability. However, the current reaction library of electrosynthetic methods is limited. Therefore, there is a critical need for new electrolytic methods that offer new chemical reactivities. The proposal is focused on studying the mostly unexplored alternating current electrolysis for organic synthesis. Unlike the conventional electroorganic synthetic methods using a constant voltage or current, alternating current electrolysis uses an alternating voltage to drive the redox transformations of substrates. Alternating current electrolysis offers a unique reaction environment where two redox-opposite reactions can occur spatially and temporally close to each other and can be easily adjustable by merely controlling the alternating current voltage supply. The overall goal of this proposal is to exploit this unique reaction environment of alternating current electrolysis to achieve new reactivities that are not currently accessible by the existing synthetic methodologies, serving as a critical step towards the long-term vision of the electrically driven green synthesis of drugs.

NIH Research Projects · FY 2026 · 2025-01

PROJECT ABSTRACT Obesity is associated with a higher risk for the development of malignant ventricular tachyarrhythmias (VT), particularly under conditions of repolarization disorders and QT interval prolonging mechanisms (an established risk factor for VT), and sometimes tragically transitions to sudden cardiac death. In obesity, excess dietary fat in adipose tissues stimulates the release of immunomodulatory cytokines such as interleukin(IL)-6, leading to a state of chronic inflammation in patients. In the past decade, IL-6 trans-signaling has emerged as a powerful predictor of risk for VT. The first selective inhibitor of IL-6, olamkicept, has shown encouraging results in phase II clinical studies for inflammatory bowel disease. Nevertheless, the connection between IL-6 and VT remains undiscovered. The long-term goal is to help inform the development of therapeutically novel anti-cytokine drugs for the clinical treatment of life-threatening malignant VT. The overall objectives in this application are to (i) elucidate the molecular mechanism(s) by which IL-6 signaling triggers dramatic and arrhythmogenic electrical changes in vitro and (ii) determine in vivo anti-IL-6 signaling anti-arrhythmic efficacy using a guinea pig high-fat diet-induced inflammation model. Our central hypothesis is that over-activation of IL-6 trans-signaling triggers proarrhythmogenic changes in the rapidly activating delayed rectifier K channel (IKr) and calcium (Ca) handling in vitro and promotes lethal VT in vivo by promoting electrical disturbances in the ventricular myocardium. The rationale for this project is that a determination of the therapeutic potential of IL-6 signaling inhibition and associated cellular mechanisms is likely to reveal a strong mechanistic basis whereby new strategies to treat lethal ventricular arrhythmias in patients can be developed. The central hypothesis will be tested by pursuing two specific aims: 1) determine anti-arrhythmic effects of IL-6 signaling inhibition; and 2) identify the mechanism(s) of arrhythmogenesis by over-stimulation of IL-6 trans-signaling. Under the first aim, Langendorff perfused guinea pig hearts, and telemetered guinea pigs will be used to evaluate IL-6 trans-signaling-mediated electrical remodeling and inducibility of ventricular tachyarrhythmias and sudden cardiac death. For the second aim, guinea pig and obese/heart failure human epicardial adipose- tissue derived secretome, and guinea pig ventricular myocytes will be used to evaluate the effects IL-6 trans- signaling have on IKr biophysics and Ca handling, and the underlying mechanisms. Additionally, proven hyper- IL-6 and olamkicept methodologies and assays to evaluate the effects that loss-of-function phenotypes (anti- arrhythmic potential) have on obesity- and IL-6 trans-signaling-induced VT will be employed. The research proposed in this application is innovative, in the applicant’s opinion, because it focuses on pathological IL-6 trans-signaling and the potential of anti-IL-6 as an anti-arrhythmic in future anti-cytokine clinical trials. The proposed research is significant because it is expected to provide strong scientific justification for the continued development and future clinical trials of anti-cytokine drugs. Ultimately, such knowledge has the potential of offering opportunities of innovative therapies to treat VT.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Arrhythmogenic cardiomyopathy (ACM) is a devastating inherited disease that causes sudden cardiac death in young people, accounting for up to 22% of sudden cardiac deaths in adults under 35. Despite the identification of causative mutations, the mechanisms triggering ACM remain elusive, and there are no preventative therapies for individuals carrying pathogenic allele variants. This project aims to elucidate the role of early immune cell infiltration in the development of ACM using a mouse model with a mutation in the desmosomal protein desmoglein-2 (DSG2). The central hypothesis is that early myocardial immune cell populations and inflammation determine ACM phenotype severity. Aim 1 will test whether increased neonatal immune cell recruitment accelerates arrhythmias, scar formation, and death in DSG2 mice using an adeno-associated viral vector expressing a modified COVID-19 spike protein. Aim 2 will investigate if neonatal treatment with gene therapy expressing the connexin-43 isoform GJA1-20k reduces immune cell burden, inflammation, arrhythmias, and death. Aim 3 will examine whether neonatal inhibition of NFκB signaling using AAV9-A20 can prevent immune cell recruitment, inflammation, arrhythmias, and scarring. This research is significant because it explores a novel preventative treatment strategy for ACM, focusing on early immune-mediated events that precede overt cardiac dysfunction. The approach is innovative in its examination of the early stages of ACM pathophysiology and the use of gene therapies targeting different pathways involved in disease development. The expected outcomes include identifying the role of immune cell infiltration in ACM, demonstrating the efficacy of two gene therapies, and offering a new treatment paradigm focusing on early intervention to prevent disease onset in genetically susceptible individuals. If successful, this work could transform the clinical management of ACM and potentially other genetic cardiomyopathies.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract Biocatalytic reactions are critical to the production and discovery of modern pharmaceuticals. Directed evolution (DE) of enzymes enables the tuning of enzymatic selectivity to address the growing demand for complex natural product-derived therapeutics. These DE campaigns suffer from an enormous search space of possible mutations and slow initial optimization with unnatural substrates, which hinders the development of new biocatalytic pathways. Despite the importance of robust biocatalytic platforms, generalizable methods for predicting optimal mutations that enhance selectivity of an unnatural substrate remain elusive. To address these issues, this proposal applies data-driven reaction optimization methodology to the DE of aminotransferase ARO8. Recently, our collaborators at the Narayan group have discovered a novel C–C bond forming reaction of the PLP- dependent enzyme ARO8. Given the industrial importance of aminotransferases, a mechanistic understanding of this novel reactivity is critical for leveraging aminotransferases as flexible biocatalysts. The proposed data- driven workflow will reveal the subtle non-covalent interactions that govern this reactivity by computationally modeling multiple mutations in silico to predict mutations to maximize C–C bond formation. Furthermore, a multiple linear regression model will be developed to probe the fundamental residue-substrate interactions that promote C–C bond formation and further our understanding of aminotransferases. The studies in this proposal focus on ARO8. However, we anticipate that the proposed computational workflow and prediction methodology is transferable to other enzymes and substrates.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT Non-melanoma keratinocyte carcinomas, namely basal cell (BCC) and squamous cell (SCC) carcinomas, represent the most common form of cancer and their incidence is increasing. When diagnosed at the earliest stage, such as superficial forms of BCC or SCC-in-situ confined to the epidermis, they are usually treatable by non-surgical means. Curative therapy for more advanced tumors, such as micronodular or infiltrative BCC subtypes or invasive SCC with extensive dermal involvement, requires surgery that can be disfiguring and costly. Some SCC can resemble actinic keratosis (AK, precancer) or inflamed seborrheic keratosis (SK). Visual detection of these skin cancers and benign keratoses can be facilitated with the aid of dermoscopy, but determining whether a lesion is more deeply invasive or distinguishing between SCC-in-situ, AK and inflamed SK is not always clinically apparent. There is no currently available low cost, non-invasive technique to overcome these diagnostic hurdles to inform whether to biopsy or which biopsy technique (shave for superficial lesions vs. punch for invasive lesions) is most appropriate. Electrical impedance dermography (EID) can measure electrical properties of the skin that are altered in skin cancers, however, whether EID technology can distinguish superficial from invasive subtypes, or SCC-in-situ from actinic and inflamed keratoses, is unknown. We have built and tested a novel machine-learning (ML) augmented EID device, which can quickly perform non-invasive measurements on the skin and requires minimal training for use. We have published studies on cohorts of 17 and 35 subjects with BCC and SCC, respectively, and demonstrated high reproducibility. We have also recently completed a pilot blinded study on cohorts of 35 subjects with BCC, invasive SCC, SCC-in-situ, and SK, and demonstrated superior diagnostic accuracy in distinguishing SCC subtypes from inflamed SK than commercially available devices (Nevisense). Our overarching hypothesis is that EID can distinguish BCC subtypes and between SCC-in-situ, invasive SCC, and benign keratoses. In Aim 1, we will collect EID data in 80 subjects with lesions clinically suspicious for BCC. Then, we will use the EID data to train our pilot ML algorithm, including morphologic and histologic characteristics, to distinguish BCC subtypes. Finally, we will test its performance in a blinded study with a separate test cohort in 40 subjects. In Aim 2, we will expand our SCC/SK cohort to further improve the diagnostic performance of our pilot ML algorithm at distinguishing SCC-in- situ, invasive SCC, AK, and inflamed SK in 80 subjects with lesions clinically suspicious for SCC. Analyses will include standard reproducibility metrics (first vs. second measurement), two-group comparisons, and correlations to histology. Successful application of this EID technology will contribute to overall clinical assessment by increasing diagnostic confidence and guiding decisions to biopsy (and biopsy technique). The data collected will set the stage for validating our findings in a multicenter cohort to evaluate the utility of this approach for non-invasive diagnosis and management of suspicious skin lesions.

NIH Research Projects · FY 2026 · 2025-01

This K23 award is for Dr. Michael Incze, a general internist, addiction medicine physician, and emerging clinician-investigator with expertise in leading interdisciplinary programs to improve the integration of substance use disorder (SUD) treatment into primary care settings. To study the implementation of novel models to support transitions to longitudinal SUD and primary care after a medical hospitalization, this K23 will allow Dr. Incze to acquire key skills in four career development areas: 1) implementation science methods for designing and evaluating SUD care interventions across care settings, 2) designing and conducting clinical trials with vulnerable groups, 3) qualitative evaluation of intervention implementation, and 4) leading an interdisciplinary research team. Dr. Incze has assembled a team of mentors and advisors with expertise in implementation science, clinical trial design, and research with vulnerable populations to guide his training and research program. His Department is fully committed to his success and growth as an early-stage clinician investigator. The overdose public health crisis continues to account for tens of thousands of preventable deaths each year. Despite the urgency of this crisis, less than half of people with SUD receive any treatment. Medical hospitalizations are common among people with SUD and represent crucial opportunities to engage them in SUD treatment. Ensuring seamless linkage to longitudinal SUD and primary care after hospital discharge is a fundamental aspect of hospital-based SUD treatment; however, multiple barriers may interrupt these transitions of care, and there are no rigorously studied models to support patients with SUD during these high- risk events. Primary care may play a central role in addressing this care gap, given its geographic reach, team- based care models, expertise in care coordination, and focus on chronic disease management. However, primary care clinicians need mentorship and support to adopt SUD treatment into practice. Dr. Incze’s objective is to use implementation science methods to design, refine, and conduct a pilot clinical trial of a primary care-based Interdisciplinary Addiction Care Transition (IntACT) team to support care transitions between hospital and primary care settings for patients with SUD. His proposed Specific Aims (SA) are: SA1) Identify key stakeholder perspectives on the optimal role, activities, and implementation of the IntACT intervention; SA2) Design and refine a protocol for the implementation of the IntACT Intervention using the PRISM and RE-AIM frameworks; and SA3) Test the feasibility, acceptability, and preliminary effectiveness of the IntACT intervention through a pilot feasibility clinical trial. The proposed research is significant because it aims to increase linkage to longitudinal primary care and SUD treatment during the high-risk period following medical hospitalization. It is innovative because it leverages stakeholder engagement and implementation science frameworks to develop and evaluate a novel, potentially scalable, primary care-based intervention to support post-hospitalization care transitions and primary care/SUD treatment access for individuals with SUD. This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction.

NIH Research Projects · FY 2026 · 2025-01

SUMMARY Heart failure (HF) is a leading cause of morbidity and mortality affecting nearly 2% of the US population1,2. It has been long appreciated that fuel choice and metabolism of cardiomyocytes is altered in HF, impairing the core function of the organ and contributing to disease progression, but there are no approved therapies to refuel the failing heart. Carbohydrates are known to play an enhanced role in supporting cardiac ATP production in failing hearts, but more recent studies have identified lactate and not glucose as the direct substrate for cardiac metabolism in HF. We discovered using in vivo and in vitro 13C stable isotope tracing approaches that lactate is directly imported into healthy cardiac mitochondria via the monocarboxylate transporter 1 (MCT1/ Slc16a1). Direct mitochondrial import of lactate enables its efficient utilization as an energy substrate without conversion to cytoplasmic pyruvate and transport into mitochondria via the mitochondrial pyruvate carrier. Our preliminary data demonstrates that MCT1iCKO animals undergo hypertrophy in response to trans-aortic constriction (TAC) and rapidly decompensate and suffer heart failure with reduced ejection fraction. 13C tracing suggests these hearts cannot increase the contribution of glucose carbon to total ATP synthesis. In human HF patients, we observed an increase in MCT1 in the mitochondria of their hearts compared to normal donors. Our data suggest a profound paradigm shift in how lactate oxidation occurs in the heart, and reveals a substantial gap in knowledge about the biochemical mechanisms of carbohydrate oxidation in both the healthy and failing heart. Thus, there is a critical need to understand how lactate is metabolized in the mitochondria of failing hearts to guide the design of future therapies to improve cardiac bioenergetics and restore organ function. We hypothesize that direct lactate uptake and oxidation within the mitochondria of cardiomyocytes is a previously unknown protective adaptation for cardiac function. We will test this with the following aims: Aim 1: Quantify direct vs indirect mitochondrial lactate oxidation in health and in models of cardiac hypertrophy and failure; Aim 2: Determine whether mitochondrial localized MCT1 is necessary and sufficient for enhanced lactate metabolism in cardiac injury; Aim 3: Identify the lactate dehydrogenase (LDH) isoform responsible for mitochondrial LDH activity. Completion of the research in this proposal will lead to new knowledge about how cardiomyocyte mitochondria are fueled, the mechanisms by which carbohydrates (lactate) support bioenergetics in HF and provide testable therapeutic approaches for restoring cardiac metabolism in HF.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY This advanced-level short course will provide intensive training in innovative approaches for designing and conducting randomized clinical trials (RCTs) of behavioral interventions. Currently there is insufficient evidence from behavioral RCTs to inform public health campaigns, clinical guidelines, and insurance coverage for behavioral interventions. A stronger evidence base will emerge from more rigorous and definitive efficacy and effectiveness trials. In the field of behavioral medicine, the intervention development process is not standardized or accepted as it is for pharmacotherapy and devices. Investigators require didactic training not often included in medical and graduate programs, as well as mentorship, to implement best practices for RCT design and conduct. Greater reliance on interdisciplinary team science and translational research models, and wider adoption of advanced methodologies, will increase the impact of behavioral intervention research. This course is designed for early- to mid-career scientists who are already planning or conducting a behavioral RCT or who are conducting early-stage intervention development research that is expected to lead to an RCT. It is designed to provide a longitudinal learning experience during which learners (hereafter “fellows”) acquire foundational knowledge and apply it to a planned RCT. This hybrid course includes a four-day, in-person meeting at which foundational concepts will be discussed, and five learning communities comprising two faculty members and six fellows will be formed. Each learning community will engage in nine monthly, two-hour video conference calls. Prior to each call, fellows will watch videos or listen to podcasts about selected RCT topics. The program will employ a facilitated peer mentoring model in which two experienced faculty members will work with six fellows, who in turn serve as peer mentors. During the virtual meetings, they will discuss how to apply the didactic content to their planned RCTs. The core faculty members are leading experts in various behavioral intervention research methodologies and have real-world experience conducting behavioral RCTs. Adjunct faculty members and guest speakers will include rising stars who are developing cutting-edge RCT methodologies and staff from funding agencies and payers. Course content will be organized by the NIH Stage Model for Behavioral Interventions and focus on Stages II (efficacy) through V (dissemination and implementation) to complement existing R25 offerings. In short, this course will train the next generation of scientists to design and conduct programmatic, strategically-focused, interdisciplinary behavioral RCTs. In so doing, we will contribute the rigorous evidence needed to change clinical guidelines, practices, and policies.

NIH Research Projects · FY 2026 · 2024-12

Project Summary Although effective therapies exist in many cancers, an initial response to therapy is often followed by relapse. An extreme example is multiple myeloma, a plasma cell malignancy in the bone marrow, which responds to treatment in almost all patients, but which cannot be cured. Myeloma patients therefore receive many different lines of therapy during the course of their disease. Repeated bone marrow biopsies are crucial for monitoring of treatment response and for informing the optimal choice of treatment and are therefore currently recommended with any change in treatment. However, the excessive number of biopsies over time creates an enormous burden for patients, and these tissue biopsies are often not performed beyond initial diagnosis. In addition, bone marrow biopsies only capture myeloma cells from a single site, and therefore do not provide a complete representation of the heterogeneity and ongoing evolution of this multifocal disease that is characterized by patchy bone marrow involvement. It is therefore imperative to develop novel approaches that allow to frequently assess myeloma evolution during therapy and choose those treatments that are most efficacious. We are proposing to use novel “liquid biopsy” approaches to replace bone marrow biopsy by interrogating circulating myeloma cells and cell-free DNA in myeloma patients, obtained from a simple blood draw. We hypothesize that liquid biopsy provides more comprehensive and clinically relevant insights into the molecular dynamics and genomic evolution of myeloma than can be obtained through single-site bone marrow biopsies. To accomplish this task, we have pioneered technologies for highly sensitive isolation and deep molecular and genomic characterization of circulating multiple myeloma cells (CMMCs) with single cell resolution, as well as whole genome and targeted sequencing of cell-free DNA (cfDNA). We will leverage these technologies to inform clinical decision-making in a way that is impossible with the current practice of using bone marrow biopsies as standard-of-care. Specifically, we will demonstrate that: 1) Liquid biopsy is a better predictor of survival than parameters currently used in clinical routine, 2) Liquid biopsy has greater sensitivity and specificity to detect established prognostic and predictive genetic disease variants than bone marrow biopsy, the current gold-standard, 3) Liquid biopsy provides a therapeutically more relevant representation of the clonal composition and actionable treatment targets of myeloma than bone marrow biopsy, 4) Liquid biopsy outperforms bone marrow biopsy in determining minimal residual disease (MRD) status. Importantly, replacing repeated invasive biopsies with liquid biopsy from a simple blood draw will dramatically reduce risk and discomfort for patients. We expect that the concepts we are investigating will be practice-changing for the care of myeloma patients and will be broadly relevant across many different cancers and produce important new opportunities for therapies.

NIH Research Projects · FY 2026 · 2024-12

Project Summary Acute ischemic stroke (AIS) is a leading cause of death worldwide, and survivors experience neurological and motor deficits that impair their quality of life. Here we leverage innovative murine models and novel ceramide biosynthesis inhibitors to (i) determine whether interventions that target cerebral endothelial cells might improve stroke outcomes (Aim 1) and (ii) test a novel therapeutic strategy for lowering ceramides to mitigate the tissue injury, neurological impairments, motor deficits that accompany AIS (Aim 2). AIS increases plasma ceramides that correlate with the prevalence and severity of neural damage and motor deficits in patients. Mice undergoing AIS display heightened ceramides in plasma and ipsilesional (ischemic) hemispheres, as well as neurological and motor deficits, relative to sham-operated controls. To assess the contribution from cerebral ECs to AIS-induced ceramide generation, we obtained EC- and non-EC- enriched fractions from ipsilesional hemispheres. Compared to sham-operated mice, AIS elevates ceramide generation selectively in the EC-enriched fraction. Based on rationale provided by our published and preliminary data, together with findings from others, we hypothesize that AIS-induced, EC-derived ceramides induce arteriolar and mitochondrial dysfunction, ultimately leading to tissue injury, neurological deficits, and motor defects. Aim 1 will discern whether AIS-induced cerebral EC ceramide generation drives pathology by dysregulating arteriolar and mitochondrial function in lean and obese mice. To accomplish this, we generated mice allowing for inducible, brain-selective, EC-specific gain or loss of ceramides. The brief time-window during which approved treatments for AIS must be initiated limits their implementation. New intervention strategies are needed. The enzyme dihydroceramide desaturase 1 (DES1) catalyzes the insertion of a double-bond into inert dihydroceramides to produce toxic ceramides. Centaurus Therapeutics developed small molecule inhibitors of DES1 that are nearing phase 1A human trials. Centaurus completed in vitro absorption, distribution, metabolism, and excretion studies, with several compounds exhibiting good solubility, permeability, and metabolic stability in vitro and outstanding pharmacokinetics in vivo. In Aim 2 we will test the hypotheses that DES1 inhibition, which protects against ischemic damage in other disease contexts, can effectively attenuate AIS-induced infarct volume and neurological and motor deficits. Results from Aims 1 and 2 could uncover new sites of intervention (i.e., ECs) and provide pre-clinical validation of a novel therapeutic strategy (i.e., DES1 inhibition) for combating the debilitating complications of AIS.