Duke University

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT: Spatial transcriptomics technologies are revolutionizing our understanding of how cells are organized, communicate, synergize to function, and drive tissue phenotypes. Although previously limited by resolution-gene coverage tradeoffs, emerging spatial technologies are enabling genome-wide expression profiling at sub-cellular resolution. With technical platform limitations resolving, new computational methods are urgently needed to realize the full potential provided by high resolution and molecular breadth. Although specialized computational approaches have been developed for previous spatial technologies, the high- dimensionality and sparsity of new types of spatial data introduces significant obstacles to modeling and interpretation. Thus, we here propose to develop advanced machine learning methods and bioinformatics software to discern cell types, discover cell states, and deduce cell-cell interactions from high-resolution, high- dimension spatial transcriptomics data. First, we will develop a series of machine learning methods for supervised cell type mapping by integrating reference single-cell transcriptomics. We will comprehensively evaluate the performance of methods using single-cell RNA-based simulations and validate annotations from experts in tissue histology. Second, we will develop machine learning methods for unsupervised cell state discovery to delineate the spatial organization and potential regulators of cell states beyond cell types. We will benchmark performance and efficiency against other clustering-based tools for spatial transcriptomics data. Finally, we will develop analytical approaches that correct diffusion noise to identify direct cell-cell interactions in high resolution and interaction-associated genes. By developing and implementing these approaches in diverse tissue contexts, such as tumor microenvironments and inflammation, we will provide a robust and generalizable framework for understanding cellular organization, genomic function, and intercellular communications in tissues. 1

NIH Research Projects · FY 2026 · 2026-05

Inflammatory diseases are currently treated using biologics that block single inflammatory mediators such as specific cytokines, and while these therapies have significantly advanced the treatment of many diseases including inflammatory bowel disease, rheumatoid arthritis, psoriasis, and others, they still possess numerous serious shortcomings. Cytokine-blocking biologics only neutralize one target in a complex network of signalling molecules, so they suffer from highly variable efficacy, and they cease working for large percentages of patients. They also must be dosed repeatedly, which can induce the development of anti-drug antibodies that result in treatment failure. These shortcomings of current treatments mean that patients experience significant unpredictability in the management of their disease, frequent treatment changes, extensive monitoring, and a high volume of provider visits as treatments are continuously assessed and updated, leading not only to significant morbidity but considerable burden on the US healthcare system. For these reasons, there is a critical unmet need for entirely new treatment approaches that can safely and stably provide long-lasting immunomodulation for the treatment of chronic inflammatory conditions. This project focuses on designing a new broadly applicable therapeutic approach to treat chronic inflammatory diseases using supramolecular (self-assembling) biomaterials to engage multifactorial repair pathways central to chronic and acute inflammation. The technology, termed Immunomodulatory Self-Assembled Peptides (ISAP) engages a critical aspect of the immune system known as natural autoantibodies (NAAbs), which have been identified as protective factors for multiple chronic inflammatory diseases including inflammatory bowel disease, inflammatory lung disease, atherosclerosis, lupus, chronic kidney disease, and others. The central objectives of the proposed research are to optimize ISAP to treat inflammation of the colon and lung and to develop design rules for maximizing its therapeutic efficacy. The work will be conducted by a collaborative team of engineers and physicians with expertise in biomaterials, colitis, and inflammatory lung diseases. The outcomes of this project are expected to be a demonstration that durable NAAb-engaging responses can be generated using ISAP, and that these responses have therapeutic efficacy in mouse models of colitis and inflammatory lung disease. The project will also lay the groundwork for the future exploration of biomaterials, and molecular assemblies in particular, as broadly applicable immunomodulatory platforms for treating a wide range of inflammatory diseases and conditions.

NIH Research Projects · FY 2026 · 2026-05

PROJECT ABSTRACT Cataracts and glaucoma are the two leading causes of blindness worldwide. Crucial ophthalmic procedures to treat cataract, glaucoma, and other vision conditions require precise visualization of anatomy and microsurgical instruments. Visualization in such surgeries has been limited to stereo optical microscopes since the early 20th century. With advancements in optical coherence tomography (OCT), we can now obtain real-time 3D visualization within the eye. Over the past decade, intraoperative OCT (iOCT) systems have become widely researched and integrated into the latest ophthalmic microscopes built by companies such as Zeiss and Leica. These iOCT systems come with the potential to revolutionize ophthalmic surgery, with an unparalleled ability to resolve key anatomic features at micron-level precision. However, there is a crucial challenge that hampers the clinical utility of iOCT. This challenge stems from the fundamental tradeoff between OCT field-of-view and imaging speed. This tradeoff constrains state-of-the-art systems to operate with a relatively small (e.g. 5x5 mm) field of view to achieve the volume update speeds (~10-15 Hz) required for surgical visualization. Consequently, a trained operator on the surgical team must manually reposition the OCT scan throughout the surgery. The current implementation of iOCT results in a “point-and-shoot” approach to imaging, i.e. using OCT as an intermittent snapshot tool, rather than as a continuous surgical visualization technology. With even small movements of the surgical instruments, the OCT image can quickly lose sight of the surgical region of interest (ROI). Manual tracking of iOCT discards a key advantage of OCT, which is real-time 3D data collection. With advances in deep learning methods for image processing and object recognition, there are new opportunities to tackle this problem. The goal of this project is to engineer a novel computational system for automatic, real- time tracking of the surgical ROI in a clinical iOCT system. Our vision is to develop a system that can be readily applied to existing clinical microscopes, and adaptable to future robotic surgical systems. As part of our preliminary work, we have created a lateral tool tracking OCT system using deep learning models applied to the microscope feed. Our current system utilizes a novel synthetic data approach, making use of 3D-rendered models of eyes and tools to accelerate deep learning model development. In the proposed project, we expand on this preliminary work by developing a system for 3D multimodal surgical ROI tracking of iOCT that can be applied to many different types of ophthalmic surgeries. We will then evaluate our platform via ex-vivo porcine and human cadaver eye studies with wet-lab benchmarking and simulated surgeries with our clinical collaborators. Our immediate application is ophthalmic surgery, but the methodology has relevance to a wide range of 3D imaging systems for microsurgical procedures. By developing this system for dynamic OCT surgical tracking, we hope to improve ophthalmic visualization in both training and surgical practice.

NIH Research Projects · FY 2026 · 2026-05

Project Abstract Olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma, is a rare and life-threatening tumor with limited treatment options. A lack of model systems and limited access to human tissue has hindered progress in understanding the genes, pathways, and mechanisms driving ONB. This project aims to address this critical need by using new genetically-engineered mouse (GEM) and organoid models of ONB to uncover key drivers and mechanisms of cell fate plasticity. We recently created the first GEM model of ONB (Finlay et al, Cancer Cell, 2024) through the loss of tumor suppressors Rb1 and Trp53 and gain of the Myc oncogene in the olfactory epithelium. We have also developed multiple organoid models derived from mouse and human tissue. These models express the neuronal lineage driver NEUROD1, a defining feature of human ONB, along with evidence of intratumoral cell fate heterogeneity. Interestingly, ONB shares molecular states found in small cell lung cancer (SCLC) and prostate neuroendocrine cancer, with remarkable similarity to the ASCL1, NEUROD1, and POU2F3+ states of human SCLC. In this project, we hypothesize that NEUROD1 serves as a master regulator and dependency in ONB, and that its loss will impede tumor growth. However, we anticipate that tumors will evade NEUROD1 loss by adopting non-neuronal fates through the influence of RUNX1 and other transcription factors. Our long-term goal is to identify key genes and pathways driving ONB and to understand the mechanisms underlying cell fate plasticity to ultimately constrain this process. To achieve this, we will pursue two specific aims. First, we will determine the function of NEUROD1 in ONB initiation and progression using in vivo models and organoid transplant models, assessing the impact of NEUROD1 loss on tumor latency, development, and cell fate. Additionally, we will identify NEUROD1 target genes through ChIP-seq analysis and compare them to SCLC, shedding light on similarities and differences between these tissues. Innovative single-cell-based lineage tracing will enable us to investigate the lineage trajectory of tumors escaping NEUROD1 loss. Second, we will determine mechanisms of ONB cell fate plasticity, with a focus on RUNX1. Preliminary data suggest that RUNX1 acts as a master regulator of non-neuronal fates in ONB and normal olfactory neurogenesis. By employing ChIP- seq, genetic knockout and overexpression studies, and single-cell-based lineage tracing, we will identify RUNX1 targets and investigate its impact on ONB growth, progression, and cell fate. This aim will uncover additional predicted regulators of cell fate plasticity. This project's impact lies in the development of innovative new GEM and organoid models that identify NEUROD1 and RUNX1 as master regulators of ONB fate. Furthermore, the mechanisms of ONB cell fate plasticity unraveled here are expected to have relevance for other neuroendocrine cancers including SCLC and prostate neuroendocrine tumors. Ultimately, this knowledge will contribute to improved diagnosis and treatment strategies for both ONB and normal olfaction.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT/PROJECT SUMMARY Transcription factor A mitochondrial (TFAM) has canonical roles in transcription and replication of mitochondrial DNA (mtDNA). Our laboratory has compelling preliminary data that TFAM also has a role in sensing mtDNA lesions caused by UV radiation, resulting in compaction of the mtDNA molecule and its associated proteins, or nucleoid. Because translesion synthesis of replicative machinery past DNA lesions has the capacity to fix them into mutations, a compact nucleoid shape may have the beneficial function of excluding replication machinery and repressing replication. In Aim 1, I will use stimulated emission depletion (STED) microscopy to quantify nucleoid size and colocalization with markers of mtDNA replication and UV damage. This will allow me to test if nucleoids with more damage are more compact in vivo and if they are excluded from replication. Additionally, the compact shape or altered TFAM binding could recruit other proteins to trigger a hitherto unknown process of selective removal from mitochondria. The protein ATAD3A is of particular interest because it binds to both mtDNA and to TFAM and it spans both the outer and inner mitochondrial membranes. To address the hypothesis of selective removal, Aim 2 will test whether knockdown of ATAD3A impairs mtDNA damage removal, and using immunofluorescence, determine the role of ATAD3A in selective localization of damaged nucleoids with lysosomes. To uncover other, unknown protein interactors, Aim 3 will use proximity biotinylation to comprehensively characterize damage-induced changes to the nucleoid proteome. This will be the first description of how nucleoid composition changes after UV and the most temporally-resolved description of changes after environmentally-induced mtDNA damage. Thus, this will be a novel and important contribution to our fundamental understanding of mitochondrial biology. In addition, by identifying proteins that increase in frequency surrounding TFAM after exposure to UV, this technique may identify novel candidates that can be tested for roles in nucleoid compaction and removal. Overall, elucidation of this novel mechanism of mtDNA damage removal will enable future research to identify individuals deficient in this process who may be more susceptible to the harmful effects of exogenous mtDNA damage, with potential benefits in the areas of neurodegeneration. It may also permit development of protective or therapeutic strategies.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT Diffuse gliomas are the most common primary brain cancer in adults, with the most aggressive and common form glioblastoma (GBM) having a median survival of only 15 months. Despite advances, current clinical imaging protocols lack the precision to track microscopic tumor infiltration that later becomes recurrence. This can result in poorly defined treatment margins that do not address the full extent of the tumor and can compromise patient safety. Determining the precise site of future recurrence on preoperative imaging could allow improved treatments such as boosted radiation dose to regions at risk for recurrence. Deformable image registration (DIR) enables the alignment of longitudinal MRI scans to achieve this task, but existing DIR approaches suffer from limited accuracy and unreliable verification, hindering clinical adoption. This project aims to develop a verifiable and accurate DIR method for diffuse gliomas by incorporating AI-based blood vessel segmentation and bifurcation matching into a new high-precision DIR approach. I hypothesize that incorporating blood vessel bifurcations as stable anatomical markers into the registration process will permit sub-millimeter accuracy in non-linear image registration. This level of accuracy will permit refined and precise treatment margins and support advanced imaging methods to accurately track tumor growth over time. Using the hierarchical nature of blood vessel trees, I will establish correspondence between blood vessels segmented from pre-operative and post-recurrence MRI scans of the same GBM patient. The DIR method will synthesize these matching vessel points with image features extracted from multi-sequence MRI data to precisely describe the anatomical transformation that occurred between the scans. This can then be used to pinpoint the recurrence origin on the pre-operative time point, allowing for future treatments targeting this site. In addition to GBM, I will adapt and optimize the developed method for slower-growing, low-grade diffuse glioma cases. By quantifying the deformation between low-grade scans with accurate DIR, I can detect small changes in tumor size and shape that can indicate disease progression. I will compare this approach to visual observation to demonstrate its clinical utility. Finally, I will utilize the developed vessel-matching tools to establish the most comprehensive DIR accuracy baseline across diffuse glioma grades to date, supporting further algorithm development and clinical implementation. This research will provide robust, verifiable DIR methods tailored for GBM and low-grade diffuse gliomas, addressing a critical gap in neuro-oncology imaging. By improving registration accuracy, this project can improve the precision of GBM treatment planning, enhance recurrence detection, detect tumor progression, and ultimately improve patient outcomes.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Understanding how proteins interact within the cell to perform specific functions is a central goal of modern biology and crucial for understanding the diverse roles these molecules play in biomedicine. Single-particle cryo-electron tomography (SP-cryo-ET) is currently the only technology capable of visualizing macromolecules in their native environment at high resolution. Despite recent advances in sample preparation, data acquisition, and image processing, structural analysis by SP-cryo-ET is still largely confined to naturally abundant targets—such as ribosomes or ordered supramolecular assemblies—or to resolutions that are insufficient to reveal molecular-level interactions. Furthermore, the complexity and high computational demands of SP-cryo-ET workflows for data processing have restricted access to the technology for structural biologists. These challenges present a significant barrier to fully unlocking the potential of SP-cryo-ET in advancing our understanding of how proteins interact within cells to carry out specific functions and the essential roles they play in biology and disease. Building on recent progress made by our group, the goal of this project is to develop methods to address remaining bottlenecks in the SP-cryo-ET workflow that will result in broader applicability and improved access. Our long-term goal is to enable the routine visualization of a wide range of biomedically important targets in the cellular context at near-atomic resolution. By working closely with a network of experimental collaborators, we will ensure that our method development efforts are driven by diverse and impactful biological projects. Ultimately, our tools will help expand the applicability of SP-cryo-ET and accelerate its adoption, empowering structural biologists to tackle new questions regarding molecular interactions and cellular mechanisms.

NIH Research Projects · FY 2026 · 2026-05

Abstract Salmonella enterica is an intracellular bacterial pathogen that causes millions of cases of gastroenteritis and typhoid fever each year. Over 1,500 S. enterica serovars have been found to infect humans, and these serovars vary widely in genomic content, pathogenesis, and virulence. By leveraging the natural diversity that exists among these serovars, we can uncover novel aspects of the host-pathogen interactions that take place during infection and better define how mechanisms of pathogenesis differ among serovars. Recently, my laboratory discovered a novel interaction between the human gene MCOLN2 and S. enterica. We have found that MCOLN2 (a divalent cation channel) restricts the intracellular growth of S. enterica by depriving it of Mg2+. Interestingly, while MCOLN2 is effective against certain serovars such as S. Typhi, other serovars such as S. Typhimurium are largely resistant to MCOLN2-mediated restriction. My preliminary data demonstrate that these differences in susceptibility to MCOLN2 are not due to variation in serovar requirements for environmental Mg2+, nor variation in ability to escape from the Salmonella-Containing Vacuole. Rather, some aspect of the host response must differ during infection with different serovars. I hypothesize that certain serovars are able to manipulate the host’s MCOLN2 response to generate a more permissive environment for growth. My preliminary data indicate that MCOLN2 expression is upregulated in specific immune cell types during infection with S. Typhi and is suppressed during infection with S. Typhimurium. I expect that this suppression protects S. Typhimurium from MCOLN2-mediated restriction. I will further define MCOLN2 expression during infection and will determine whether sustained overexpression can limit the growth of MCOLN2-resistant serovars. I will also directly measure the effect of MCOLN2 expression on serovar access to Mg2+ using inductively-coupled plasma mass spectrometry. My preliminary data also suggest that S. Typhimurium’s secreted effectors play a role in its resistance to MCOLN2. I hypothesize that MCOLN2-resistant serovars use secreted effectors to modify MCOLN2 expression, thereby protecting the serovar from restriction. I will identify the bacterial effectors that modulate MCOLN2 expression and will elucidate their mechanism of action with transcriptomics and immunoprecipitation-mass spectrometry. This proposal will enhance our understanding of S. enterica pathogenesis and how it varies among serovars, define how human immune cells utilize MCOLN2 during infection, and uncover novel functions of bacterial effectors.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT Neuroendocrine prostate cancer (NEPC) is an aggressive and lethal subtype of prostate cancer (PC). While NEPC can develop as de novo disease, more commonly it develops as a resistance mechanism to Androgen Receptor (AR) targeted therapies in castrate resistance prostate cancer (CRPC) patients. NEPC patients often present with high metastatic burden. The prognosis of NEPC is poor with a 5-year survival rate of less than 20% with limited treatment options. Thus, new tractable molecular targets to combat NEPC are urgently needed. In our preliminary studies we have identified Tyrosine Threonine Kinase (TTK) as a new high value NEPC molecular target. TTK, also referred to as Monopolar Spindle 1 (Mps1), is a dual specificity protein kinase that plays a significant role in mitosis and the spindle assembly checkpoint (SAC). TTK expression is undetectable in normal cells and upregulated in transformed cells, making it an ideal therapeutic target. Moreover, TTK is a highly translational target, which as five small molecule inhibitors in clinical development. TTK expression progressively increases throughout PC disease progression and is highest in NEPC. The TTK expression trend holds in PC cell lines and patient-derived xenograft (PDX) models, wherein TTK expression is highest in cell lines and PDXs of NEPC origin. Genetically and pharmacologically targeting TTK slows NEPC cell growth in vitro and in vivo. These data support that TTK is an actionable target that may impede NEPC tumor growth. The objective of our proposal is to test the potential of TTK as a target for NEPC and define TTK mechanisms of action. For the latter, we conducted high resolution differential phospho-proteomic analysis in TTK targeted NEPC cells. We have prioritized Rab-Like Protein 6 (RABL6) as a candidate TTK NEPC phospho-target. In specific Aim 1, we will evaluate TTK phospho-target RABL6 and test the role of RABL6 in NEPC. In Aim 2, we will utilize a combination of NEPC cell line, patient derived xenografts and syngeneic NEPC models to rigorously test the effects of targeting TTK in vivo. Along with genetic approaches we will utilize clinical grade TTK inhibitors and preclinical TTK proteolysis targeting chimeras (PROTAC). In Aim 3 we will evaluate the therapeutic efficacy of combining leading TTK clinical inhibitor with first line NEPC chemotherapies. Transcriptomic analysis and immune cell profiling of tumors will be conducted to assess therapeutic response and identify biomarkers. Successful completion of these studies will confidently determine if TTK is a high value target which may ultimately help to lessen the morbidity of NEPC.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT Aspergillus fumigatus is the most common cause of invasive fungal infections worldwide, with cases continuing to rise due to a growing immunocompromised population. Antifungal therapeutics are currently limited to just 3 drug classes with limited efficacy, and the development of effective treatments is hindered by an incomplete understanding of the strategies this organism employs to resist drugs and persist in the host environment. Agricultural use of fungicides rapidly selects for cross-resistance to antifungal drugs used to treat infections in patients, and the mechanisms contributing to the emergence of antimicrobial resistance is a critical knowledge gap in the field that my dissertation project seeks to address. In order to better understand pathogenic adaptations, we can look to evolutionary mechanisms A. fumigatus may have developed to persist in its complex environmental niche. I discovered that exposure to FK506, a compound produced by soil-dwelling Streptomyces bacteria that has both antifungal and immunosuppressive activity, rapidly selects for unstable full-chromosome disomies in this normally haploid fungus. These disomies confer resistance to both FK506 and clinically-used azole antifungals. I used RNA sequencing to pinpoint upregulation of the neosartoricin biosynthetic gene cluster as one potential tolerance mechanism shared between Chr. 4 and Chr. 7 aneuploids and demonstrated that increasing expression of the transcriptional regulator of this cluster confers FK506 tolerance in a euploid background. Building on these recent discoveries, I hypothesize that full-chromosome disomy leads to transient antifungal resistance via dynamic transcriptional rewiring in A. fumigatus. This proposal will investigate unstable responses that facilitate antifungal resistance, uncovering novel genes and pathways implicated in these adaptive responses. In Aim 1, I will use biochemical and molecular genetic approaches to study target genes and processes conserved between Chr. 4 and Chr. 7 aneuploids in the response to FK506, revealing novel mechanisms of tolerance. Aim 2 will focus on unstable voriconazole resistance, employing different clinical and environmental isolates to identify distinct and conserved resistance mechanisms and investigating transcriptional changes in known and unknown azole resistance genes resulting from aneuploidy. These studies will shed light on a novel phenomenon that serves as a flexible, mutation-independent means to adapt to a range of stresses, ultimately informing our understanding of this organism’s ability to persist during human infections.

NIH Research Projects · FY 2026 · 2026-04

Abstract Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer deaths in the US. Patients with primary CRC will receive curative surgical resection, but up to 40% of patients will recur and develop metastatic disease after resection due to minimal residual disease. Minimal residual disease (MRD) results from cancer cells in the blood after resection. Unfortunately, MRD doesn't cause symptoms and isn't detectable by standard clinical tests such as CT scans. In our preliminary studies, we used a novel droplet-based microfluidics based technology to generate MicroOrganoSpheres (MOS) that can be used to grow cancer cells collected from portal venous blood during resection of the primary CRC. This has allowed us to isolate and characterize cancer cells representing MRD after resection of primary CRC. We now hypothesize that cancer cells that represent MRD that are resistant to standard of care therapy will lead to recurrence. In this grant, we propose to 1) Determine if cancer cells that are resistant to standard of care therapy are more likely to metastasize and lead to recurrence and 2) Perform high throughput drug screen on resistant clones to determine therapy that can prevent recurrence. The rationale for and impact of this study is that it will allow us identify and characterize cancer cells representing MRD after resection of a patient's primary CRC. The completion of this proposal will result in better understanding of tumor biology of MRD that determines recurrence and metastasis. This will lead to the development of clinical trials in the adjuvant setting to improve upon current adjuvant treatment after primary resection and ultimately, such findings will improve outcomes for patients with primary CRC by eradicating MRD leading to higher rates of cure after surgical resection

NIH Research Projects · FY 2026 · 2026-04

Cardiorespiratory conditions such as the acute respiratory distress syndrome (ARDS), congestive heart failure, COVID pneumonia, and sepsis are among the most common causes of mortality and morbidity. They are also notable for high rates of persistent psychological distress symptoms including depression, anxiety, and PTSD that worsen quality of life and outcomes of the underlying conditions. Yet there are few effective strategies able to overcome barriers of limited access to mental health care. To address this gap, we developed Lift, a completely automated and self-directed mindfulness training intervention, from the ground up with patient input. First, Lift reduced depression symptoms and improved quality of life compared to an education program control in a multicenter pilot RCT (R34 AT008819) among those recently hospitalized with serious cardiorespiratory conditions. Next, a 247-person multicenter 2x2x2 factorial optimization trial (U01 AT00974) compared 8 intervention versions differing by program introduction (app vs. therapist), dose (standard vs. high), and approach to in-the-moment symptom management (app vs. therapist). This trial demonstrated that while all versions had a strong effect on depression, anxiety, and PTSD symptoms, the high dose, app-only version was optimized for effect, adherence, and retention. Given these promising findings, a formal test of the optimized Lift mobile mindfulness intervention’s efficacy is needed. Therefore, we propose a 4-site multicenter RCT with 6-month follow up among 450 cardiorespiratory failure survivors with elevated post-discharge symptoms of psychological distress. Our specific aims will: (1) Test Lift vs. an education program control delivered by similar platforms on symptoms of depression, anxiety, PTSD, and quality of life; (2a) Determine patient-level characteristics associated with a greater treatment response among a priori-defined subgroups using a heterogeneity of treatment effects analysis; (2b) Explore novel adherence metrics and outcomes; and (3) Ensure off-the-shelf intervention readiness with an exploratory mixed-methods hybrid type 1 implementation framework analysis that integrates quantitative trial implementation data with semi-structured trial participant interviews. Innovative and unique elements include a fully automated mobile health delivery system that personalizes content in response to changes in symptom trajectories, a focus on enrolling a population representative of the US, and strong community engagement with formalized roles. This project addresses national research priorities and could advance the field with a personalizable yet population-scalable therapy that has the potential to broadly improve mental health access.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Invasive infections caused by resistant pathogens are a growing public health threat. Optimizing the use of anti- infective drugs is critical to reduce the morbidity and mortality associated with invasive infections. Anti-infective dose optimization studies depend on the characterization of pharmacokinetic/pharmacodynamic (PK/PD) relationships and drug safety. Yet these studies are challenging due to the limited number of investigators with expertise in clinical pharmacology and pharmacometrics. My K24 Midcareer Investigator Award proposal aims to address this gap by mentoring junior researchers in clinical pharmacology and pharmacometrics, equipping them with the skills needed to design and execute PK/PD studies, optimize anti-infective drug dosing, and tackle anti-infective drug resistance. I am uniquely positioned to mentor the next generation of researchers in this field due to my PharmD and PhD training, postdoctoral fellowship in clinical pharmacology, K23 Career Development Award training, my success in securing independent R01 grants, and leadership roles in federally funded T32 and K12 training programs. My research has helped to guide anti-infective drug dosing guidelines for pediatric populations, including premature infants and children with obesity. I have published 117 peer-reviewed articles, and 64 of these publications were published together with my mentees. As a mentor, I have successfully guided over 30 mentees, many of whom now hold faculty positions. By serving as the contact Principal Investigator for T32 and K12 grants, I have established a robust pipeline of trainees in clinical pharmacology and pharmacometrics. This K24 application will leverage my NIH-funded research programs, the infrastructure of the Duke Clinical Research Institute (DCRI), and partnerships with the Pediatric Trials Network (PTN) and the Antibacterial Resistance Leadership Group (ARLG). Mentees will receive access to rich clinical datasets, and structured mentorship in PK/PD study design, pharmacometrics methods, grant writing, and research dissemination. Mentees will be expected to complete graduate-level didactic coursework and hypothesis-driven research projects, culminating in peer-reviewed publications and preliminary data for independent grant applications. Through protected time and focused effort, I aim to foster a talented pool of mentees committed to addressing challenges in anti-infective dose optimization in vulnerable patient populations. This K24 award will enhance my capacity to mentor junior investigators while cultivating future leaders equipped to advance clinical pharmacology research across vulnerable patient populations and contribute to developing safe and effective anti-infective therapies with scalable mentoring approaches applicable to other therapeutic areas.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT The mission of the Duke Cancer Institute (DCI) is to “Discover, Develop, and Deliver the Future of Cancer Care Now”. A critical component of this mission is an institutional commitment to practice-changing clinical research. As such, Duke has prioritized and will continue to prioritize development of i.) institutional leadership and organizational capacity to support National Clinical Network (NCTN) efforts, ii.) scientific leadership for both trial development and on-going programmatic leadership within the NCTN and iii.) infrastructure to support a robust and growing accrual program for NCTN trials. To fully contribute the academic and infrastructural resources at the DCI and more broadly at Duke University toward realizing clinical advances in cancer care and the shared missions of the DCI and the NCTN, we are applying to continue our participation as Lead Academic Participating Site (LAPS). This award will further Duke's leadership and robust accrual to NCI-funded clinical trials, specifically multicenter clinical treatment and imaging trials across a broad range of cancers and therapeutic modalities as part of NCI’s overall clinical research program. An important focus will be an emphasis on trials in special populations, including patients with uncommon molecular alterations or rare tumors. To achieve these goals, we propose to provide senior-level clinical trial expertise, mentor future clinical trial leaders, and provide substantial institutional support. The current proposed leadership team are established investigators who provide complementary skills to build an environment which supports Duke investigator contributions to the NCTN. DCI will continue to provide robust complementary resources, investing in the success of this research. We further propose to continue scientific and organizational leadership for NCTN clinical trials and NCTN scientific activities. Duke investigators will continue to provide leadership across the 4 groups of the NCTN, and across all cancer types for trial design and conduct. A particular focus will be cross-NCTN and NCI initiatives. Finally, for this cycle we will seek to enhance accrual to NCTN trials through our 5-point Plan which includes further expanding NCTN trials into the rapidly growing DCI integral site network, to fully offer trial access in our region. At Duke, this grant will foster multidisciplinary collaborations and develop the next generation of clinical investigators dedicated to cancer research. The support provided to Duke as a LAPS will be complemented with further significant scientific and clinical resources of the DCI to provide robust participation in this nationally established cancer clinical trial program toward the goals of advancing cancer care and diminishing suffering from cancer.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Kinase signaling plays a pivotal role in regulating neuronal physiology, yet the mechanisms underlying kinase specificity, subcellular compartmentalization, and disease-associated dysfunction remain poorly understood. Dysregulated kinase activity is a key driver of neurodegenerative disorders, including Parkinson’s Disease (PD), where mutations such as LRRK2G2019S alter kinase function and neuronal survival. This project leverages innovative AI/ML algorithms, advanced CRISPR-based proteomics, and in vivo models to bridge existing gaps in our fragmentary knowledge of how kinases alter neuronal signaling and contribute to disease. By integrating a unique combination of predictive computational frameworks with experimental validation, we aim to uncover how kinases dynamically regulate proteomes in dopamine neurons and how disease-associated mutations alter allostery and rewire kinase-substrate interactions. These findings are expected to advance our understanding of kinase neurobiology, provide insights into neurological disease mechanisms, and pave the way for future therapeutic strategies targeting kinase signaling.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY. Introduction: HLA-E is a non-classical HLA class Ib molecule, which like classical HLA class Ia (HLA-A/B/C) presents intracellular virus-derived peptides. Unlike class Ia molecules, HLA-E is limited in polymorphisms and has an additional major role in presenting a conserved self peptide “VL9” that is derived from the leader sequence of other HLA molecules. HLA-E in complex with VL9 (HLA-E-VL9) binds the inhibitory receptor NKG2A on a subset of natural killer (NK) and CD8+ T cells, downmodulating their cytotoxicity. The Haynes Lab discovered HLA-E-VL9 binding B cells among the natural antibody pool of mice and humans and used these as substrates to develop the first HLA-E-VL9 high-affinity antibodies. I have demonstrated that high affinity HLA-E-VL9 specific antibodies can mediate checkpoint release of NK and CD8+ T cell killing of HLA-E-VL9 overexpressing targets and, as well, mediate NK antibody-dependent cellular cytotoxicity. Furthermore, I demonstrated for the first time that HLA-E-VL9 is expressed on the HIV-infected cell surface. I hypothesize that HLA-E-VL9 expression mediates HIV-1 evasion from NKG2A+ NK and T cells, and that this inhibition can be countered by anti-HLA-E- VL9 antibodies derived from the natural antibody repertoire. Research: In Aim 1, I will determine functional consequences of HLA-E-VL9 expression on HIV-infected CD4+ T cells on NK/T cell killing of HIV-infected target cells. In Aim 2 , I will evaluate the role of endogenous HLA-E- VL9/Mamu-E-VL9 binding antibodies in responding to retroviral infection. Training: I will continue my training with Dr. Haynes at Duke University to further my skillsets in assessing immune responses from human and non-human primate samples, and as well, fill gaps in my skillsets with regard to T cell functional assays and complex NK phenotyping. With co-mentor Dr. Azoitei at Duke University, I will develop new skillsets in structural antibody modelling and engineering. I will also pursue training in scientific writing, effective collaboration, and laboratory management, to further facilitate my success as an independent investigator. Environment: The Duke Human Vaccine Institute (DHVI) is a well-resourced, collaborative, and productive environment in which to train in translational immunology. Both the DHVI and Duke University are committed to the success of early stage investigators. I have assembled a mentoring team of advisors and collaborators who are leaders in the fields of probing immune function and regulation and HLA biology. Impact on Public Health. The results of this work will define strategies to safely harness HLA-E-VL9 mediated enhancement of NK and CD8+ T cell activity to inform the development of a new anti-viral or anti-cancer immunotherapy, and yield new insights into mechanisms of viral evasion and roles of the natural antibody pool.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract This R01 application for the NOSI: Somatic Cell Gene Editing Therapies to Improve Transplantation Outcomes details a novel method of AAV vector delivery during normothermic ex vivo lung perfusion (EVLP) to genetically modify donor lung grafts. While early post-operative outcomes have marginally improved, lung transplantation continues to be limited by the lowest rates of organ utilization, the highest rates of early allograft dysfunction, and the worst long-term recipient survival due to acute cellular rejection (ACR) and resultant chronic lung allograft dysfunction (CLAD).High-dose systemically-administered immunosuppression regimens intended to mitigate ACR further contributes to poor outcomes due to complications including infection and renal toxicity. There is a clear unmet need for novel therapeutic interventions to prevent alloimmune injury and resultant CLAD, and PD-L1 overexpression may be one method of preventing rejection allowing for lower immunosuppression, and thereby extending survival and minimizing complications of immunosuppression. The long-term goal of this work is to establish a new paradigm to genetically augment all solid organ grafts for clinical transplantation and this proposal serves the long-term goal by detailing AAV based gene therapy to isolated lung grafts during ex vivo machine perfusion. Collaborative efforts by the research team have experimentally demonstrated the feasibility of this approach, and give confidence that the therapeutic transgene, PD-L1, will impart a protective effect on donor lungs. Aim 1 will test the efficacy AAV-mediated PD- L1 over-expression using two AAV serotypes, AAV9 and AAV4, delivered during EVLP that preferentially infect epithelium and endothelium respectively, on the amelioration of alloimmune injury after transplant. Aim 2 will then examine the durability of AAV transduction among cell types as well as evaluate the impact of acute lung injury on expression. Finally, Aim 3 will extend observations from Aim 1 to a clinically-relevant large animal lung transplant model and discarded human lung. Demonstrating effective gene therapy deliver to lung allografts ex situ would radically change organ preservation, while concomitantly enhancing long-term outcomes via immunomodulation. Therefore, the development of the proposed approach would be of tremendous public health importance and will leverage the team’s transdisciplinary expertise of lung transplantation, organ preservation, viral based gene therapy and pulmonary regeneration. The technology proposed herein, once developed, could be translated into clinical use by transplant programs across the globe. Importantly, principles developed herein are generalizable to other solid organs, including heart, kidney, and small bowel, to extend the longevity of transplanted solid organs.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Standard treatment of prostate cancer (PCa) with anti-androgen agents fails due to development of therapy resistance and castration-resistant prostate cancer (CRPC), a terminal disease. Enhancer of Zeste Homolog 2 (EZH2), a histone methyltransferase and catalytic subunit of Polycomb Repressive Complex 2 (PRC2), and Androgen Receptor (AR) are the two most crucial gene/chromatin regulators involved in the development and progression of advanced PCa, including CRPC. How these oncoproteins contribute to CRPC development and progression remains far from clear. Recent works by us and others show that the EZH2 regulome in CRPC goes well beyond its well-studied, canonical gene-repressive role. Specifically, EZH2 also binds AR and its constitutively active variant, AR-V7, and has a non-canonical function in activation of prostate oncogenes, which differs from the well-known PRC2:EZH2-driven canonical function related to repression of tumor- suppressive genes (TSGs). EZH2’s cryptic transactivation domain (EZH2TAD) and AR’s poly-glutamine (polyQ) and poly-glycine (polyG) motifs were identified to be important for the activation of oncogenes in AR+ PCa. To target both canonical and non-canonical oncogenic functions by EZH2, we generated EZH2 small-molecule degraders including MS177 and MS8815 using the Proteolysis Targeting Chimera (PROTAC) technology. Our extensive preliminary studies have demonstrated that MS177 effectively degrades both PRC2:EZH2 and non- PRC2 partners of EZH2 (e.g., AR/AR-V7), thus suppressing both activities of EZH2 in canonical and non-canonical oncogenic PCa cells. Importantly, our preliminary results also show that MS177 is superior to all available enzymatic inhibitors of EZH2 in cell line models of PCa including CRPC. Thus, we hypothesize that: (i) EZH2 drives a non-canonical program via EZH2TAD:ARPolyQ/G interaction for oncogene activation, which operate in parallel with the canonical PRC2:EZH2-driven repression of TSGs and that (ii) EZH2 PROTACs simultaneously repress both canonical (PRC2/EZH2) and non-canonical (EZH2/AR) oncogenic pathways, providing a novel and more effective therapeutic strategy for lethal PCa. Dissection of the mechanisms underlying EZH2-mediated oncogenesis and evaluation of the in vitro and in vivo efficacy of EZH2 PROTACs using various PCa preclinical models will have significant impact on improving treatments of lethal PCa. Towards this goal, we will further characterize such a new non-canonical oncogenic role of EZH2 in CRPC (Aim 1a) and define effects of EZH2 PROTACs on suppressing both canonical and non-canonical oncogenic activities of EZH2 (Aim 1b). We will also determine in vitro and in vivo therapeutic effects of EZH2 PROTACs by employing independent PCa models (Aim 2). Completion of the proposed research will not only provide novel mechanistic understanding of how advanced PCa develop, but also validate an innovative therapeutic strategy and generate novel lead compounds for the treatment of CRPC patients.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Sepsis is an often life-threatening medical condition in which the body has a dysregulated response to in- fection. A number of studies have attempted to identify sepsis subtypes based on patient similarities across demographic, clinical, and biological/immunological data, with the hope of identifying subtypes responsive to personalized treatments. Although clustering is a promising approach, its significant limitations are not always well recognized. These include a lack of robustness to small differences in datasets and a lack of reproducibility across different study types and populations. This project develops new statistical methods designed to help clinicians in the search for subtypes of disease, while taking advantage of heterogeneous data both within and across different studies. With improved statistical tools, medical researchers will have a better chance of iden- tifying meaningful subtypes that can be further interrogated in the search for improved treatments that lead to better survival. Specifically, our project aims to (1) develop, validate, and apply Bayesian multiview pyramids as an alternative to standard clustering techniques; (2) develop, validate, and apply Bayesian multistudy pyramids to maximize reproducibility across different studies and populations; and (3) develop, validate, and apply robust frameworks for assessing how disease subtypes evolve dynamically over time. We will study properties of these new approaches both from a theoretical perspective and via extensive simulation studies with comparisons to other leading approaches, and we will use these approaches to explore sepsis subtyping in a number of im- portant sepsis cohorts. While the disease under study in this application is sepsis, the methods will be broadly applicable to other diseases and syndromes for which clustering could be used to facilitate endotype discovery.

NIH Research Projects · FY 2026 · 2026-04

Abstract Middle East respiratory syndrome coronavirus (MERS-CoV) infection has the highest mortality rate (36%) of any of the known human-pathogenic Betacoronaviruses. MERS-CoV continues to circulate in the Middle East, and due to global travel has spread to 27 other countries making it a global health priority. A number of viruses related to MERS-CoV have been identified in mammals worldwide, and several have been found to utilize human DPP4- or ACE2-receptors for cell entry. Therefore, the MERS-related betacoronaviruses (Merbecoviruses, MERBs) have considerable zoonotic potential. While many medical countermeasures like vaccines and antibody therapeutics were developed to fight SARS-CoV-2, these countermeasures do not prevent disease caused by MERBs. The long-term goal of this proposal is to generate such MERB broadly neutralizing antibody (bnAb) therapeutics. The significance of this project includes the identification of broadly protective antibodies (Abs) and their epitopes, enabling rational design of antibody-based therapeutics and vaccines against a deadly virus. While previous research has focused on identifying potent neutralizing antibodies against MERS-CoV, no antibodies have been shown to be cross- protective against MERS-CoV and other MERBs. In preliminary studies in vaccinated rhesus macaques (RMs), we elicited robust cross-binding and cross-neutralizing plasma Abs against multiple MERBs. Post- vaccination RM B cells bound both MERS-CoV receptor binding domain (RBD) and bat MERS-CoV-related virus NL140422 RBD. Individual Abs from these RMs bound to as many as 7 different MERS-CoV-related RBDs and MERS-CoV. The objectives of this study are to 1) determine the neutralization breadth of monoclonal nAbs from these vaccinated RMs, 2) determine the critical features of the binding interface between cross-reactive nAb and virus spike RBD, and 3) determine the cross-protective efficacy of the mAbs. The innovations of this project include human, bat, and pangolin live-virus MERB models (MERS-CoV, PDF2180, NL140422 (MERS 422), MjHKU4r, HKU-5), 13 genetically diverse MERB spike and RBD antigens, MERS-CoV and MjHKU4 mouse challenge models, and the use of a machine-learning Ab optimization to improve natural Abs. The impact of this project includes the demonstration that vaccination can elicit broad MERB nAbs against multiple conserved epitopes, the development of trispecific immunotherapies, and the definition of bnAb epitopes that inform rational design of immunogens targeting cross-protective B cells. Our Abs will be potential tools to combat MERS-CoV outbreaks and prepare for future outbreaks from pre- emergent MERBs.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Epstein-Barr virus (EBV) is a latent, recurring herpesvirus that replicates in the oral cavity and is transmitted by saliva. While most infections are relatively benign, EBV can cause malignancies in the immune suppressed, such as transplant patients and HIV-infected individuals, and is also a potential trigger for certain autoimmune diseases. In addition, rare germline genetic variants lead to increased susceptibility to EBV- associated diseases. EBV is a highly successful virus with nearly 95% of adults worldwide being latently infected. This efficiency is due to the unique and evolutionarily conserved ability of EBV to mimic B cell signaling pathways and evade the innate immune response. The balance of these activities determines whether EBV is successful in establishing latency and in some genetic backgrounds, the consequences range from autoimmunity to cancer. It is therefore our ultimate goal to define the molecular mechanisms for EBV latency establishment and persistence in the oral cavity. In this proposal, we aim to characterize how EBV evades innate immune signaling and usurps intrinsic B-cell signaling to promote latency establishment and pathogenesis. It is our central hypothesis that EBV establishes B-cell latent infection through antagonizing innate immune signaling and mimicry of constitutive B-cell signaling pathway activation. We have formulated our central hypothesis based on preliminary data including a CRISPR screen following up on our recent early infection scRNA/ATACseq experiments in primary human B cell infection leading to mechanistic studies demonstrating a positive role for the ubiquitin like molecule, ISG15, and restrictive roles for BCR signaling regulators in EBV-driven B cell immortalization. We further found that ISG15 acts as a regulator of type I interferon signaling such that ISGylation enzymes were suppressors of B cell outgrowth and STAT1/2 or IFNAR1/2 loss rescued ISG15 loss. Excitingly, we also identified patients with poor control of EBV harboring deleterious variants of these EBV regulators suggesting that our CRISPR screen identified clinically relevant molecules as arbiters of EBV infection in vivo. Therefore, the rationale for this proposed research is that understanding how EBV regulates innate immune and BCR signaling to establish latency and transform B cells provides insight into therapeutic modalities to eliminate EBV-infected cells from the oral cavity. We plan to test our central hypothesis and complete the objectives in this proposal through the following three specific aims: i) to determine the molecular mechanism by which EBV regulates type I interferon signaling to promote latency establishment and tumorigenesis, ii) to determine the unique role of B-cell receptor signaling regulators in EBV transformation and tumorigenesis, and iii) to determine the mechanistic roles of rare germline variants in regulatory genes from patients with EBV-associated diseases impacting ISGylation, signaling, and B cell fate decisions.

NIH Research Projects · FY 2026 · 2026-04

The growing burden of kidney disease in the U.S. and worldwide is attributed in part to non-traditional risk factors. The potential public health impact is staggering, with over 850 million people currently affected by chronic kidney disease (CKD) alone and global costs for CKD projected to top $400 billion by 2027. Exposure to airborne hazards is one prominent but poorly understood CKD risk. Air pollution has been convincingly linked to adverse kidney health outcomes, including incident CKD, CKD progression, end stage kidney disease, albuminuria, and hospitalization for acute kidney injury. Occupational exposure to silica dust has been linked to renal-related mortality and inhalation of silica dust from kilns, silica-rich crops, ash, and other sources is implicated in the complex pathogenesis of CKD of unknown etiology (CKDu), an emerging disease now reported in over 35 tropical countries and manifest primarily as chronic tubulointerstitial injury. The mechanisms by which inhaled toxins such as respirable silica contribute to remote renal tubule injury and subsequent kidney disease, particularly in communities experiencing high heat exposures, are unclear. This is a critical knowledge gap and highlights the need for rigorous preclinical studies. We propose that kidney cells are injured indirectly by endogenous soluble nephrotoxic mediators released into the bloodstream from damaged lung, noting that lung- kidney communication has already been implicated in glomerulopathies. Our long-term goal is to identify molecular mechanisms of interorgan communication that mediate remote organ injury after environmental exposures that impact human health. The short-term goals are to document kidney injury using complementary sensitive functional assays and to determine if circulating microRNAs (MiRs) are altered early after silica inhalation at time points likely to reflect injury-modulating pathways. Our hypothesis is that silica exposure alters renal function in part by inducing circulating MiR capable of engaging cognate mRNAs in critical kidney cell compartments, and that concurrent heat stress, a common co-exposure, exacerbates this response. Our transdisciplinary team will test this hypothesis in two complementary but independent Aims, the feasibility of which is supported by preliminary data: Aim 1: Quantify early changes in kidney function and cell transcriptomes induced by exposure to inhaled silica, with and without concurrent simulated heat wave co-exposure, and Aim 2: Identify circulating MiRs as candidate mediators of interorgan signaling, using prediction and prioritization algorithms in both aims to gain novel insight into molecular mechanisms. Ultimately these proof-of-principle studies aim to establish regulation of kidney mRNA and/or circulating MiRs as plausible molecular events involved in lung-kidney crosstalk and kidney injury early after inhalational exposures. Our results should stimulate new ideas to prevent and treat exposure-related remote organ injury, particularly for individuals facing multiple CKD risks.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Glycosylation – the enzymatic attachment of carbohydrates onto biomolecules – is the most abundant post-translational modification (PTM) of proteins in nature. In mammals, glycosylation influences all aspects of cell biology, including protein quality control and secretion, intracellular signaling, membrane composition and fluidity, cell adhesion and migration, cell-cell communication, and organogenesis. Aberrant glycosylation also underlies a wide range of human diseases, such as developmental defects, obesity and metabolic syndrome, cancer, neurodegeneration, and atherosclerosis. Despite its significance, protein glycosylation remains an under-studied aspect of cell biology, due partly to the unique challenges in characterizing it. Indeed, protein glycosylation is heterogeneous, chemically complex, and created ab initio, without a template molecule, unlike DNA, RNA, or protein biosynthesis. New, interdisciplinary approaches are needed to understand protein glycosylation in physiology and disease. My research program focuses on protein O-glycosylation (i.e., glycans modifying serine and threonine side-chains). In particular, we have a longstanding interest in O-linked β-N-acetylglucosamine (O-GlcNAc), a ubiquitous intracellular PTM in mammals, which decorates thousands of nuclear and cytoplasmic substrates. O- GlcNAc is an essential regulator of myriad aspects of cell physiology and is dysregulated in numerous human diseases, such as cancer, X-linked intellectual disability, and neurodegeneration. However, major aspects of O- GlcNAc signaling are incompletely understood, including the biochemical mechanisms through which O-GlcNAc transduces information. Our work has addressed this challenge by studying O-GlcNAc-mediated protein-protein interactions (PPIs) in fundamental cell biological processes, including intermediate filament structure and dynamics, vesicle trafficking in the early secretory pathway, and regulation of proteostasis through ubiquitin E3 ligase adaptor proteins. We have also systematically identified candidate human O-GlcNAc “reader” proteins that bind this glycan directly and reported the first structures of potential readers with model glycopeptides, illuminating the biophysical basis of these PPIs. Our work is highly interdisciplinary, combining cell biology with structural biology, glycoproteomics, protein biochemistry, and embryonic development. Moreover, as an important complement to conventional techniques, we frequently develop and deploy novel chemical biology approaches to understand O-glycosylation. Building on this foundation, here we propose to study the biochemical mechanisms and downstream functions of O-glycosylation, with a specific focus on O-GlcNAc-mediated PPIs in key cell biological processes. Our work will provide new insight into several pathways dysregulated in human disease and advance our long-term goal of understanding the mechanisms and functions of mammalian O-glycosylation.

NIH Research Projects · FY 2026 · 2026-04

Abstract Acute pancreatitis is an inflammatory disorder of the pancreas that causes severe pain, gastrointestinal dysfunction, and systemic injury, with a mortality rate of 5-20% in severe cases. It is one of the most common gastrointestinal emergencies, affecting more than 280,000 people in the United States annually and representing the leading gastrointestinal cause for hospitalization. Despite this profound burden, how acute pancreatitis develops is poorly understood, and no specific treatments have been shown to improve the disease course. Thus, there is a critical need to improve our understanding of this disease and identify novel effective therapies based on this new information to improve outcomes from acute pancreatitis. Recent observational clinical data have shown that up to 60% of hospitalized patients with acute pancreatitis develop low phosphate levels requiring phosphate supplementation. Furthermore, 30% of those with low phosphate developed severe pancreatitis, suggesting that phosphate may play a crucial role in the development of the disease. However, these studies could not determine whether low phosphate levels predispose to pancreatitis or if pancreatitis causes hypophosphatemia. More recently, our group has shown that phosphate depletion through low phosphate diet increases the onset of acute pancreatitis in animal models. Importantly, we found that phosphate supplementation reduced pancreatitis severity in mice even when phosphate levels were normal. These findings suggest that hypophosphatemia predisposes to acute pancreatitis and that pancreatitis severity can be diminished by phosphate treatment. This hypothesis will be tested in a two-phase clinical trial of adult emergency department (ED) patients presenting with acute pancreatitis. The first phase will consist of a control (observational) group receiving usual care only, in which we will determine the associations between serum phosphate levels over time and disease severity. The second phase will consist of a pilot treatment group treated with intravenous phosphate for the first 72 hours of their hospital stay. In this group, we will determine how much phosphate is required to maintain a high-normal phosphate level, and whether it differs based on pancreatitis severity (mild, moderately-severe, severe). We will also determine how feasible it is to enroll patients in this study, administer phosphate according to the infusion protocol, and collect data to assess preliminary outcomes. These proposed pilot clinical trial findings will provide data needed to develop a future definitive, multi-centered, randomized clinical trial of phosphate for the clinical treatment of acute pancreatitis.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT: Speeding Immune Reconstitution after Thymus Transplantation Pivotal prior work by our team showed that cultured thymus tissue implantation (CTTI; also called thymus transplantation) into athymic humans generates a functional immune system where T cells protect against infection and are tolerant to both recipient (self) and to donor MHC antigens on the implanted thymus. We have extended these findings to reprogram the immune system of immunocompetent rats to recognize a transplanted allogeneic heart as self, then translated this paradigm-changing proof of concept via the successful first human CTTI/heart co-transplantation into an infant with both a damaged heart and very low T cell numbers. However, therapies that can drive more rapid T cell reconstitution are urgently needed to prevent unnecessary early deaths post-CTTI from infection before immune reconstitution has occurred, in order to extend this potentially life-saving method for inducing tolerance to a broader range of recipients. Using single cell RNA sequencing and spatial profiling of murine and human thymus, our team has identified multiple separately targetable pathways that regulate the transition of the thymus from its robust growth during the perinatal period to the homeostasis that is observed in juveniles. In this proposal, two of these pathways will be manipulated in murine models via either ex vivo gene therapy using adeno- associated virus vectors or pharmaceutical intervention. Impacts of these interventions on growth of implanted thymus and the speed and quality of immune reconstitution post-CTTI will be determined. As developers of CTTI with expertise in thymus biology and gene therapy, our research team is extraordinarily well-qualified to lead this study. The potential impact is large, since these rapidly translatable approaches may also speed T cell reconstitution after cancer treatment, advance progress toward the long sought-after goal of generating donor-specific tolerance to transplanted organs, improve treatment of autoimmunity, and even potentially ameliorate age-related declines in immunity.