University Of California At Davis

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY / ABSTRACT This application is submitted in response to RFA-RM-24-007 with the overriding objective of providing validated assays to understand the immunology of gene editors in pre-clinical studies supporting investigational new drugs (INDs) and eventually in clinical trials. Immunomonitoring is critically important to ensure safety as gene editing therapies transition to the clinical setting for a wide range of applications and diseases. The goals of these studies will be accomplished through the following Specific Aims: (1) Validate a cytokine flow cytometry assay measuring T-cell immunity to commonly used gene editors, vectors, and related peptides from the human peptidome; and (2) Provide a validated multiplex assay for binding antibodies against the domains of relevant gene-editing proteins. We will validate these assays by demonstrating accuracy, precision, specificity, linearity, and range with Quality Assurance monitoring. The assays proposed are based on cytokine flow cytometry and the adaptation of a multiplex microbead immunoassay to accommodate multiple antigens of interest for genome editors being tested for future human use. We will also track the implications of T-cell responses to editors or self-proteins in vivo using total-body positron emission tomography (PET) to assist in fully characterizing the assays proposed. These studies will accelerate the progress of safe and effective somatic cell genome editing therapies to the clinic by providing rigorously validated assays for multiple editing strategies. The assays are designed to address many Cas9-only editors, prime editors, and base editors— while in addition providing a rigorous framework that can be adapted to future gene editors. FDA approved PET imaging methods will also provide a powerful tool for accurately understanding in vivo events and best practices for IND-enabling studies and clinical trials.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY/ABSTRACT ADHD and autism spectrum disorder (ASD) are two prevalent, heritable neurodevelopmental conditions that frequently co-occur. Evidence of overlapping genetic risk suggests they may also share developmental pathways and broader phenotypes. Prospective, genetically-informed, transdiagnostic familial risk designs provide an opportunity to investigate the interplay between genetic risk and early life experiences that may mitigate or exacerbate such risk. Parent-infant synchrony during dyadic interaction across a range of behavioral and biological targets is linked to the development of processes known to be disrupted in ADHD and ASD. Despite these links, studies in ASD have largely examined individual behavior during interactions, with only a handful reporting on dyadic aspects. This is a critical gap, since the temporal structure of the synchronous component of an interaction may represent an emergent property distinct from each individual’s contributions. No studies have examined these questions in infants at risk for ADHD, but research in older youth has documented reduced synchrony. Moreover, despite shared risks, nothing is known about shared vs. distinct influences of early dyadic synchrony on ADHD vs. ASD symptom development, nor the influence on outcomes beyond the preschool period. Middle childhood represents a key transition period characterized by the emergence of relevant clinical phenotypes like ADHD and dramatic changes in domains influenced by parent-infant synchrony, including social competence and self-regulation, making longer-term follow-up of these samples critical not only for the infants who develop ADHD or ASD, but also for the large number of at-risk infants who do not, but who experience subthreshold symptoms and other challenges as they age. This project will leverage 3 prospective longitudinal cohorts of infants (n=326) recruited through the PI’s prior NIMH-funded studies, previously seen at 6/9, 12, 18, 24, and 36 months of age, extending follow-up to ages 6-10 years. These samples are enriched for a range of phenotypic variation, having over-enrolled infants with a family history of ADHD or ASD, and infants at low risk. Middle childhood outcomes will be carefully characterized across key clinical, social, and self-regulatory domains (Aim 1). Previously collected videos of naturalistic parent-infant play will be subjected to novel automated methods to detect behaviors relevant to RDoC constructs of cognitive systems, negative/positive valence systems, and social processes, allowing examination of the influence of early-life dyadic synchrony on middle childhood outcomes (Aim 2). Aim 3 explores moderators and mediators of these associations, including capitalizing on the genetically-informed design to test the degree to which early-life dyadic synchrony moderates genetic risk for ADHD and ASD. Results could help to understand etiological links between ADHD and ASD, elucidate protective and modifiable risk factors, and identify targets for caregiver-mediated, transdiagnostic prevention and early interventions that have broad effects across the lifespan.

NIH Research Projects · FY 2025 · 2025-05

The proposed project should enhance the safety of human and animal foods. The Analytical Toxicology Section of the California Animal Health and Food Safety laboratory (CAHFS) is requesting funding to develop analytical methods for detecting microcystins in fish tissues with the goal of assessing and preventing contamination of fish based foods and feeds in the food supply of the domestic animal and human food chain. Microcystins are an important One Health issue, in that it impacts wildlife, domestic animals, and people alike. They are found in both degraded and oligotrophic waterways and can contribute significant damage to ecosystems.

NIH Research Projects · FY 2025 · 2025-04

PROJECT SUMMARY/ABSTRACT The University of California at Davis (UCD) is a diverse educational institution recognized for excellence in medical, veterinary, agricultural and engineering education and research. The UCD Medical Center houses the UCD Comprehensive Cancer Center (UCDCCC), a patient treatment and research center that supports and coordinates the collaborative research efforts of over 100 cancer researchers. The UCD Flow Cytometry Shared Resource Laboratory (FCSR) provides cell sorting and analytic cytometry support campus-wide and is used heavily by UCDCCC members. In recent years, several UCDCCC investigators have begun to study the role of small, nanometer sized extracellular vesicles, such as exosomes, in cancer diagnosis, metastasis and treatment. Extracellular vesicles (EVs) are a variety of nanoscale membrane vesicles released by cells that are widely present in body fluids. The study of EVs is hampered by their small size (≤100nm), as well as their variable surface protein expression and internal composition. Flow cytometry is a preferred method to rapidly characterize, enumerate and purify EVs based on size and brightness. However, many clinically-relevant EVs are between 30-80nm and fall below the limit of detection of most standard flow cytometers. EV research also requires rigorous isolation and labeling techniques, and detecting EVs apart from instrument and reagent noise is challenging, especially for novice EV investigators. Certain cytometers, such as the FCSR’s 8-year-old Beckman Coulter “Cytoflex S”, have sufficiently sensitive optical detectors and other features that allow it to detect EVs  80nm. For the past four years, this Cytoflex S has supported the EV cytometry needs of UCDCCC investigators. However, the Cyoflex S was not specifically designed to support consistent, reliable EV measurements and suffers from periodic optical drift and other issues that are difficult to address. This situation has led to unacceptable unreliability of the Cytoflex S platform for EV work. Further, at its best, the Cytoflex S cannot detect EVs smaller than 80nm. Meanwhile, as the role of flow cytometry has gained more importance in the EV field, new cytometers, like the Cytoflex Nano, have been developed specifically to support EV research. The proposed Cytoflex Nano, described in this application, is engineered exclusively for EV research, is capable of detecting particles as small as 40nm, has rigorous cleaning and QC procedures that simplify cytometer setup and qualification for EV studies and will receive improved maintenance support from the supplier. The success of NIH-supported EV research at UC Davis depends on the availability of a sensitive, reliable, small particle cytometer that will simplify the user experience and enable biomedical breakthroughs. The Cytoflex Nano will be housed in, managed and maintained by the Flow Cytometry Shared Resource facility so that UCD investigators have access to sensitive, reliable nano-particle detection and EV flow cytometry expertise for years to come.

NIH Research Projects · FY 2025 · 2025-04

ORIGINAL PROJECT SUMMARY – OVERALL PARENT AWARD The present application seeks funding to continue the MIND Institute Intellectual and Developmental Disabilities Research Center (IDDRC) at the University of California, Davis. The IDDRC was launched in 2013 and is the newest of the 14 IDDRCs in the network. The MIND Institute IDDRC will address four specific aims. Aim 1 is to conduct interdisciplinary translational research that yields insights into the nature, causes, and consequences of IDD and leads to innovative evidence-based approaches to prevention and treatment. To this end, we propose 81 externally funded projects that reflect the themes of Integrated Biobehavioral Characterization of IDD, Genetic and Environmental Contributions to IDD, and Treatment of IDD. These projects are led by 43 investigators from 16 academic departments and 5 schools/colleges. 68 projects are funded by the NIH, including 16 by NICHD. Aim 2 is to accelerate the pace of interdisciplinary translational research via the operation of cost-effective, innovative, and widely used scientific cores. In addition to an Administrative Core, we propose four scientific cores. The Clinical Translational Core will facilitate recruitment of various populations of human participants, provide specialized clinical expertise to diagnose and characterize participants, support complex phenotyping, collect and store biospecimens, and integrate digital technologies into treatment studies. The Biological and Molecular Analysis Core will provide access to expertise and technologies in the areas of immune function, cellular and molecular imaging, epigenetics, and environmental exposures as they relate to neural development. The Rodent Behavior Core will provide assays of mouse and rat behavior, guidance in the development of mutant rodent models, and support for preclinical evaluations of drug safety and efficacy. The Biostatistics, Bioinformatics, and Research Design Core will provide support for study design, creation of electronic data capture and management systems, and statistical analysis of complex multidimensional datasets. Aim 3 is to improve the lives of people with IDD and reduce health and social discrepancies in care by developing a robust plan for disseminating and implementing scientific discoveries. The plan will involve multiple paths of communication to target professionals and policy makers, reach numerous communities, while being informed by the perspectives of people with IDD and their families. Aim 4 is to conduct a signature research project that examines the heterogeneity of outcomes and mechanisms underlying those outcomes in maternal autoantibody related (MAR) autism spectrum disorder (ASD), which may account for as much as 20% of ASD cases. The project will make use of existing human clinical data to inform the creation of rat model systems to test hypotheses about causal mechanisms. The signature project addresses three RFA themes: Preventing and mitigating the impact of exposures that can cause IDD, Outcome measures or biomarkers for interventions or treatments, and Development of biomarkers or assessment measures in more than one IDD condition.

NIH Research Projects · FY 2026 · 2025-03

ABSTRACT Spina bifida (SB) is the most common congenital cause of lifelong paralysis in the United States, and approximately four children are born daily with this devastating disease. Myelomeningocele (MMC), the most severe form of SB, results from the incomplete closure of the neural tube and absent overlying spine, resulting in lifelong paralysis, bowel and bladder dysfunction, musculoskeletal deformities, and cognitive disabilities. In utero surgical repair improves morbidity, but functional recovery is incomplete, and most children are still unable to walk independently. We developed a treatment for MMC that augments the in utero surgical repair with placental mesenchymal stem cells (PMSCs) and found that in utero treatment with PMSCs prevents hindlimb paralysis at birth in the fetal sheep MMC model via a neuroprotection mechanism. However, treated lambs developed severe kyphosis, causing spinal cord compression and decreased motor function long-term due to a lack of spinal bone support. Therefore, regenerating the bony vertebrae defect is critical in protecting the newly repaired spinal cord and maintaining long-term motor function. It is well known that the dynamic regenerative milieu in the womb naturally supports the generation of fetal tissues by endogenous stem cells. Therefore, leveraging the abundant endogenous cells in the fetal environment presents a unique opportunity for tissue regeneration in utero. The behavior of endogenous cells during bone development in the fetal environment is highly dependent on several critical and complementary factors, such as integrins and extracellular vesicles (EVs). Given that exogenous morphogenetic factors are contra-indicated for fetal and pediatric uses by the FDA, recruiting and guiding endogenous stem cells through engineered materials with integrin ligands and EVs represents an innovative, safe, and effective approach to drive the assembly of appropriate cells and form functional bony tissues in the developing fetus. Using one-bead one-compound (OBOC) combinatorial technology, we identified specific integrin ligands, LLP2A and LXW7, with a high affinity for integrins α4β1 and αvβ3, respectively, that are highly expressed on MSCs and endothelial progenitor cells (EPCs)/endothelial cells (ECs), and that are critical for recruiting endogenous MSCs and EPCs/ECs to the bone defect site. We also demonstrated placental MSCs-derived EVs (PMSC-EVs) possess strong osteogenic and angiogenic potentials. In this study, we propose to develop a collagen-based scaffold modified with LLP2A/LXW7 and PMSC-EVs to synergistically recruit and guide endogenous stem cells for vascularized bone regeneration in utero. We will evaluate the regenerative functions of this product using our well-established fetal sheep spinal bone defect and fetal sheep MMC models. This fetal tissue engineering approach provides a transformative solution for regenerating the bony structural defect in MMC patients. Once established, this solution could combine with our previous neuroprotective approach, significantly improving the care for MMC patients and lowering healthcare costs. This technology can also have wider implications in treating other congenital skeletal defects.

NIH Research Projects · FY 2026 · 2025-03

Kaposi's sarcoma-associated herpesvirus (KSHV) was discovered in 1994 and is one of the eight human herpesviruses. KSHV is the causative agent of Kaposi's sarcoma, two human lymphoproliferative diseases, primary effusion lymphoma, AIDS-related multicentric Castleman's disease, and a more recently described interleukin-6 related disease called KSHV-inflammatory cytokine syndrome. KSHV Latency-associated nuclear antigen (LANA) is consistently identified in those KSHV-infected tumor cells in patients and also plays a role in KSHV-mediated tumorigenesis through its manipulation of cell cycle machinery and deregulation of tumor suppressor pathways. Accordingly, many researchers have focused on the LANA protein as a therapeutic target for inhibiting tumorigenesis and KSHV replication. However, despite the continuous efforts to establish specific therapeutics to control KSHV-associated malignancies, we have not succeeded; we need to explore new directions. Capitalizing on the interaction between KSHV terminal repeat (TR) and LANA, as well as the enhancer properties of TR, we devised a gene therapy vector using the adeno-associated virus (AAV) system for KSHV- associated malignancies. This vector selectively expresses therapeutic genes in LANA-expressing KSHV- associated tumor cells. We selected the thymidine kinase (TK)/ ganciclovir (GCV) as an indirect gene therapy. This antiviral drug has been shown to control KSHV-associated tumor progression. The HSV-TK initiates the conversion of the GCV to the toxic metabolite GCV-triphosphate, which inhibits DNA synthesis and induces cell apoptosis. Introducing our AAV vector should facilitate cancer cell killing by adding exogenous TK to the endogenous KSHV TK with GCV treatment. To further enhance the therapeutic gene expression from our AAV vector in KSHV-infected cells, we will implement the combination therapy using FDA-approved drugs such as the histone deacetylase inhibitor Suberoylanilide Hydroxamic Acid or BET inhibitor. These drugs are known to trigger KSHV reactivation, potentially amplifying the therapeutic gene's effect and further promoting the killing of cancer cells. In this application, we aim to complete proof-of-concept studies, evaluating the biological activity and efficacy in killing cancer cells through in vitro assays and xenograft mouse models.

NIH Research Projects · FY 2026 · 2025-03

Project Abstract/Summary Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is an advanced molecular imaging technique to measure metabolic activities within the human body. Unlike standard static PET, which yields a semi-quantitative standard uptake value (SUV) for quantification, dynamic PET imaging combined with tracer kinetic modeling enables parametric imaging, offering critical physiological information such as metabolic rate. The standard Patlak plot, a simple yet efficient linear model, is widely used to describe FDG kinetics. The resulting slope parameter 𝐾i, which represents the FDG influx rate, has demonstrated significant advantages for cancer diagnosis and therapy assessment compared to SUV alone. Whole-body parametric imaging with the standard Patlak plot has been implemented on conventional PET scanners with an axial field- of-view (AFOV) ranging from 15-30 cm using a multi-bed and multi-pass acquisition strategy. The advent of total- body PET scanners with an AFOV greater than 1 meter, such as UIH EXPLORER and Siemens Quadra, has further simplified and improved the implementation for standard Patlak parametric imaging because of much- improved detection sensitivity and simultaneous coverage of multiple organs. However, despite these advancements, the full-time dynamic scan duration (e.g., 1 hour) has remained the same due to the need for an image-derived blood input function. In this project, we aim to develop an efficient total-body PET parametric imaging approach that can be applied to a short dynamic scan regenerated from the routine clinical static scan (e.g., a 20-minute or shorter scan at 1-hour post-injection). The enabling approach uses a Relative Patlak (RP) plot that does not require the early-time input function. The RP plot has recently been deployed on GE commercial scanners. Our early study and another recent clinical study have demonstrated the equivalence between the RP slope 𝐾i′ and the standard Patlak 𝐾i in clinically relevant tasks, such as lesion detection and tumor volume segmentation. However, one major challenge of applying this approach is the higher noise level in parametric images when the scan duration is shortened. Our preliminary work has indicated the potential of shortening the scan duration to 20 minutes for RP parametric imaging, making it possible to be directly applied to clinical static scans. The specific aims of this proposal are to further develop the enabling technique, push the method for shorter scans (e.g., 10 minutes), and evaluate the benefits of RP parametric images on top of SUV. Specifically, we will (1) develop a deep learning solution for improving RP parametric imaging within a shortened scan duration and (2) evaluate the benefits of RP parametric images on top of SUV using clinical cohorts. Completing these specific aims will improve the diagnosis and comfort of patients by providing an efficient total- body PET parametric imaging approach that is adaptive to clinical static scan protocols without adding any imaging time and scan costs. Our proposed approach will offer a unique solution for pediatric parametric imaging, as the full-time dynamic scan is impractical for pediatric patients.

NIH Research Projects · FY 2026 · 2025-03

Giardia lamblia is a widespread zoonotic intestinal parasite that causes acute and chronic diarrheal disease, affecting over 280 million people annually. Hosts ingest cysts, which excyst into trophozoites that extracellularly attach to the small intestine using the ventral disc, a complex and unique microtubule (MT) organelle. Attachment allows Giardia to resist host peristalsis and colonize the epithelium and may also directly damage and shorten the microvilli of epithelial cells, disrupt the intestinal epithelial barrier, or trigger apoptosis and malabsorption. The ventral disc is eight microns in diameter and is composed of upwards of 100 disc-associated proteins (DAPs) that create unique substructural disc components whose movements may generate forces required for attachment. How these disc substructures function to generate the varied biophysical forces underlying disc-mediated attachment is not well understood. Using live imaging, we recently provided direct evidence of disc contraction during attachment, supporting early observations of contractile attachment mechanisms causing damage to the epithelium. Here we leverage new CRISPR-based genetic tools to create quadruple allelic knockouts in this double diploid parasite. We then employ live imaging approaches with fluorescently tagged marker strains and state-of-the-art biophysical assays using rigid and deformable surfaces to evaluate the contribution of three key disc structural elements (the MR-CB complex, the lateral crest, and the overlap zone) to the modes and forces of disc contraction governing attachment. Both new and existing DAP mutants that comprise these substructural elements will be used to test three different hypothetical force-generating mechanisms for disc-mediated contraction and attachment. More than one DAP associated with a given substructure is tested, as null mutants of different DAPs may have different disc functional phenotypes. New DAPs contributing to disc contractility will also be identified and tested using two unbiased CRISPRi-based attachment and contractility screens. Unravelling the molecular intricacies of how disc substructures generate forces of attachment will enhance our understanding of this key virulence component of giardiasis and offer potential therapeutic targets to combat Giardia infection and its associated pathology.

NIH Research Projects · FY 2026 · 2025-03

Project Summary/Abstract Mutation of the tumor suppressor gene TP53 occurs in more than half of human cancers. Mutant p53 is known to actively drives tumor progression, metastasis, and therapy resistance and thus, is considered as a promising target for cancer therapy. Our pilot studies showed that RNA-binding protein Rbm38, upon phosphorylation by CDK4 at serine 195, is able to interact with eIF4G and subsequently, enhances mutant p53 mRNA translation. We also found that a peptide derived from Rbm38, called Pep8SD, can bind to a pocket in eIF4G and thereby, disrupt the interaction between RBM38 and eIF4G, leading to decreased mutant p53 expression and subsequently, growth inhibition. Moreover, in silico screening identified a small molecule, called 094-63, which bound to the same pocket as Pep8SD peptide and elicited growth suppression by inhibiting mutant p53 expression. Furthermore, we found that compound 094-63 was able to attenuate mutant p53 expression in response to various chemo reagents. Notably, Rbm38, CDK4 and eIF4G are found to be over- expressed in triple negative breast cancers and associated with mutant p53 expression. Thus, we hypothesize that targeting the RBM38-eIF4G complex can be explored as a therapeutic strategy for triple negative breast cancer by specifically suppressing mutant p53 expression. To test this, the following three aims are proposed: (1) To determine how mutant p53 expression is regulated by the CDK4/6-RBM38-eIF4G axis and the role of mutant p53 as a target of CDK4/6 inhibitors to suppress mutant p53-expressing TNBCs; (2) To determine whether disruption of RBM38-eIF4G interaction suppresses mutant p53 expression and mutant p53-expessing tumors; (3) To determine whether compound 094-63 blocks DNA damage induction of mutant p53 and sensitizes mutant p53-expressing tumors to DNA-damaging drugs.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY: Asthma is the most common respiratory disease worldwide affecting the entire life spectrum. Current systemic and inhaled therapies do not adequately control symptoms or prevent acute asthma exacerbations. There is an ongoing urgent need for alternative and effective inhaled bronchodilator therapies. Over the past decade the Zeki Lab has investigated the HMG-CoA-reductase inhibitors (i.e., the ‘statins’) as a novel therapy for the treatment of airway disorders including asthma and chronic obstructive pulmonary disease (COPD). Beyond their known lipid-lowering capacities in the treatment of cardiovascular diseases, the statins also possess immunomodulatory, anti-inflammatory, anti-proliferative, anti-oxidant, and anti-fibrotic properties. In pre-clinical models of asthma systemic statin therapy works, however, human clinical trials using oral statins were inconclusive. We have shown that orally ingested statins in human subjects have poor airway penetration resulting in undetectable airway drug levels. This led us to pivot and innovate the statin drugs for inhaled delivery. We have identified Pitavastatin as the lead statin for inhaled drug development. Before progressing to more expensive testing in human populations (i.e., Phase 1 and 2 clinical trials), we intend to test our proprietary formulation in a human-relevant airway hyperresponsiveness (AHR) asthma model using rhesus macaque non- human primates (NHP). To address this important and pivotal point in drug development, we hypothesize that inhaled Pitavastatin will (a) improve lung function as a monotherapy and (b) enhance the efficacy of existing standard-of-care (SoC) asthma medications as a combination therapy, in a NHP model of asthma. We will address this central hypothesis via two Specific Aims: AIM 1: To determine the efficacy of inhaled Pitavastatin as a bronchodilator in a rhesus macaque model of AHR in vivo. We will use the California National Primate Research Center’s established asthma model of AHR to test our novel inhaled Pitavastatin formulation as a monotherapy (delivered as a nebulized aerosol to the airways using established drug dose ranges) in a crossover clinical trial design. AIM 2: To determine the efficacy of Pitavastatin as a combination therapy with b2- agonists and/or corticosteroids using PCLS ex vivo from juvenile and adult rhesus macaques. The Zeki Lab has established the use of precision-cut lung slices (PCLS) including those from mice and human lungs. Using our established protocols, we will generate plentiful lung slices from rhesus macaques across the lifespan. Naïve lungs will be pre-treated with Type 2 pro-inflammatory cytokines to model an asthmatic airway. We will use pre- and post-treatment approaches using a combination of Pitavastatin, Formoterol, and Dexamethasone with appropriate controls. We will also test the anti-inflammatory effects of Pitavastatin ± Dexamethasone by measuring secreted cytokines/chemokines in lung slice media. Accomplishing this work will bring us closer to developing inhaled statins, in particular Pitavastatin, for the treatment of asthma. Accomplishing this goal will usher in a new drug class for the treatment of obstructive airway diseases.

NIH Research Projects · FY 2026 · 2025-02

Project Summary/ Abstract In the United States, approximately 60% of cancer patients undergo surgical resection. In prostate cancer surgery, the second leading cause of cancer death in men, some tumor regions are missed in 20% to 60% of cases. Employing 12 mm maximum diameter trocars, the surgical approach balances instrument accommodation and tissue damage minimization during laparoscopic procedures. While various imaging techniques help to reduce missed tumor regions, radio-guided probes face limitations with Positron Emission Tomography (TEP) prostate cancer specific tracers. Mechanical collimation effectively detects Single-photon Emission Computed Tomography (SPECT) radiotracers within the energy range of 80 keV to 300 keV, but challenges arise with higher-energy gamma rays such as the 511 keV emitted in PET. This results in bulky probes due to the dense material surrounding the detector, rendering them unsuitable for laparoscopic surgery and with poor directionality. As an alternative, detecting β+ particles instead of the 511 keV annihilation gamma rays offers a potential solution. However, this method has limited sensitivity, particularly in detecting high fixations that are not in direct contact with the probe. The aim of this project is to create a surgery probe prototype specifically designed for PET radiotracers and firstly aimed to be used during laparoscopic prostate cancer resection—adhering to the constraint of a diameter less than 12 mm. The central and novel approach is the use of two back-to-back detectors with high energy resolution, which allows the selection of small Compton angles. Selecting small Compton angles interaction means detecting only gamma rays that impinge almost from the front of detector's alignment axis. This innovative collimation method offers a remarkable improvement in signal- to-noise ratio compared to existing commercial probes, addressing limitations in laparoscopic surgery suitability. A first prototype with a bigger diameter has been developed and showed promising results compared to commercial probes with an increased signal-to-noise ratio, a weight three times lower and a reduced diameter. This first prototype will be (1) improved by using the GATE Monte Carlo simulation platform. Some different geometries and materials will be tested to find the better compromise between size and sensitivity of detectors. (2) A new prototype will be built and (3) will be compared to the commercial probes and tested by surgeons using anthropomorphic phantoms that mimic tumors in the body. Our long-term goal is to develop the world’s first laparoscopic probe for detecting 511 keV gamma rays from PET tracers that can be used in surgery routine to better identify tumors and lymph nodes by making it available to the sell market. If successful, this project will drastically ease surgeon’s procedures and will allow providing better patient’s outcomes as well as shorten the procedures, thus, reduce risks and sequels from surgery.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY Simon Ascher, MD, MPH is establishing himself as a clinical investigator in patient-oriented research that focuses on individualizing clinical decision-making in hypertension. This K23 award will provide the necessary training for Dr. Ascher to successfully transition to an independent investigator and achieve the following goals: 1) develop expertise in advanced statistical methods for predicting individualized treatment effects from clinical trials; 2) acquire essential knowledge and skills in using surveys to quantify patient preferences; 3) obtain hands-on experience in developing patient decision aids embedded in the electronic health record (EHR); and 4) gain proficiency in designing and conducting behavioral clinical trials. Dr. Ascher has assembled a mentorship team led by his co-primary mentors, Dr. Richard Kravitz, an established leader in doctor-patient communication and heterogeneous treatment effects; and Dr. Michael Shlipak, an internationally renowned researcher in kidney and cardiovascular disease epidemiology, and comprised of co-mentors and advisors who provide complementary expertise in advanced biostatistics methods, health preferences, digital health, and clinical trials. Hypertension affects nearly half of all U.S. adults, yet optimal blood pressure (BP) targets continue to be heavily debated and poorly implemented. The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated among non-diabetic individuals that intensive BP treatment reduces CVD events and deaths, but also increases serious adverse events. The broad application of SPRINT could have enormous public health impact, but well-documented heterogeneity in risks and preferences requires individualized decision-making. Building on Dr. Ascher's KL2-supported work, the current proposal aims to develop a personalized approach to BP targets by combining several powerful strategies: individualized risk prediction for multiple outcomes, calibration of the benefits and harms from BP treatment according to patient preferences, and use of a BP target decision aid to guide shared decision-making. In Aim 1, he will refine models in SPRINT that predict for each outcome an individual's change in absolute risk with intensive versus standard BP lowering and then seek external validation in the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD BP) trial. In Aim 2, he will use an instrument he previously developed to characterize the variation in patient preferences for BP treatment outcomes, and to identify a limited set of patient clusters with similar preferences. In Aim 3, he will first develop an interactive BP target decision aid embedded in the EHR that translates a patient's risks and preferences into a personalized BP target recommendation; he will then evaluate the decision aid's feasibility in a pilot trial. The proposed plans are realistic and feasible within the 5- year award period, and will lay the groundwork to pursue funding to conduct a large-scale trial of the BP target decision aid. In addition, Dr. Ascher will have acquired the skills and experience necessary to achieve his career goal of becoming a leader and innovator in efforts to individualize CVD prevention strategies.

NIH Research Projects · FY 2025 · 2025-02

PROJECT SUMMARY Metabolic disorders, including obesity and diabetes affect 1 in 3 individuals in the United States exacting a huge cost on individuals and society. Epidemiologic studies have reported a positive correlation between exposure to traffic-related air pollution (TRAP) and increased risk of metabolic disorders. Preclinical studies support this association, but many of these studies used acute exposure to concentrated ambient particles or diesel exhaust that do not recapitulate the complexity of chronic real-world human exposures to TRAP. Moreover, the mechanism(s) by which TRAP increases individual risk for metabolic disorders remain speculative. We have designed a unique exposure model in which rats are exposed in real-time to TRAP collected from a major freeway tunnel system, which preserves the gaseous and particulate components of real-world TRAP and captures daily fluctuations in pollutant levels. We will leverage this model to test our central hypothesis that chronic TRAP exposure exacerbates metabolic disease by interfering with the resolution of neurogenic inflammation. Using an established high-fat diet rat model of the metabolic syndrome, we will test whether chronic TRAP exposure activates neurogenic inflammation in peripheral organs, initially in the lungs and subsequently in organs involved in metabolic disease, such as the liver and adipose tissue. We hypothesize that chronic activation of neurogenic inflammation tips the balance towards pro-inflammatory pathways and away from inflammation resolution. In Aim 1, we will determine whether chronic TRAP exposure causes neurogenic inflammation leading to increased pro-inflammatory (M1) and decreased inflammation resolving (M2) macrophage phenotypes. Further we will characterize changes in the turnover of pro-inflammatory and pro- resolving lipid mediators using deuterated tracers. In addition to examining the temporal relationships between these outcomes, we will determine whether TRAP exacerbates metabolic disease, evidenced as a decreased time to onset and/or increased severity of symptoms. In Aim 2, we will use a drug that blocks neurogenic inflammation, and a drug that promotes inflammation resolution, to assess the causal relationship of TRAP- induced neurogenic inflammation to both impaired inflammation resolution and symptoms of metabolic disease. This will be determined by M1/M2 macrophage phenotypes and relative balance of pro-inflammatory and pro- resolving lipid synthesis. Our broad long-term objectives are to understand how chronic exposure to TRAP exacerbates the burden of metabolic disease, to inform regulatory and health interventions aimed at reducing metabolic risk for individuals living, working, or attending school near busy roadways. This proposal is directly aligned with the Notice of Special Interest (NOT-ES-20-018) goals of characterizing “cell and tissue specific resolution phenotype in normal and disease models and the impact of exposure to environmental agents”.

NIH Research Projects · FY 2026 · 2025-01

Project Summary Respiratory tract infections and air pollution separately are each major causes of morbidity and mortality worldwide. The COVID-19 pandemic revealed that the environment strongly contributed to the severity of infectious respiratory tract diseases as communities with higher air pollution were most affected. However, currently, there is a critical knowledge gap at the nexus of respiratory tract disease infections and environmental stressors, including air pollutants. This is partly because toxicologists and experts in respiratory tract viral infections work in silos. Hydrogen sulfide (H2S) and Influenza A (IAV) virus are common and relevant public health hazards affecting the respiratory tract globally. To our knowledge, no studies have examined the interaction between exposure to environmentally relevant H2S concentrations and IAV infection, a zoonotic pathogen, on the respiratory system. The potential for exposure to H2S and IAV exists daily in the workplace, homes, and communities. There are > 80 occupational settings in which H2S is a human health hazard. The current Occupational Safety and Health Administration’s (OSHA) H2S guideline for a 40 h work week is 10 ppm to protect workers from toxic effects of H2S. We have obtained striking preliminary data showing that pre- exposing mice to 5 or 10 ppm H2S for 2 h/day, 5 days/week, for 25 days caused acute mortality in mice challenged with IAV. No mortality was recorded in control mice breathing room air challenged with an equal dose of the virus. The goal of this proof of principle study is to generate sufficient pilot data and to identify underlying toxic mechanisms for future development of target-specific therapeutic drugs to reduce morbidity and mortality of IAV infection. Our overarching hypothesis is that environmental H2S exposure predisposes mice to respond to respiratory tract viral infections in an overly robust manner with high mortality. The study will consist of 2 Specific Aims (SA). SA #1: to test the hypothesis that repeated exposure to H2S causes lung immunotoxicity. An equal number (6) of M/F C57BL/6j mice will be exposed to room air (RA) or H2S at 0.5 or 5 ppm 2 h/day, 5 days/week for 25 days and euthanized to assess lung injury by histopathology, flow cytometry, RNA-Seq, and cytokine analysis using multiplex technology. In SA #2 we shall investigate the mechanisms by which pre-exposure to 0.5 or 5 ppm H2S significantly aggravates the outcome of IAV infection in mice. An equal number (6) of M/F C57BL/6j mice will be exposed to RA or H2S as in SA1 followed by a single challenge with 10 plaque forming units IAV PR/8. Cohorts of mice will be sacrificed at 72 h and on DPI 7. In addition to the lung assays as in SA1, oxygen saturation, immunoblotting, flow cytometry and viral load will be performed to determine mechanisms and severity of lung injury. Successful completion of this interdisciplinary study will open a novel line of inquiry on environment/host interaction and susceptibility to IAV, a major zoonotic pathogen globally. We shall use strengthened preliminary data from this work to apply for NIH grants to map out underlying toxic mechanisms in order to effectively treat patients and to protect public health better.

NIH Research Projects · FY 2026 · 2025-01

Adaptive transcriptome evolution likely underlies a substantial component of all adaptations. Here I propose to study two main types of transcriptome evolution using Drosophila. First, we will identify transcriptome novelties in Drosophila melanogaster, focusing on reproductive tissues. We will then investigate the functions of these novelties using CRISPR and RNAi to learn about the possible agents of selection acting on them. Second, we will investigate convergent local adaptation at the transcriptome level in two distantly related species, D. simulans and D.hydei, and identify the underlying regulatory basis to determine whether convergent expression adaptation has a shared genetic basis or whether it generally proceeds by different trajectories in different species. Finally, we will carry out a more general investigation of the role of directional selection in driving expression divergence between Drosophila species.

NIH Research Projects · FY 2025 · 2025-01

Project Summary Invasive fungal mycoses are a major threat to global human health. Despite the morbidity and mortality caused by fungal infections, and the looming threat of multi-resistance, there has been no substantial advancement in the development of antifungal agents. Although antifungal peptides (AFPs) are gaining popularity as potentially new antifungal agents, the lack of innovation in the AFP space has stifled development. To tackle these major challenges, we capitalized on the one-bead one-compound (OBOC) combinatorial technology and devised a high-throughput, multi-step, fluorescence-based platform for screening chemically synthesized peptide libraries to identify membrane-active antifungal peptides on the basis of their ability to discriminate between fungal and mammalian plasma membrane compositions of giant unilamellar vesicles (GUV). The proposed research will test the hypothesis that the enabling OBOC technology, in combination with two powerful screening strategies (GUV binding assay and cell-based anti-fungal lawn assay), will enable us to rapidly develop and optimize novel antifungal agents possessing defined physiochemical features required for broad-spectrum antifungal activity, diverse mechanisms of action and a high therapeutic index. The scientific premise supporting this hypothesis includes our published data and preliminary evidence demonstrating: (1) a new peptide K-oLBF127 that shows high selectivity and potency towards fungal cells thus validating our OBOC GUV binding assay; (2) the feasibility of our high-throughput cell-based antifungal lawn assay with OBOC cleavable peptides and (3) the promising in vivo antifungal activity of our lead peptide, K-oLBF127. Our goals are to scale up our OBOC GUV binding assay and expand our screen to include more complex peptide structures, and to use homolog OBOC releasable peptide libraries with a cell-based antifungal lawn assay to further optimize these membrane active AFPs. In addition, we will use the antifungal lawn assay to screen OBOC libraries for new antifungal agents. The most promising AFPs will be fully characterized for their efficacy, safety and antifungal activity in vitro as well as in murine models. Our studies will focus on Aspergillus fumigatus, Candida albicans, Candida auris and Cryptococcus neoformans – all designated as fungal threats of the highest priority by the World Health Organization. The highly complementary expertise of the PIs will generate meaningful interactions and foster data sharing for greater impact.

NIH Research Projects · FY 2026 · 2025-01

While many interventions promote some degree of axonal regeneration in mice, we are still far from translating this knowledge into therapies, and this may be in part because we have very limited information as to how regeneration is accomplished in related vertebrate species that successfully regenerate their damaged axons. This project is focused on trying to systematically deconstruct how the frog Xenopus laevis recovers from axon injuries to retinal ganglion cells, managing to reconnect those damaged axons and regain vision. This proposal largely uses a new surgical optic nerve crush model and live imaging platform that we recently developed in very young tadpoles. With this system, we have already demonstrated that central players in conveying the injury signal back to the cell body, a pathway involving the gene Dlk, as well as how axons are removed from the optic nerve, a pathway involving the gene Sarm1, are highly similar in tadpoles as they are in mammals. However, in our studies we have some surprising findings that, if we further understand them, have potential to move forward the field. These findings include finding that the Dlk effect on regeneration does not go through the transcription factor Jun, a role for Sarm1 in axon regeneration as well as degeneration, and studies that implicate myeloid cells in the successful regeneration program, possibly acting downstream of Sarm1. The proposal focusses on the intrinsic pathways of Dlk and Sarm1 in the first Aim, mainly in tadpoles, though also validating results and searching for effector genes in adult frogs. In the second aim, in also largely live imaging-based experiments, we will use novel transgenes and varied genetic perturbations to parcel out the role of myeloid cells, including also searching for effector genes. In contrast to these two highly mechanistic aims, the third technique development aim moves to create a much more glaucoma-relevant axon injury model, while also optimizing genetic and pharmacological screening, so that hopefully in the near future we will be able to carry out very large unbiased screens in a glaucoma-relevant axon injury model which take full advantage of the unique properties of the frog as an experimental model organism.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY: Atrial fibrillation (AF) is the most common cardiac arrhythmia (affecting ~1-2% of the general population), resulting in markedly reduced quality of life and increased mortality, due to a combination of altered hemodynamics, progressive atrial and ventricular dysfunction, and embolic stroke. Limitations in current therapy allow AF paroxysms to progress to persistent forms of AF, as a result of extensive atrial structural and electrical changes that facilitate AF maintenance (“AF begets AF”). Myocardial remodeling, particularly atrial fibrosis, is a prominent feature of AF and contributes importantly to the vulnerable substrate promoting and stabilizing the arrhythmia. From a therapeutic perspective, the time course of fibrotic development is likely to define a window early in disease in which anti-arrhythmic pharmacotherapy can terminate AF and slow disease progression, before losing efficacy in grossly remodeled tissue. Therefore, therapies targeting the structural maladaptation, particularly fibrosis, could constitute novel antiarrhythmic strategies. Ca2+ dysregulation is broadly recognized as a critical element in AF pathophysiology, and Ca2+- dependent processes, both in atrial myocytes and fibroblasts, are thought to play an important role in AF- associated structural remodeling. However, while fibroblast Ca2+ homeostasis has been clearly linked to fibrotic outcomes, the mechanisms by which Ca2+ contributes to atrial fibroblast proliferation, differentiation, and transcription of extracellular proteins remain largely unknown, particularly in human fibroblasts and during AF. The overarching goals of this proposal are to investigate the basic molecular and cellular mechanisms of human atrial fibroblast calcium homeostasis and to study their derangements in AF promoting atrial fibrosis. Our approach will involve direct measurements of the major ion channels and molecular regulators of cytosolic Ca2+ in human atrial fibroblasts, which will then be combined in mathematical models defining mechanisms of Ca2+ entry, intracellular release and removal, and downstream fibrotic signaling. Together, these objectives will establish a multiscale mechanistic platform for understanding the precise role of Ca2+ in the human atrial fibroblast phenotypes that underlie remodeling of atrial myocardium in AF. We contend that these quantitative frameworks will provide new mechanistic insights into atrial fibrogenesis in AF, potentially serving as platforms for identifying new therapeutic targets. Each aim includes rigorously generated and validated modeling frameworks, informed by novel experiments in human atrial fibroblasts, and testing of specific hypotheses. Models and data will be distributed freely and widely via software and database infrastructure supported by Dr. Grandi's lab and scientific networking sites.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Eukaryotic cells require messenger (m)RNAs to be exported through a nuclear pore complex for translation. From the start of transcription, RNA binding proteins (RBPs) are needed to package, surveil, and ultimately export processed mRNAs. One third of all RBPs are associated with disease and an overwhelming majority are involved in RNA metabolism, including mRNA export. These perturbations cause gene expression changes that lead to developmental delays and disease. A major challenge to defining how mutations in these RBPs contribute to tissue-specific disease is that export events occur within seconds making observation and study difficult. Recent advancements in fractionation and isolation methods of nuclear mRNA-protein complexes at distinct stages now provide a means to capture these elusive complexes for study. The central hypothesis of the work proposed here is that mRNA structure is a critical factor that leads to efficient nuclear export and that disruptions in RNA structure cause inefficient export and nuclear retention. To address this hypothesis, I aim to combine RNA structure probing with optimized fractionation and isolation methods to determine how RBPs organize and package nuclear mRNAs for export in S. cerevisiae. Given the high sequence similarity and conserved functional pathways, budding yeast offers a powerful model system to address this hypothesis utilizing highly optimized methods in an innovative way. Specifically, this project will be the first to define RNA structure, with single nucleotide resolution, within nuclear mRNA-protein complexes prior to export and address the synergy within these complexes from the perspective of both macromolecules. RNA structure modeling will be used in Aim 1 to define the principles of nuclear mRNA structure that lead to efficient export or retention by sequentially probing RNA structure in cells, fractioning or isolating nuclear mRNA-protein complexes, and subjecting mRNAs to mutational profiling. The outcome of these efforts will define organizational principles of mRNAs within nuclear mRNA-protein complexes to provide knowledge of how RNA structure and RBP occupancy influence gene expression. In Aim 2, I will define the role of a highly stoichiometric protein within nuclear mRNA-protein complexes, Yra1 (ALY/REF), in packaging and folding mRNAs for export. In Aim 3, I will attempt to shift RNA structure of an inefficiently exported mRNA, through mutation or tethering Yra1, to recover mRNA export and reinstate gene expression. Completion of these aims are fundamental to unraveling the complex relationship between mutations in RNA binding proteins essential for mRNA nuclear export and the emergence of tissue- specific disease. Moreover, this knowledge can be used to design therapeutics aimed at altering mRNA structure and gene expression to replace the function of proteins mutated in disease and alleviate disease pathology.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY The ultimate goal of this F31 Ruth L. Kirchstein NRSA is to request support to address a fundamental gap in knowledge of the local immune response in bacterial skin infections. There is an escalating threat of antibiotic skin infections worldwide. Persons who suffer from neutropenia, such as diabetic patients or persons undergoing chemotherapy treatment, are particularly at risk for developing a severe antibiotic-resistant skin infection. Their first line of innate immune defense, neutrophils, are quantitively insufficient in both circulation and at the site of infection, leading to complications. Meanwhile, otherwise healthy individuals are increasingly suffering from these life-threatening infections. Traditionally it has been thought that neutrophils traffic to a site of infection/wounding solely through circulation, however, new studies are showing this is no longer the case, at least in mice. We now understand that the precursors to these neutrophils, hematopoietic stem and progenitor cells (HSPCs), also traffic to the sites of these infections, and are able to locally produce functional neutrophils capable of combating infection. While unable to directly test in humans, our innovative skin-on-a-chip model offers a unique platform to monitor these interactions in a controlled, sterile environment. This will provide us mechanistic insight into HSPC migration into human skin and granulopoiesis in response to bacterial and inflammatory stimuli. Building on results in my preliminary data, I will carry out this project in two steps: 1. Demonstrate the HSPC signaling axis of SDF-1/CXCR4 between soluble and membrane-bound SDF-1 is necessary to attract and maintain a stable population of HSPCs in the skin. 2. Demonstrate that direct TLR2 activation on HSPCs enhances DAMP-mediated local granulopoiesis within the infected skin environment. This research promises to offer novel insights into the immune responses in the skin, potentially informing new strategies against antibiotic-resistant bacterial infections by understanding the dynamics of local granulopoiesis. Long-term, the findings of this project may launch further investigations where autologous patient HSPCs can be extracted, isolated, and therapeutically used in at-risk patients. This project is complemented by a robust training plan designed to enhance my expertise in immunology, dermatology, and translational medicine. This comprehensive approach will not only facilitate the project's success but also aid my transition to become an independent researcher. The university's abundant resources for professional and educational development will be instrumental in achieving these objectives.

NIH Research Projects · FY 2026 · 2025-01

Abstract Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as Human Herpesvirus 8 (HHV-8), is the etiologic agent of three AIDS-associated malignancies: Kaposi sarcoma (KS), a plasmablastic variant of multicentric Castleman disease (MCD), and primary effusion lymphoma (PEL). Although their incidence in HIV+ patients has decreased since the introduction of antiretroviral therapy, KS remains the most common HIV-associated malignancy. Concerningly, nearly one-third of patients who develop KS have well-controlled HIV infection, and it is estimated that the incidence of KS may increase as the life expectancy of HIV+ patients increases. Although less common than KS, MCD and PEL do not have standardized treatments and both exhibit poor prognosis. A current area of research focus is to better understand the KSHV gene regulation to identify new drug targets to control KSHV replication and associated neoplasms. Amounts of nuclear enzymes and transcriptional factors are limited in the cell nucleus and cannot support all of cellular transcription at the same time, the nuclear architecture including chromatin structure must allow for these molecules to be located at the proper time and place for coordinated gene expression to occur. Alterations in this organization could thus lead to a variety of diseases, including cancer. The principles underlying this process are still poorly understood. We previously revealed (i) a 3D KSHV genomic structural and (ii) identified key cellular proteins that play essential roles in both establishing/maintaining latency and induction of lytic replication. The 3D structure modeling and recruitment sites of these key enzymes suggested to us an important role for evolutionally maintaining multiple copies of terminal repeat sequences in the function of concentrating specific protein near KSHV inducible promoters. Accordingly, we hypothesize that having large copies of terminal repeat sequence foster an increase in the local concentration of LANA, and the 3D KSHV genomic structure is designed to allow locally-concentrated LANA complexes to regulate viral lytic gene promoters located in unique region. We will focus on function of terminal repeat sequence in regulation of lytic gene promoters.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT Over half a million autistic young adults will graduate from high school over the next ten years. As they enter early adulthood and no longer receive funded services through the education system, they will become increasingly disengaged from expected adult roles including getting and staying employed. Based on current statistics, about 40% of these adults will be placed in state-funded day programs or sheltered workshops where they will not work in actual paid employment. Most of the remaining 60% will remain chronically unemployed, underemployed or employed in non-competitive jobs that don’t match their skills or interests. Although engaging in meaningful work is one of the most important determinants of mental health, physical health, and quality of life in all adults the autism services field lacks an empirically validated supported employment model that can be scaled up and financially sustained in community settings and that promotes competitive integrated employment (CIE) as an endpoint. In this R34 application we address this urgent problem by continuing and advancing our current pilot study funded by the California Department of Developmental Services (DDS; Grant A22-334). In this pilot, we are implementing the Individualized Placement and Support (IPS) model of supported employment – a person-centered model with a strong evidence base of 28 randomized clinical trials (RCTs). Thus far, using the core un-adapted IPS model, we have achieved CIE rates of 41%. Notably, we have observed potentially mutable issues related to improving agency selection and training. We also propose that increasing positive parent engagement, and helping consumers improve work- related social cognition, may serve as mediators of intervention success and potentially improve model outcomes. In Aim 1 of this R34 application, draw upon our experience in the DDS pilot, where we identified challenges to agency selection and training, and conduct iterative focus groups with the DDS pilot consumers, parents/carers, vocational support professionals (VSPs), employers and members of a community academic partnership panel (C/APP) to investigate these and additional barriers and facilitators of IPS success. We will then integrate this information to create a consumer support toolbox (CST) to be used to improve IPS model fit. We also field test the CST used with IPS – together they are referred to as IPS-AUT-- in 5 consumers. In Aim 2, we conduct a 12-month Hybrid Type1 trial of IPS-AUT where we examine acceptability, feasibility and preliminary effect sizes for employment outcomes as well as IPS fidelity. We hope to achieve at least 75% acceptability and feasibility and to achieve at least 50% CIE. In Aim 3, we preliminarily investigate signals of effect for proposed mediator (target) variables including parent/carer engagement and work-related social cognition. The goal of this project is to prepare us to successfully compete for an adequately powered R01- funded effectiveness trial of IPS-AUT in community settings. Our goal is to address the need to competitively employ the large population of able autistic persons, and in so doing, to improve their mental health outcomes.

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT The ultimate goal of this F31 Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship to Promote Diversity in Health-Related Research is to request support to address the mechanisms of HSPC and neutrophil mobilization from the bone marrow. The bone marrow microenvironment (BMM) is an intricate system composed of different cell types including osteoblasts, osteoclasts, mesenchymal stem cells, endothelial cells, fibroblasts, macrophages, and many others. This system plays a significant role in pathogenesis by regulating the production of blood cells to maintain homeostasis and responding to stress signals that contribute to cell production. In infections and cancer, there are changes in the BMM associated with HSPC and neutrophil proliferation. However, in both cases, the mechanisms driving the release of HSPC and neutrophil are only partially understood. Some studies suggest that the CXCR4/SDF-1 interaction between stromal cells, neutrophils and HSPCs retains these immune cells in the bone marrow and interaction with G-CSF mobilizes these cells. The primary goal of the project is to use our bone marrow microphysiological system (BM MPS), which I have proven produces neutrophils and HSPCs (preliminary data), to study the mobilization of HSPCs from the bone marrow microenvironment (BMM) in response to inflammation at distant sites. I will test the hypothesis that hematopoietic stem/progenitor cells (HSPCs) can be mobilized from the bone marrow in response to extracellular vesicles (EVs) derived from inflamed cells (derived from cancer and skin infections) . Understanding the mechanism that leads to HSPC mobilization is important as it is believed to play a significant role in tumor progression and hematopoiesis dysfunction in cancer and is thought to be a key mediator of innate immune response in skin and viral infections. The research milestones include: 1) Quantify number of HSPCs in BM MPS when dosed with G-CSF; 2) Isolate and characterize EVs derived from keratinocytes, dermal fibroblasts, and the MCF10A cell line series and confirm expression of G-CSF within these particles; and 3) Examine HSPC mobilization mechanism in the BM MPS by introducing inflammation derived EVs in the presence and absence of CSL324, a G-CSF antagonist. In addition to the research milestones, the proposal will seek to accomplish a series of milestones associated with my career development including: 1) prepare for my qualifying exam by attending seminars and lectures in biomedical research 2) continue to mentor undergraduate researchers; 3) present my work at the MPS World Summit, and the SACNAS conference; and 4) publish my work in a peer-reviewed archived journal(s); Accomplishing these milestones will equip me with the writing and project development skills necessary for a career as an independent investigator.

NIH Research Projects · FY 2026 · 2024-12

This HIVRAD program will develop an HIV vaccine regimen that is based on cooperative interactions between Env fusion peptide (FP)-directed antibodies and follicle-homing helper and cytotoxic T cells. We will use innovative vaccine modalities and adjuvants that are designed to elicit high-quality T cells in support of anti-FP antibodies. Strategies for eliciting broadly neutralizing antibodies (bnAbs) against HIV have made substantial progress. There are indications that germline targeting, divided doses, mRNA vaccination, and other strategies may all contribute to the goal of reliably eliciting bnAbs in humans. If these strategies are successful, however, the elicited bnAbs will likely be of lower titer than required to protect against HIV. An effective vaccine will therefore elicit a concomitant high-quality T-cell response, in addition to bnAbs. The proposed research program combines investigation of cooperative antibody and T-cell responses in people with testing innovative tools for eliciting helper and cytotoxic T cells that are distinguished, not by magnitude, but rather by longevity, localization to B-cell follicles, functional effector functions and/or avidity. Project 1 will examine humoral responses and follicular T cells in human beings receiving combined SOSIP/HTI vaccines, and will examine the anti-FP responses that contribute to effective HIV neutralization in clade C-infected people. Project 2 will leverage IL-10 inhibitors to safely elicit high-quality CD8+ T cells—and will then selectively boost cells of higher avidity. Project 3 will use immunogens that are targeted to Tf cells and/or mucosal surfaces to elicit anti-FP bnAbs that are supported by high-intensity Tf responses. As a culmination, P3 will also integrate information from all program components to test a new “cooperative” vaccine regimen in macaques. A shared objective of our program is to test the influence of pre-existing Tf responses on humoral responses to vaccination, and examine if CD8+CXCR5+ T cells contribute meaningful helper function. A second major objective is to evaluate the importance of T-cell avidity for both follicular-helper and cytotoxic functions. A third collective goal is to understand how FP-directed antibodies contribute to protective breadth against clade-C HIV envelopes.