Selected Grantee Publications
- 644 results found
Activated Polyreactive B cells are Clonally Expanded in Autoantibody Positive and Patients With Recent-Onset Type 1 Diabetes
Nicholas et al., Cell Reports. 2025.
https://pubmed.ncbi.nlm.nih.gov/40117290
Type 1 diabetes (T1D) develops from a sustained attack on the pancreas’ insulin-producing cells by the body’s immune system. Previous research has emphasized the role of autoreactive (acting against a person’s own tissues) T cells in T1D disease progression. Patients who are prediabetic do not have symptoms but do have autoantibodies (immune proteins that target a normal molecule in the body) present. However, it remains largely unknown how autoreactive B cells affect the development of T1D. Researchers isolated B cells from the blood of patients with T1D, patients who were prediabetic (AAB), and relatives who were nondiabetic and not autoreactive. Results showed that B cells from AAB and T1D patients have altered gene expression in cell signaling, antigen-presentation (what tells your immune system whether something is harmful), and inflammation pathways. These results provide a foundation for future studies focused on identifying biomarkers (molecules found in the body that show a specific disease or disease stage) or creating cell-targeted treatments for T1D. Supported by ORIP (K01OD028759), NCI, NIA, NIAID, NIDDK, and NIGMS.
Engineered Epithelial Curvature Controls Paneth Cell Localization in Intestinal Organoids
Yavitt et al., Cell Biomaterials . 2025.
https://pubmed.ncbi.nlm.nih.gov/40270579
Intestinal organoids, laboratory-grown mini-organs that model the intestine, are emerging as a new complementary approach to study disease progression, provide functional tissue for transplantation, and use in drug screening applications. Researchers have developed a new method to design the architecture of intestinal organoids by engineering the curvature of their tissue. Using a light-sensitive hydrogel, researchers precisely controlled the width and depth of intestinal organoids, mimicking the natural intestinal folds. This structure guided the placement of Paneth cells, which are key to gut health and immunity. By improving the consistency of cell organization, this approach enhances the reproducibility and functionality of organoid models, making them more useful for studying diseases, testing drugs, and advancing restorative medicine. Supported by ORIP (S10OD034320), NCI, NHLBI, and NIDDK.
Inferring Drug–Gene Relationships in Cancer Using Literature-Augmented Large Language Models
Lai et al., Cancer Research Communications. 2025.
https://pubmed.ncbi.nlm.nih.gov/40293950
Scientific literature contains a vast wealth of information on cancer and cancer-targeting drugs. Researchers developed GeneRxGPT, a large language model (LLM)–powered tool that analyzes biomedical literature to uncover drug–gene relationships for cancer treatment. By integrating PubMed data and advanced LLMs, this tool overcomes limitations of static LLMs (e.g., outdated knowledge, misleading results). GeneRxGPT was validated against curated databases and identified both established and emerging therapeutic cancer treatments. A case study in liver cancer showed a key link between a particular set of mutations and sensitivity to the cancer drug sorafenib, pointing to a new treatment strategy. Designed for accessibility, GeneRxGPT is a promising resource to accelerate cancer drug discovery that helps researchers without coding expertise explore drug–gene interactions. Supported by ORIP (S10OD028483, R03OD036494), NCI, NIBIB, NIDDK, and NIGMS.
Canine Distemper Virus Phylogenetic Structure and Ecological Correlates of Infection in Mesocarnivores Across Anthropogenic Land Use Gradients
Wilson et al., Microbiology Spectrum. 2025.
https://pubmed.ncbi.nlm.nih.gov/40029380
Humans’ use of land affects infectious diseases and how they interact with wildlife, domestic animals, and other humans by changing host spatial distribution, behavior, density, and population dynamics. This study examines how human-driven changes to the environment affect the spread of canine distemper virus (CDV) in mesocarnivores—mid-sized predators like raccoons, red foxes, and skunks. Researchers analyzed a database of CDV-infected animals (both sexes included) across the southeastern United States. They found that infection patterns were influenced by environmental factors, such as elevation, land use, precipitation, and age. CDV cases were more likely in areas with intense human activity and lower elevations. These findings can help identify high-risk zones for monitoring, improving early detection and helping prevent CDV from spreading between wildlife, domestic animals, and humans. Supported by ORIP (T35OD010433).
Mutant Prion Protein Enhances NMDA Receptor Activity, Activates PKC, and Triggers Rapid Excitotoxicity in Mice
Lin et al., The Journal of Clinical Investigation. 2025.
https://pubmed.ncbi.nlm.nih.gov/40185484
This study examined how a mutant form of a prion protein (PrPC) linked to Alzheimer’s disease can harm neurons, one type of brain cell. The team used genetically modified male and female mice and showed that changes in PrPC disrupt neuronal communication and lead to overactivation of Nmethyl-d-aspartate (NMDA) receptors in the brain, which are important for neuronal signaling. Mice experienced seizures and damage to neurons that are important for memory. The findings suggest that PrPC triggers toxic chain reactions in the brain and that these reactions play a key role in neurodegeneration. This discovery may ultimately help scientists better understand the mechanisms behind neurodegenerative diseases. Supported by ORIP (T32OD017863, S10OD023527) NCI, NHLBI, NIA, and NINDS.
Sperm Derived H2AK119ub1 is Required for Embryonic Development in Xenopus laevis
Francois-Campion et al., Nature Communications. 2025.
https://pubmed.ncbi.nlm.nih.gov/40188103
Previous research shows that exposure of males to various environmental factors can affect offspring by modifying the genetic material in sperm. Epigenetics—changes in gene expression that occur without altering the DNA sequence—plays an important role in how embryos develop. DNA is wrapped around groups of histones, a type of structural support protein that regulate DNA compaction and gene expression. DNA compaction can be regulated by modifications to histones—including the attachment of ubiquitin molecules. Researchers studied the role of a particular ubiquitin modification to histones, H2AK119ub1, in embryo development of Xenopus laevis (African clawed frog). The results showed that sperm-derived H2AK119ub1 instructs egg factor–mediated remodeling of the DNA contributed by the sperm and is required for embryonic development. Supported by ORIP (R24OD031956).
Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Mutation Reduces Endothelial TDP-43 and Causes Blood–Brain Barrier Defects
Cheemala et al., Science Advances. 2025.
https://pubmed.ncbi.nlm.nih.gov/40238886
Mutations in the TARDBP gene, which encodes nuclear protein TAR DNA-binding protein 43 (TDP-43), are linked to neurodegenerative diseases, such as familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This study showed that TDP-43 is reduced in brain endothelial cells (ECs) of male and female mice with this mutation—leading to blood–brain barrier (BBB) disruption and causing inflammation, protein buildup, and cognitive issues—mimicking key features of neurodegeneration. These findings suggest that endothelial TDP-43 loss contributes directly to BBB breakdown and disease pathology in ALS-FTD. Supported by ORIP (U54OD020351), NCI, NHLBI, NIA, and NINDS.
Synaptic Dysregulation in a Mouse Model of GRIN2D Developmental and Epileptic Encephalopathy
Teoh et al., Brain. 2025.
https://pubmed.ncbi.nlm.nih.gov/40200555
Researchers studied a gain-of-function mutation, V667l, in the GRIN2D gene, which is linked to severe developmental delays and epilepsy in children. Using a mouse model carrying the V664I variant (both sexes used), findings showed that the mutation caused early-onset seizures, abnormal brain activity, and learning impairments. Functional analysis demonstrated increased synaptic activity, notably in inhibitory GABAergic interneurons, leading to heightened hippocampal excitability. These findings highlight how this mutation alters excitatory and inhibitory neuronal signaling in the brain, supporting precision genetic therapy as a promising treatment strategy for patients with mutations in the GRIN2D gene. Supported by ORIP (U54OD020351), NCI, NIA, NICHD, NIMH, and NINDS.
IL-15/IL-15Ra Synergies with IL-12 to Induce Functional CD8 T Cells and NK Cells During Chronic SHIV Infection
Govindaraj et al., AIDS Research and Human Retroviruses. 2025.
https://pubmed.ncbi.nlm.nih.gov/39041621
Cytokines are key mediators of immune regulation—orchestrating communication between immune cells and shaping the immune landscape during diseases. Researchers investigated whether combining the cytokine treatments interleukin 15 (IL-15)/IL-15Rα and IL-12 would enhance antiviral immunity during chronic simian/human immunodeficiency virus (SHIV) infection. Results indicate that in vitro combination therapy treatment led to an expansion of virus-fighting immune cells (CD8 T and natural killer cells) from uninfected and chronically infected male rhesus macaques with SHIV, compared to single treatment (IL-15/IL-15Rα). Combination treatment also reduced the expression of CCR5, a key receptor that HIV uses to enter and infect CD4 T cells, limiting the number of viral targets. These findings suggest that combined IL-15/IL-15Rα plus IL-12 treatment could strengthen immune defenses and reduce viral spread, supporting its potential use in future therapies for chronic viral infections and cancer. Supported by ORIP (P51OD011132, U42OD011023) and NIAID.
IL-21 and Anti-α4β7 Dual Therapy During ART Promotes Immunological and Microbiome Responses in SIV-Infected Macaques
Johnson et al., JCI Insight. 2025.
https://pubmed.ncbi.nlm.nih.gov/39903521
Despite combination antiretroviral therapy (ART), HIV causes persistent gut barrier dysfunction, immune depletion, and dysbiosis. This study examined the use of interleukin 21 (IL-21) and anti-α4β7 dual therapy to improve immune and gut health outcomes in simian immunodeficiency virus (SIV)–infected male and female rhesus macaques receiving ART. Both dual- and mono-treated animals preserved immune cells and reduced harmful inflammation in the gut. This therapy also boosted levels of helpful gut bacteria, Roseburia, which are associated with better health. The amount of virus stayed similar between groups after stopping treatment; however, animals given combination therapy showed signs of stronger immune protection. These findings support the potential of IL-21 and anti-α4β7 as adjunct therapies in HIV treatment. Supported by ORIP (P51OD011132, U42OD011023), NIAID, NIDA, and NIMH.