Selected Grantee Publications
Establishing the Hybrid Rat Diversity Program: A Resource for Dissecting Complex Traits
Dwinell et al., Mammalian Genome. 2025.
https://pubmed.ncbi.nlm.nih.gov/39907792
Rat models have been extensively used for studying human complex disease mechanisms, behavioral phenotypes, and environmental factors and for discovering and developing drugs. Systems genetics approaches have been used to study the effects of both genetic variation and environmental factors. This approach recognizes the complexity of common disorders and uses intermediate phenotypes to find relationships between genetic variation and clinical traits. This article describes the Hybrid Rat Diversity Program (HDRP) at the Medical College of Wisconsin, which involves 96 inbred rat strains and aims to provide a renewable and reusable resource in terms of the HRDP panel of inbred rat strains, the genomic data derived from the HRDP strains, and banked resources available for additional studies. Supported by ORIP (R24OD024617) and NHLBI.
Liver-Specific Transgenic Expression of Human NTCP In Rhesus Macaques Confers HBV Susceptibility on Primary Hepatocytes
Rust et al., PNAS. 2025.
https://pubmed.ncbi.nlm.nih.gov/39937851
This study establishes the first transgenic nonhuman primate model for hepatitis B virus (HBV). Male and female rhesus macaques were engineered to express the human HBV receptor, NTCP (hNTCP), specifically in the liver. Researchers used PiggyBac transposon technology to introduce a liver-specific NTCP transgene into embryos, which were then implanted into surrogate females. The resulting offspring expressed hNTCP in hepatocytes and demonstrated high susceptibility to HBV infection. This model overcomes the species-specific limitations of HBV research, providing a powerful tool for studying HBV biology and evaluating HBV treatments in a clinically relevant model system. Supported by ORIP (P51OD011092), NIDA, and NIAID.
A Comprehensive Atlas of AAV Tropism in the Mouse
Walkey et al., Molecular Therapy. 2025.
https://pubmed.ncbi.nlm.nih.gov/39863928
Over the past three decades, adeno-associated viruses (AAVs) have emerged as the leading viral vector for in vivo gene therapy. This study presents a comprehensive atlas of AAV tropism in male and female mice, evaluating 10 naturally occurring AAV serotypes across 22 tissues using systemic delivery. Researchers employed a fluorescent protein activation approach to visualize AAV transduction patterns and detected transduction of unexpected tissues, including in adrenal glands, testes, and ovaries. Biodistribution closely matched the fluorescent signal intensity. This publicly available data set provides valuable insights into AAV vector targeting and supports optimal serotype selection for basic research and preclinical gene therapy applications in murine models. Supported by ORIP (U42OD026645, U42OD035581, U42OD026635), NCI, NHLBI, NICHD, and NIDDK.
In Vivo Expansion of Gene-Targeted Hepatocytes Through Transient Inhibition of an Essential Gene
De Giorgi et al., Science Translational Medicine. 2025.
https://pubmed.ncbi.nlm.nih.gov/39937884
This study explores Repair Drive, a platform technology that selectively expands homology-directed repair for treating liver diseases in male and female mice. Through transient conditioning of the liver by knocking down an essential gene—fumarylacetoacetate hydrolase—and delivering an untraceable version of that essential gene with a therapeutic transgene, Repair Drive significantly increases the percentage of gene-targeted hepatocytes (liver cells) up to 25% without inducing toxicity or tumorigenesis after a 1-year follow-up. This also resulted in a fivefold increase in expression of human factor IX, a therapeutic transgene. Repair Drive offers a promising platform for precise, safe, and durable correction of liver-related genetic disorders and may expand the applicability of somatic cell genome editing in a broad range of liver diseases in humans. Supported by ORIP (U42OD035581, U42OD026645), NCI, NHLBI, and NIDDK.
Peripherally Mediated Opioid Combination Therapy in Mouse and Pig
Peterson et al., The Journal of Pain. 2025.
https://pubmed.ncbi.nlm.nih.gov/39542192
This study evaluates novel opioid combinations for pain relief with reduced side effects. Researchers investigated loperamide (a μ-opioid agonist) with either oxymorphindole or N‑benzyl-oxymorphindole—both δ-opioid receptor partial agonists—in mice (male and female) and pigs (male). These combinations produced synergistic analgesia across species without causing adverse effects or respiratory depression. The therapies significantly reduced hypersensitivity in post-injury models, outperforming morphine alone. These findings suggest that peripherally acting opioid combinations can offer effective, safer alternatives for pain management, potentially lowering opioid misuse and side effects. This approach could improve clinical strategies for treating chronic and acute pain with limited central opioid exposure. Supported by ORIP (T32OD010993), NHLBI, and NIDA.
Plural Molecular and Cellular Mechanisms of Pore Domain KCNQ2 Encephalopathy
Abreo et al., eLife. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11703504
This study investigates the cellular and molecular mechanisms underlying KCNQ2 encephalopathy, a severe type of early-onset epilepsy caused by mutations in the KCNQ2 gene. Researchers describe a case study of a child with a specific KCNQ2 gene mutation, G256W, and found that it disrupts normal brain activity, leading to seizures and developmental impairments. Male and female Kcnq2G256W/+ mice have reduced KCNQ2 protein levels, epilepsy, brain hyperactivity, and premature deaths. As seen in the patient study, ezogabine treatment rescued seizures in mice, suggesting a potential treatment avenue. These findings provide important insights into KCNQ2-related epilepsy and highlight possible therapeutic strategies. Supported by ORIP (U54OD020351, S10OD026804, U54OD030187), NCI, NHLBI, NICHD, NIGMS, NIMH, and NINDS.
Matrikine Stimulation of Equine Synovial Fibroblasts and Chondrocytes Results in an In Vitro Osteoarthritis Phenotype
Gagliardi et al., Journal of Orthopaedic Research. 2025.
https://pubmed.ncbi.nlm.nih.gov/39486895
Advancements in therapy development for osteoarthritis (OA) currently are limited due to a lack of physiologically relevant in vitro models. This study aimed to understand the effect of matrikine stimulation, using human recombinant fibronectin fragment containing domains 7–10 (FN7–10), on equine synovial fibroblasts and chondrocytes. Inflammatory cytokines, chemokines, and matrix degradation genes in equine synovial fibroblasts and chondrocytes were significantly altered in response to FN7–10 stimulation; marked upregulation was observed in interleukin-6 (IL-6), IL-4, IL-10, matrix metalloproteinase 1 (MMP1), MMP3, MMP13, CCL2/MCP1, and CXCL6/GCP-2 gene expression. Only IL-6 protein production was significantly increased in media isolated from cells stimulated with FN7–10. These results support the potential use of equine synovial fibroblasts and chondrocytes—employing FN7–10—as representative in vitro models to study OA. Supported by ORIP (T32OD011130) and NIAMS.
The Buoyancy of Cryptococcal Cells and Its Implications for Transport and Persistence of Cryptococcus in Aqueous Environments
Jimenez et al., mSphere. 2024.
https://pubmed.ncbi.nlm.nih.gov/39601568/
Cryptococcosis is a major fungal pathogen that causes life-threatening infections. Researchers discovered that Cryptococcus has unique buoyancy properties that help with its survival and spread through water transport. This study explores how these fungal cells remain suspended in liquid, potentially enhancing their ability to survive in their surroundings and infect new hosts. Understanding the role of cellular buoyancy in Cryptococcus transport could improve strategies to prevent spread in aqueous settings, offering new insights into fungal infection risks. Supported by ORIP (T32OD011089), NIAID, and NHLBI.
Transcriptomic and Genetic Profiling in a Spontaneous Non-Human Primate Model of Hypertrophic Cardiomyopathy and Sudden Cardiac Death
Rivas et al., Scientific Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/39733099/
Approximately 1 in 500 individuals are affected by hypertrophic cardiomyopathy (HCM). HCM is characterized by increased left ventricular wall thickness, diastolic dysfunction, and myocardial fibrosis. Outcomes of HCM range from arrhythmias and thromboembolic complications to sudden cardiac death. A current knowledge gap is in understanding the genetic cause of HCM. Researchers compared a nonhuman primate rhesus macaque HCM model to an adult human cohort data set and found that they shared 215 upregulated differentially expressed genes (DEGs); 40 downregulated DEGs; and enriched gene ontology terms, including cardiac muscle cell contraction and heart contraction. The molecular similarity in transcriptomic signatures could be used to develop novel drug therapies to treat HCM in patients. Supported by ORIP (P51OD011107, T32OD011147), NCATS, and NHLBI.
SREBP-Dependent Regulation of Lipid Homeostasis Is Required for Progression and Growth of Pancreatic Ductal Adenocarcinoma
Ishida et al., Cancer Research Communications. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11444119
Lipids are crucial for tumor cell proliferation, and sterol regulatory element-binding protein (SREBP) activation drives lipid synthesis and uptake to maintain cancer growth. This study investigated the role of the SREBP pathway and its regulator, SREBP cleavage–activating protein (SCAP), in lipid metabolism during the development and progression of pancreatic ductal adenocarcinoma (PDAC). Using female mouse xenograft models and male and female pancreas-specific Scap knockout transgenic mice, researchers demonstrated that SCAP is essential for PDAC progression in low-nutrient conditions, linking lipid metabolism to tumor growth. These findings highlight SREBP as a key therapeutic target for PDAC, offering potential strategies for improving treatment by disrupting cancer-associated metabolic reprogramming. Supported by ORIP (T32OD011089), NCI, NHLBI, and NIGMS.