Selected Grantee Publications
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- 49 results found
- Aquatic Vertebrate Models
- Other Animal Models
- Genetics
Effect of Omeprazole on Esophageal Microbiota in Dogs Detected Using a Minimally Invasive Sampling Method
Handa et al., Journal of Veterinary Internal Medicine. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11864821
Omeprazole alters the esophageal microbiome (EM) of humans and has associated effects. The changes and subsequent recovery of the EM in 3- to 6-year-old dogs after omeprazole treatment were assessed using the esophageal string test (EST). All 10 dogs tolerated the EST without adverse effects, and the EST retrieved sufficient biofluid to characterize the EM. Diversity analysis revealed no significant alterations in alpha (Observed species, Shannon and Simpson indices) and beta diversity (Bray‐Curtis) across the time points after omeprazole administration. Thus, omeprazole therapy was not observed to alter the EM of healthy dogs in this study. The application of EST in dogs illustrates its use as a minimally invasive tool for investigating the role of EM in esophageal health and disease in dogs. Supported by ORIP (K01OD030515).
De Novo and Inherited Variants in DDX39B Cause a Novel Neurodevelopmental Syndrome
Booth et al., Brain. 2025.
https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awaf035/8004980?login=true
DDX39B is a core component of the TRanscription-EXport (TREX) super protein complex. Recent studies have highlighted the important role of TREX subunits in neurodevelopmental disorders. Researchers describe a cohort of six individuals (male and female) from five families with disease-causing de novo missense variants or inherited splice-altering variants in DDX39B. Three individuals in the cohort are affected by mild to severe developmental delay, hypotonia, history of epilepsy or seizure, short stature, skeletal abnormalities, variable dysmorphic features, and microcephaly. Using a combination of patient genomic and transcriptomic data, in silico modeling, in vitro assays, and in vivo Drosophila and zebrafish models, this study implicates disruption of DDX39B in a novel neurodevelopmental disorder called TREX-complex-related neurodevelopmental syndrome. Supported by ORIP (U54OD030165).
Differentiation Success of Reprogrammed Cells Is Heterogeneous In Vivo and Modulated by Somatic Cell Identity Memory
Zikmund et al., Stem Cell Reports. 2025.
https://pubmed.ncbi.nlm.nih.gov/40086446
Nuclear reprogramming can change cellular fates, yet reprogramming efficiency is low, and the resulting cell types are often not functional. Researchers used nuclear transfer to Xenopus eggs to follow single cells during reprogramming in vivo. Results showed that the differentiation success of reprogrammed cells varies across cell types and depends on the expression of genes specific to the previous cellular identity. Subsets of reprogramming-resistant cells fail to form functional cell types and undergo cell death or disrupt normal body patterning. Reducing expression levels of genes specific to the cell type of origin leads to better reprogramming and improved differentiation trajectories. This study demonstrates that failing to reprogram in vivo is cell type specific and emphasizes the necessity of minimizing aberrant transcripts of the previous somatic identity for improving reprogramming. Supported by ORIP (R24OD031956).
Enhanced RNA-Targeting CRISPR-Cas Technology in Zebrafish
Moreno-Sánchez et al., Nature Communications. 2025.
https://pubmed.ncbi.nlm.nih.gov/40091120
CRISPR-Cas13 RNA-targeting systems, widely used in basic and applied sciences, have generated controversy because of collateral activity in mammalian cells and mouse models. In this study, researchers optimized transient formulations as ribonucleoprotein complexes or mRNA-gRNA combinations to enhance the CRISPR-RfxCas13d system in zebrafish. Researchers used chemically modified gRNAs to allow more penetrant loss-of-function phenotypes, improve nuclear RNA targeting, and compare different computational models to determine the most accurate prediction of gRNA activity in vivo. Results demonstrate that transient CRISPR-RfxCas13d can effectively deplete endogenous mRNAs in zebrafish embryos without inducing collateral effects, except when targeting extremely abundant and ectopic RNAs. Their findings contribute to CRISPR-Cas technology optimization for RNA targeting in zebrafish through transient approaches and advance in vivo applications. Supported by ORIP (R21OD034161), NICHD, and NIGMS.
Spatiotemporal Characterization of Cyclooxygenase Pathway Enzymes During Vertebrate Embryonic Development
Leathers et al., Developmental Biology. 2025.
https://pubmed.ncbi.nlm.nih.gov/39581452/
The cyclooxygenase (COX) pathway plays a fundamental role in embryonic development. Disruptions of the COX pathway during pregnancy cause developmental anomalies, including craniofacial clefts, impaired gut innervation, and neural tube defects in the embryo. Researchers used Gallus gallus embryos to study the expression of COX pathway enzymes during neurulation. COX-1 protein expression was upregulated in cells undergoing mitosis, whereas COX-2 protein expression was ubiquitous. This study provides spatiotemporal expression data of COX pathway enzymes at key embryonic development stages in G. gallus and guides future studies focused on defining the role of these enzymes during embryonic development. Supported by ORIP (T35OD010956), NEI, NIDCR, and NIGMS.
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.
Stat3 Mediates Fyn Kinase-Driven Dopaminergic Neurodegeneration and Microglia Activation
Siddiqui et al., Disease Models & Mechanisms. 2024.
https://pubmed.ncbi.nlm.nih.gov/39641161
The FYN gene is a risk locus for Alzheimer’s disease and several other neurodegenerative disorders. FYN encodes Fyn kinase, and previous studies have shown that Fyn signaling in dopaminergic neurons and microglia plays a role during neurodegeneration. This study investigated Fyn signaling using zebrafish that express a constitutively active Fyn Y531F mutant in neural cells. Activated neural Fyn signaling in the mutant animals resulted in dopaminergic neuron loss and induced inflammatory cytokine expression when compared with controls. Transcriptomic and chemical inhibition analyses revealed that Fyn-driven changes were dependent on the Stat3 and NF-κB signaling pathways, which work synergistically to activate neuronal inflammation and degeneration. This study provides insight into the mechanisms underlying neurodegeneration, identifying Stat3 as a novel effector of Fyn signaling and a potential translational target. Supported by ORIP (R24OD020166).
Proinflammatory Cytokines Suppress Stemness-Related Properties and Expression of Tight Junction in Canine Intestinal Organoids
Nakazawa et al., In Vitro Cellular & Developmental Biology—Animal. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11419940
Cells in the gastrointestinal tract are exposed to numerous stressors that can promote excessive inflammation, including environmental chemicals and dietary substances. Researchers studied how canine intestinal epithelial cell (IEC)–derived organoids responded to exposure to one of three proinflammatory cytokines; interferon-γ (IFN-γ), tumor necrosis factor-α (TNFα), or interleukin-1β (IL1β). Exposure to IFN-γ resulted in downregulation of the stem cell marker Lgr5. Only IFN-γ exposure resulted in increased production of caspase 3 and caspase 8. Exposure to either IFN-γ or IL1β resulted in suppressed cell proliferation. The pro-inflammatory cytokines caused reduced tight junction protein expression and compromised membrane integrity. These findings are important to understanding IEC response to different inflammatory stimuli and to broadening knowledge of gut physiology. Supported by ORIP (K01OD030515, R21OD031903).
Establishment and Characterization of Three Human Ocular Adnexal Sebaceous Carcinoma Cell Lines
Lee et al., International Journal of Molecular Sciences. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11432008
Researchers established three new cell lines to model ocular adnexal sebaceous carcinoma (SebCA) and test new therapies. SebCA is a highly problematic periorbital tumor requiring aggressive surgical treatment, and its pathobiology remains poorly understood. With consent from one male and two female patients, tumor tissue was cultured under conditional reprograming, and the cells were analyzed for growth, clonogenicity, apoptosis, and differentiation using methods including western blotting, short tandem repeat profiling, and next-generation sequencing. These newly developed cell lines provide valuable preclinical models for understanding and treating SebCA. Supported by ORIP (K01OD034451).
Temperature-Dependent Alterations in the Proteome of the Emergent Fish Pathogen Edwardsiella piscicida
Jacobsen et al., Journal of Fish Diseases. 2024.
https://pubmed.ncbi.nlm.nih.gov/39304982
Reported outbreaks of Edwardsiella piscicida, a bacterial pathogen among cultured and wild fish, have been steadily increasing over the past decade in tandem with climate change–mediated increases in water temperatures. The capacity for this increasingly prevalent fish pathogen to infect and cause disease in mammals is important to understand. Researchers examined the role of temperature on the virulence of E. piscicida to understand its pathogenesis in the context of climate warming trends and better understand its zoonotic potential. Findings revealed downregulation of virulence-related proteins, such as flagellar and Type VI secretion system proteins, at colder temperatures. These findings highlight the potential environmental factors influencing the pathogen’s threat to aquaculture and public health. Supported by ORIP (S10OD026918, T32OD011147).