Selected Grantee Publications
- Clear All
- 14 results found
- Other Animal Models
- 2024
- 2020
Extracted Plasma Cell-Free DNA Concentrations Are Elevated in Colic Patients With Systemic Inflammation
Bayless et al., Veterinary Sciences. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11435807
Researchers investigated cell-free DNA (cfDNA) as a potential biomarker to detect colic in humans. In horses, colic is a life-threatening gastrointestinal (GI) condition. Measurements of cfDNA released from damaged or dying cells in the blood of male and female horses with colic were compared across groups based on GI disease type, signs of inflammation, and survival status. Elevated cfDNA levels were prominent in horses with systemic inflammation, but did not significantly differ by GI disease type or survival. This study suggests that cfDNA may be linked to inflammatory responses in colic conditions. Supported by ORIP (T32OD011130).
A Comparative Review of Cytokines and Cytokine Targeting in Sepsis: From Humans to Horses
Hobbs et al., Cells. 2024.
https://pubmed.ncbi.nlm.nih.gov/39273060
Bacterial infections resulting in endotoxin or exotoxin exposure can lead to sepsis because of dysregulated host responses. Sepsis causes organ dysfunction that can lead to death if not treated immediately, yet no proven pharmacological treatments exist. Horses can serve as a comparative and translational model for sepsis in humans because both species share mechanisms of immune response, including severe neutropenia, cytokine storms, formation of neutrophil extracellular traps, and decreased perfusion. Research on sepsis has focused on the pathophysiological role of interleukin-6, interleukin-1β, tumor necrosis factor-α, and interleukin10. Research on novel sepsis therapies has focused on monoclonal antibodies, cytokine antagonists, and cytokine removal through extracorporeal hemoperfusion. Future sepsis research should focus on optimizing therapeutic strategies of cytokine modulation and analyzing the underlying mechanisms of cytokine dysregulation. Supported by ORIP (T32OD011130).
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).
The Splicing Factor hnRNPL Demonstrates Conserved Myocardial Regulation Across Species and Is Altered in Heart Failure
Draper et al., FEBS Letters. 2024.
https://pubmed.ncbi.nlm.nih.gov/39300280/
The 5-year mortality rate of heart failure (HF) is approximately 50%. Gene splicing, induced by splice factors, is a post-transcriptional modification of mRNA that may regulate pathological remodeling in HF. Researchers investigated the role of the splice factor heterogenous nuclear ribonucleoprotein-L (hnRNPL) in cardiomyopathy. hnRNPL protein expression is significantly increased in a male C57BL/6 transaortic constriction–induced HF mouse model and in clinical samples derived from canine or human HF patients. Cardiac-restricted knockdown of the hnRNPL homolog in Drosophila revealed systolic dysfunction and reduced life span. This study demonstrates a conserved cross-species role of hnRNPL in regulating heart function. Supported by ORIP (K01OD028205) and NHLBI.
Identifying Mitigating Strategies for Endothelial Cell Dysfunction and Hypertension in Response to VEGF Receptor Inhibitors
Camarda et al., Clinical Science. 2024.
https://pubmed.ncbi.nlm.nih.gov/39282930/
Vascular endothelial growth factor receptor inhibitor (VEGFRi) use can improve survival in patients with advanced solid tumors, but outcomes can worsen because of VEGFRi-induced hypertension, which can increase the risk of cardiovascular mortality. The underlying pathological mechanism is attributed to endothelial cell (EC) dysfunction. The researchers performed phosphoproteomic profiling on human ECs and identified α-adrenergic blockers, specifically doxazosin, as candidates to oppose the VEGFRi proteomic signature and inhibit EC dysfunction. In vitro testing of doxazosin with mouse, canine, and human aortic ECs demonstrated EC-protective effects. In a male C57BL/6J mouse model with VEGFRi-induced hypertension, it was demonstrated that doxazosin prevents EC dysfunction without decreasing blood pressure. In canine cancer patients, both doxazosin and lisinopril improve VEGFRi-induced hypertension. This study demonstrates the use of phosphoproteomic screening to identify EC-protective agents to mitigate cardio-oncology side effects. Supported by ORIP (K01OD028205), NCI, NHGRI, and NIGMS.
Enterohemorrhagic Escherichia coli (EHEC) Disrupts Intestinal Barrier Integrity in Translational Canine Stem Cell-Derived Monolayers
Nagao et al., Microbiology Spectrum. 2024.
https://pubmed.ncbi.nlm.nih.gov/39162490/
EHEC produces Shiga toxin, which causes acute colitis with symptoms such as hemolytic uremic syndrome and bloody diarrhea. The researchers developed a colonoid-derived monolayer model to understand EHEC’s impact on canine gut health. Colonoid-derived monolayers co-cultured with EHEC demonstrated key differences compared with the control and nonpathogenic E. coli co-cultures. Scanning electron microscopy displayed EHEC aggregated and attached to the microvilli. EHEC-infected monolayers demonstrated significantly weakened membrane integrity and increased inflammatory cytokine production, specifically TNFα. The researchers developed a novel in vitro model that offers an additional platform for understanding the mechanisms of EHEC pathogenicity, developing therapeutics for EHEC, and studying additional enteric pathogens. Supported by ORIP (K01OD030515, R21OD031903).
A Review of CD4+ T Cell Differentiation and Diversity in Dogs
Lang et al., Veterinary Immunology and Immunopathology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39173398
CD4+ T cells are an important component of both the adaptive immune response and immune maintenance. They carry out many functions and can differentiate into numerous specialized subsets, including T helper type 1 (TH1), TH2, TH9, TH17, and TH22 cells; regulatory T cells; and follicular T helper cells. CD4+ T cells also have the capacity for long-term immunological memory and rapid reactivation upon secondary exposure. However, our understanding of the role of CD4+ T cells in immune response is largely based on studies in mice, humans, and—to a lesser extent—pigs. Comparatively, our understanding of CD4+ T cells in canines is much less complete. This review summarizes the current understanding of canine CD4+ T cells from a comparative perspective by highlighting both the similarities and differences from mouse, human, and pig CD4+ T-cell biology. Supported by ORIP (K01OD027058).
Alterations in Tumor Aggression Following Androgen Receptor Signaling Restoration in Canine Prostate Cancer Cell Lines
Vasilatis et al., International Journal of Molecular Sciences. 2024.
https://pubmed.ncbi.nlm.nih.gov/39201315
Prostate cancer (PCa) ranks second worldwide in cancer-related mortality, but only a few animal models exhibit naturally occurring PCa that recapitulates the symptoms of the disease. Neutered dogs have an increased risk of PCa and often lack androgen receptor (AR) signaling, which is involved in upregulating tumorigenesis but can also suppress aggressive cell growth. In this study, researchers sought to understand more about the role of AR signaling in canine PCa initiation and progression by restoring AR in canine PCa cell lines and treating them with dihydrotestosterone. One cell line exhibited AR-mediated tumor suppression; one cell line showed altered proliferation (but not migration or invasion); and a third cell line exhibited AR-mediated alterations in migration and invasion (but not proliferation). The study highlights the heterogeneous nature of PCa in dogs and humans but suggests that AR signaling might have therapeutic potential under certain conditions. Supported by ORIP (T32OD011147).
Canine RNF170 Single Base Deletion in a Naturally Occurring Model for Human Neuroaxonal Dystrophy
Cook et al., Movement Disorders. 2024.
https://pubmed.ncbi.nlm.nih.gov/39177409/
A newly recognized progressive neurodegenerative disorder in Miniature American Shepherd (MAS) dogs affects gait in young adult dogs and is characterized by pelvic limb weakness and ataxia. The authors of this study used genetic analysis to map the underlying cause of the disorder, a single base-pair deletion in the ring finger protein 170 (RNF170) gene that was predicted to cause early truncation of the RNF170 protein. RNF170 variants previously were identified in human patients with spastic paraplegia-85 (SPG85) who exhibit similar clinical and pathological phenotypes to RNF170-mutant dogs. SPG85 belongs to a group of inherited neurodegenerative disorders collectively referred to as neuroaxonal dystrophy (NAD). The authors of this paper propose that RNF170-mutant MAS dogs serve as a large animal model to study underlying mechanisms and therapeutics for NAD. Supported by ORIP (K01OD027051).