Selected Grantee Publications
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.
Large Animal Models Enhance the Study of Crypt-Mediated Epithelial Recovery From Prolonged Intestinal Ischemia Reperfusion Injury
McKinney-Aguirre et al., American Journal of Physiology-Gastrointestinal and Liver Physiology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39404771/
Intestinal ischemia and reperfusion injury (IRI) is a severe pathological alteration that compromises the intestinal epithelial barrier, causing bacterial translocation, shock, sepsis, and potentially death. Preclinical research for IRI has focused on utilizing murine models, but mice demonstrate key anatomical and physiological intestinal differences from humans, such as tissue enzymes, intestinal permeability, and hypoxic response pathways. The researchers compared a 3-hour IRI porcine model to a 3-hour IRI murine model to reveal which demonstrated a stronger translational capacity. Both models demonstrated crypt damage, but only the porcine model showed recovery-associated crypt death expansion and re-epithelialization. At 72 hours post-IRI, mouse mortality was 84.6%, whereas porcine mortality was 0%. A porcine model would be more reliable for future translational studies focused on understanding IRI mechanisms for diagnosis and therapy advancements. Supported by ORIP (T32OD011130, K01OD010199, R03OD026598) and NIDDK.
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).
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).
Deletion of Mouse Lysyl Oxidase in Megakaryocytes Affects Bone Properties in a Sex-Dependent Manner
Karagianni, Cell. 2024.
https://pubmed.ncbi.nlm.nih.gov/38635757/
Lysyl oxidase (LOX) is a facilitator of extracellular matrix cross-linking, and the importance of LOX in bone formation has been addressed in both in vitro and in vivo studies. Using newly developed megakaryocyte-specific LOX knockout mice, the researchers show that LOX expressed in these scarce bone marrow cells leads to changes in bone volume and mechanical strength in male mice; however, no significant changes were observed within the female experimental groups. The authors’ findings suggest that sex hormones could contribute to differences within these dynamics. Supported by ORIP (K01OD025290) and NIAMS.
Acquired Dysfunction of CFTR Underlies Cystic Fibrosis-Like Disease of the Canine Gallbladder
Gookin et al., American Journal of Physiology-Gastrointestinal and Liver Physiology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39041675/
Mucocele formation in dogs is pathologically similar to cystic fibrosis. In this study, researchers investigated the role of cystic fibrosis transmembrane conductance regulator (CFTR) in the pathogenesis of the disease. They determined the location and frequency of disease-associated variants in the coding region of CFTR using whole-genome sequence data from 2,642 dogs representing breeds at low risk, high risk, or with confirmed disease. The authors’ findings establish significant loss of CFTR-dependent anion secretion by mucocele gallbladder mucosa. There were no significant differences in CFTR gene variant frequency, type, or predicted impact comparing low-risk, high-risk, and definitively diagnosed groups of dogs. Their results suggest a disease of the canine gallbladder that is similar to cystic fibrosis and is driven by CFTR dysfunction. Supported by ORIP (T35OD011070, K01OD027058).
Functional and Structural Basis of Human Parainfluenza Virus Type 3 Neutralization With Human Monoclonal Antibodies
Suryadevara et al., Nature Microbiology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38858594
Human parainfluenza virus type 3 (hPIV3) can cause severe disease in older people and infants, and the haemagglutinin-neuraminidase (HN) and fusion (F) surface glycoproteins of hPIV3 are major antigenic determinants. Researchers isolated seven neutralizing HN-reactive antibodies and a pre-fusion conformation F-reactive antibody from human memory B cells. They also delineated the structural basis of neutralization for HN and F monoclonal antibodies (mAbs). Rats were protected against infection and disease in vivo by mAbs that neutralized hPIV3 in vitro. This work establishes correlates of protection for hPIV3 and highlights the potential clinical utility of mAbs. Supported by ORIP (K01OD036063), NIAID, and NIGMS.
Isolation of Human Antibodies Against Influenza B Neuraminidase and Mechanisms of Protection at the Airway Interface
Wolters et al., Immunity. 2024.
https://pubmed.ncbi.nlm.nih.gov/38823390
In this report, researchers describe the isolation of human monoclonal antibodies (mAbs) that recognized the influenza B virus (IBV) neuraminidase (NA) glycoprotein from an individual following seasonal vaccination. Their work suggests that the antibodies recognized two major antigenic sites. The first group included mAb FluB-393, and the second group contained an active site mAb, FluB-400. Their findings can help inform the mechanistic understanding of the human immune response to the IBV NA glycoprotein through the demonstration of two mAb delivery routes for protection against IBV and the identification of potential IBV therapeutic candidates. Supported by ORIP (K01OD036063) and NIGMS.