Selected Grantee Publications
Baseline Tumor Gene Expression Signatures Correlate With Chemoimmunotherapy Treatment Responsiveness in Canine B Cell Lymphoma
Dittrich et al., PLOS ONE. 2023.
https://pubmed.ncbi.nlm.nih.gov/37624862/
Pet dogs develop spontaneous diffuse large B cell lymphoma (DLBCL), and veterinary clinical trials have been employed to treat canine DLBCL and to inform clinical trials for their human companions. Investigators evaluated gene expression in lymph node aspirates from 18 trial dogs and defined good responders as those who relapsed after 90 days, and poor responders as those who relapsed prior to 90 days. They found increased CCND3 correlated with poor prognosis and increased CD36 correlated with good prognosis, as is observed in humans. These findings identify biomarkers that may help guide the choice of chemoimmunotherapy treatment in dogs. Supported by ORIP (K01OD028268) and NCI.
A Gut-Restricted Glutamate Carboxypeptidase II Inhibitor Reduces Monocytic Inflammation and Improves Preclinical Colitis
Peters et al., Science Translational Medicine. 2023.
https://www.science.org/doi/10.1126/scitranslmed.abn7491
Many patients with moderate-to-severe inflammatory bowel disease (IBD) do not have adequate disease control, and glutamate carboxypeptidase II (GCPII) offers a promising target for therapeutic development. Researchers generated a class of GCPII inhibitors. They demonstrated that the inhibitor reduced monocytic inflammation in mice and protected against the loss of barrier integrity in primary human colon epithelial air–liquid interface monolayers. Their findings suggest that local inhibition of GCPII could be applied for the development of IBD therapeutics. Supported by ORIP (K01OD030517, T32OD011089), NIGMS, and NCCIH.
Identification of an Anergic BND Cell–Derived Activated B Cell Population (BND2) in Young-Onset Type 1 Diabetes Patients
Stensland et al., The Journal of Experimental Medicine. 2023.
https://pubmed.ncbi.nlm.nih.gov/37184563/
B cells have been shown to play a role in the pathogenesis of type 1 diabetes (T1D), but the specificity, phenotype, and function of B cells in young-onset T1D is not understood fully. The investigators performed a cross-sectional analysis comparing insulin-reactive to tetanus-reactive B cells in the blood of male and female T1D patients and control participants using mass cytometry. They found elevated insulin-reactive BND2 cells in the blood and pancreatic lymph nodes of young-onset T1D donors. This work suggests that an antigen-specific B cell subset could contribute to the rapid progression of young-onset T1D. Supported by ORIP (K01OD028759) and NIDDK.
Canine Models of Charcot-Marie-Tooth: MTMR2, MPZ, and SH3TC2 Variants in Golden Retrievers With Congenital Hypomyelinating Polyneuropathy
Cook et al., Neuromuscular Disorders. 2023.
https://pubmed.ncbi.nlm.nih.gov/37400349/
Both demyelination and hypomyelination of the nervous system are associated with various clinical diseases. Using whole-genome sequencing, researchers determined the genetic underpinnings of congenital hypomyelinating polyneuropathy in canines of both sexes. These variants genetically describe the first peripheral nervous system–exclusive hypomyelinating polyneuropathies in dogs. By testing for these mutations, breeders can prevent the production of affected offspring. Supported by ORIP (K01OD027051, K01OD027058).
A LGR5 Reporter Pig Model Closely Resembles Human Intestine for Improved Study of Stem Cells in Disease
Schaaf et al., The FASEB Journal. 2023.
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202300223R
The constant epithelial regeneration in the intestine is the sole responsibility of intestinal epithelial stem cells (ISCs), which reside deep in the intestinal crypt structures. To effectively study ISCs, tools to identify this cell population are necessary. This study validates ISC isolation in a new porcine Leucine Rich Repeat Containing G Protein–Coupled Receptor 5 (LGR5) reporter line and demonstrates the use of these pigs as a novel colorectal cancer model. Overall, this novel porcine model provides critical advancement to the field of translational gastrointestinal research. Supported by ORIP (R21OD019738, K01OD019911), NCI, and NIDDK.
Effects of Acute Femoral Head Ischemia on the Growth Plate and Metaphysis in a Piglet Model of Legg-Calvé-Perthes Disease
Armstrong et al., Osteoarthritis and Cartilage. 2023.
https://pubmed.ncbi.nlm.nih.gov/36696941/
Legg-Calvé-Perthes disease (LCPD) can lead to permanent deformity of the femoral head and premature osteoarthritis, but the underlying cause remains unknown. More work is needed to determine optimal treatment methods for LCPD. Using a piglet model for LCPD, researchers assessed the effects of acute femoral head ischemia on the proximal femoral growth plate and metaphysis. They reported that alterations to the growth plate zones and metaphysis occurred by 2 days post-ischemia and persisted at 7 days post-ischemia. These findings suggest that growth disruption may occur sooner after the onset of ischemia than researchers had hypothesized previously. Supported by ORIP (T32OD010993, K01OD021293), NIAMS, and NCATS.
Ion Channel Function in Translational Bovine Gallbladder Cholangiocyte Organoids: Establishment and Characterization of a Novel Model System
Nagao and Ambrosini et al., Frontiers in Veterinary Science. 2023.
https://pubmed.ncbi.nlm.nih.gov/37303723/
The study of biliary physiology and pathophysiology has long been hindered by the lack of in vitro models that accurately reflect the complex functions of the biliary system. Recent advancements in 3D organoid technology may offer a promising solution to this issue. Bovine gallbladder models have recently gained attention in the investigation of human diseases due to their remarkable similarities in physiology and pathophysiology to the human gallbladder. In this study, the investigators successfully established and characterized bovine gallbladder cholangiocyte organoids (GCOs) that retain key characteristics of the gallbladder in vivo, including stem cell properties and proliferative capacity. Notably, their findings demonstrate that these organoids exhibit specific and functional cystic fibrosis transmembrane conductance regulator activity. These bovine GCOs represent a valuable tool for studying the physiology and pathophysiology of the gallbladder with human significance. Supported by ORIP (K01OD030515, R21OD031903).
Effect of Viral Strain and Host Age on Clinical Disease and Viral Replication in Immunocompetent Mouse Models of Chikungunya Encephalomyelitis
Anderson et al., Viruses. 2023.
https://pubmed.ncbi.nlm.nih.gov/37243143/
Chikungunya virus (CHIKV) is associated with neurologic complications, but studies in the central nervous system are challenging to perform in humans. Using a mouse model of both sexes, researchers established the relative severity of neurological disease across multiple stages of neurodevelopment in three strains of CHIKV. The disease was found to be strain dependent, with differences in severity of neurological disease, viral titers in the brain and spinal cord, and proinflammatory gene expression and CD4+ T cell infiltration in the brain. This work provides a mouse model for future studies of CHIKV pathogenesis and the host immune response. Supported by ORIP (K01OD026529), NIAID, and NCI.
Structural Insights Into the Broad Protection Against H1 Influenza Viruses by a Computationally Optimized Hemagglutinin Vaccine
Dzimianski et al., Communications Biology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37185989/
Influenza is an ongoing public health concern, and computationally optimized broadly reactive antigen (COBRA) hemagglutinin proteins represent a potential strategy for formulating broadly effective influenza vaccines. Researchers determined the crystal structure of COBRA P1, as well as its binding to 1F8, a broadly neutralizing antibody. This work provides valuable insights into the underlying molecular basis for the broad effectiveness of P1, and these insights can be applied to future vaccine designs. Supported by ORIP (K01OD026569), NIAID, and NIGMS.
Fc-Mediated Pan-Sarbecovirus Protection After Alphavirus Vector Vaccination
Adams et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37000623/
Group 2B β-coronaviruses (i.e., sarbecoviruses) have resulted in regional and global epidemics. Here, the authors evaluate the mechanisms of cross-sarbecovirus protective immunity using a panel of alphavirus-vectored vaccines covering bat to human strains. They reported that vaccination does not prevent virus replication, but it protects against lethal heterologous disease outcomes in SARS-CoV-2 and clade 2 bat sarbecovirus challenge models. Full-length spike vaccines elicited the broadest pan-sarbecovirus protection. Additionally, antibody-mediated cross-protection was lost in absence of FcR function, supporting a model for non-neutralizing, protective antibodies. Taken together, these findings highlight the value of universal sarbecovirus vaccine designs that couple FcR-mediated cross-protection with potent cross-neutralizing antibody responses. Supported by ORIP (K01OD026529), NIAID, and NCI.