Selected Grantee Publications
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- 166 results found
- Rodent Models
- Swine Models
p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy
Faget et al., Cancer Discovery. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238649/
This study emphasizes the importance of the metastatic tumor microenvironment in metastatic breast cancer growth and the identification of effective antimetastatic therapies. Using a stromal labeling approach and single-cell RNA sequencing, the authors showed that a combination of p38MAPK inhibition (p38i) and anti-OX40 synergistically reduced metastatic tumor growth and increased overall survival. Further engagement of cytotoxic T cells cured all metastatic disease in mice and produced durable immunologic memory. The Cancer Genome Atlas data analysis revealed that patients with p38i metastatic stromal signature and a high tumor mutational burden (TMB) had increased overall survival. These findings suggest that patients with high TMB would benefit the most from the p38i plus anti-OX40 approach. Supported by ORIP (S10OD028483), NIA, NCI, and NIGMS.
Simultaneous Evaluation of Treatment Efficacy and Toxicity for Bispecific T-Cell Engager Therapeutics in a Humanized Mouse Model
Yang et al., The FASEB Journal. 2023.
https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202300040R
Immuno-oncology–based therapies are an evolving powerful treatment strategy that targets the immune system and harnesses it to kill tumor cells directly. Investigators describe the novel application of a humanized mouse model that can simultaneously evaluate the efficacy of bispecific T cell engagers to control tumor burden and the development of cytokine release syndrome. The model also captures variability in responses for individual patients. Supported by ORIP (R24OD026440), NIAID, NCI, and NIDDK.
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.
Innate Lymphoid Cells and Interferons Limit Neurologic and Articular Complications of Brucellosis
Moley et al., American Journal of Pathology. 2023.
https://www.sciencedirect.com/science/article/pii/S0002944023001980?via%3Dihub=
Brucellosis is a globally significant zoonotic disease. The current study investigated the role of innate lymphoid cells (ILCs) in the pathogenesis of focal brucellosis caused by Brucella melitensis. Following pulmonary infection with B. melitensis, mice lacking adaptive immune cells and ILCs developed arthritis, neurologic complications, and meningitis. Transcriptional analysis of Brucella-infected brains revealed marked upregulation of genes associated with inflammation and interferon responses. Collectively, these findings indicate that ILCs and interferons play an important role in prevention of focal complications during Brucella infection and that mice with deficiencies in ILCs or interferons can be used to study pathogenesis of neurobrucellosis. Supported by ORIP (T32OD011126) and NIAID.
Using Mass Spectrometry Imaging to Map Fluxes Quantitatively in the Tumor Ecosystem
Schwaiger-Haber et al., Nature Communications. 2023.
https://pubmed.ncbi.nlm.nih.gov/37208361/
Mass spectrometry imaging (MSI) can be used to identify metabolic patterns within different microenvironments of tumors but has not been fully integrated into metabolomics workflows. Investigators developed an integrated approach by combining MSI, stable isotope labeling, and a spatial variant of Isotopologue Spectral Analysis to study metabolic pathways across the brains of mice harboring GL261 glioma, a mouse model for glioblastoma. This study reveals the importance of multiple anabolic pathways, including fatty acid elongation flux, in glioma. Supported by ORIP (R24OD024624).
Therapeutic Blocking of VEGF Binding to Neuropilin-2 Diminishes PD-L1 Expression to Activate Antitumor Immunity in Prostate Cancer
Wang et al., Science Translational Medicine. 2023.
Prostate cancers often escape immune detection and destruction. Investigators report that neuropilin-2 (NRP2), which functions as a vascular endothelial growth factor (VEGF) receptor on tumor cells, is an attractive target to activate antitumor immunity in prostate cancer. They found that NRP2 depletion increased T cell activation in vitro. Additionally, inhibition of the binding of VEGF to NRP2 using a mouse-specific anti-NRP2 monoclonal antibody resulted in necrosis and tumor regression. These findings provide justification for the initiation of clinical trials using this function-blocking antibody in treatment of prostate cancer, especially for patients with aggressive disease. Supported by ORIP (R24OD026440) and NCI.
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.
Resolution of Structural Variation in Diverse Mouse Genomes Reveals Chromatin Remodeling due to Transposable Elements
Ferraj et al., Cell Genomics. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10203049/
Diverse inbred mouse strains are important biomedical research models, yet genome characterization of many strains is fundamentally lacking in comparison with humans. Here, investigators used long-read whole genome sequencing to assemble the genomes of 20 diverse inbred laboratory strains of mice. From whole-genome comparisons, they generated a sequence-resolved callset of 413,758 structural variants. These data are presented as a comprehensive resource that can be used for future genomic studies, aid in modeling and studying the effects of genetic variation, and enhance genotype-to-phenotype research. Supported by ORIP (R24OD021325), NCI, NIGMS, and NHGRI.
Topologically Associating Domain Boundaries Are Required for Normal Genome Function
Rajderkar et al., Communications Biology. 2023.
https://www.nature.com/articles/s42003-023-04819-w
Eukaryotic genomes fold into topologically associating domains (TADs), sub-megabase-scale chromatin segments characterized by high intra-domain chromatin contact frequency. Investigators selected eight independent TAD boundaries in the vicinity of genes active during embryonic development, individually deleted these boundaries from the mouse genome, and systematically examined the consequences on survival, genome organization, gene expression, and development. Results of the studies demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to consider the potential pathogenicity of deletions affecting TAD boundaries in clinical genetics screening. Supported by ORIP (UM1OD023221), NIGMS, and NHGRI.