Selected Grantee Publications
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- 16 results found
- Cancer
- COVID-19/Coronavirus
- Imaging
Characterization of Collaborative Cross Mouse Founder Strain CAST/EiJ as a Novel Model for Lethal COVID-19
Baker et al., Scientific Reports. 2024.
https://www.nature.com/articles/s41598-024-77087-1
Researchers characterized the Collaborative Cross (CC) mouse model founder strain CAST/EiJ as a novel model for severe COVID-19, exhibiting high viral loads and mortality. By leveraging genetically diverse CC strains, this study identified variations in susceptibility and survival against SARS-CoV-2 variants. CAST/EiJ mice developed lung pathology and mortality despite antiviral defenses, making them a valuable tool for understanding host–pathogen interactions. The findings emphasize the utility of diverse animal models in uncovering genetic and immunological factors that influence disease outcomes, facilitating the development of targeted therapies against COVID-19 to mitigate future pandemics. Supported by ORIP (P40OD011102).
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.
AAV5 Delivery of CRISPR/Cas9 Mediates Genome Editing in the Lungs of Young Rhesus Monkeys
Liang et al., Human Gene Therapy. 2024.
https://pubmed.ncbi.nlm.nih.gov/38767512/
Genome editing in somatic cells and tissues has the potential to provide long-term expression of therapeutic proteins to treat a variety of genetic lung disorders. However, delivering genome-editing machinery to disease-relevant cell types in the lungs of primates has remained a challenge. Investigators of this article are participating in the NIH Somatic Cell Genome Editing Consortium. Herein, they demonstrate that intratracheal administration of a dual adeno-associated virus type 5 vector encoding CRISPR/Cas9 can mediate genome editing in rhesus (male and female) airways. Up to 8% editing was observed in lung lobes, including a housekeeping gene, GAPDH, and a disease-related gene, angiotensin-converting enzyme 2. Using single-nucleus RNA-sequencing, investigators systematically characterized cell types transduced by the vector. Supported by ORIP (P51OD01110, U42OD027094, S10OD028713), NCATS, NCI, and NHLBI.
Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy
Racine et al., Journal of Immunology. 2024.
Myocarditis has emerged as a relatively rare but often lethal autoimmune complication of checkpoint inhibitor (ICI) cancer therapy, and significant mortality is associated with this phenomenon. Investigators developed a new mouse model system that spontaneously develops myocarditis. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, the treatment accelerates skeletal muscle myositis. The team performed characterization of cardiac and skeletal muscle T cells using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies. Supported by ORIP (U54OD020351, U54OD030187), NCI, NIA, NIDDK, and NIGMS.
Proof-of-Concept Studies With a Computationally Designed Mpro Inhibitor as a Synergistic Combination Regimen Alternative to Paxlovid
Papini et al., PNAS. 2024.
As the spread and evolution of SARS-CoV-2 continues, it is important to continue to not only work to prevent transmission but to develop improved antiviral treatments as well. The SARS-CoV-2 main protease (Mpro) has been established as a prominent druggable target. In the current study, investigators evaluate Mpro61 as a lead compound, utilizing structural studies, in vitro pharmacological profiling to examine possible off-target effects and toxicity, cellular studies, and testing in a male and female mouse model for SARS-CoV-2 infection. Results indicate favorable pharmacological properties, efficacy, and drug synergy, as well as complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate. Supported by ORIP (R24OD026440, S10OD021527), NIAID, and NIGMS.
Tumor Explants Elucidate a Cascade of Paracrine SHH, WNT, and VEGF Signals Driving Pancreatic Cancer Angiosuppression
Hasselluhn et al., Cancer Discovery. 2024.
https://pubmed.ncbi.nlm.nih.gov/37966260/
This study presents a key mechanism that prevents pancreatic ductal adenocarcinoma (PDAC) from undergoing neoangiogenesis, which affects its development, pathophysiology, metabolism, and treatment response. Using human and murine PDAC explants, which effectively retain the complex cellular interactions of native tumor tissues, and single-cell regulatory network analysis, the study identified a cascade of three paracrine pathways bridging between multiple cell types and acting sequentially, Hedgehog to WNT to VEGF, as a key suppressor of angiogenesis in KRAS-mutant PDAC cells. This study provides an experimental paradigm for dissecting higher-order cellular interactions in tissues and has implications for PDAC treatment strategies. Supported by ORIP (S10OD012351, S10OD021764), NCI, and NIDDK.
Epigenetic MLH1 Silencing Concurs With Mismatch Repair Deficiency in Sporadic, Naturally Occurring Colorectal Cancer in Rhesus Macaques
Deycmar et al., Journal of Translational Medicine. 2024.
https://pubmed.ncbi.nlm.nih.gov/38504345
Rhesus macaques serve as a useful model for colorectal cancer (CRC) in humans, but more data are needed to understand the molecular pathogenesis of these cancers. Using male and female rhesus macaques, researchers investigated mismatch repair status, microsatellite instability, genetic mutations, transcriptional differences, and epigenetic alterations associated with CRC. Their data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. This work provides a uniquely informative model for human CRC. Supported by ORIP (P51OD011092, R24OD010947, R24OD021324, P40OD012217, U42OD010426, T35OD010946, T32OD010957), NCATS, and NCI.
First-in-Human ImmunoPET Imaging of COVID-19 Convalescent Patients Using Dynamic Total-Body PET and a CD8-Targeted Minibody
Omidvari et al., Science Advances. 2023.
https://pubmed.ncbi.nlm.nih.gov/36993568/
Developing noninvasive methods for in vivo quantification of T cell distribution and kinetics is important because most T cells reside in the tissue. Investigators presented the first use of dynamic positron emission tomography (PET) and kinetic modeling for in vivo measurement of CD8+ T cell distribution in healthy individuals and COVID-19 patients. Kinetic modeling results aligned with the expected T cell trafficking effects. Tissue-to-blood ratios were consistent with modeled net influx rates and flow cytometry analysis. These results provide a promising platform for using dynamic PET to study the total-body immune response and memory. Supported by ORIP (S10OD018223) and NCI.
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).