Selected Grantee Publications
- Clear All
- 5 results found
- Rodent Models
- Vaccines/Therapeutics
- 2022
Distinct Sensitivities to SARS-CoV-2 Variants in Vaccinated Humans and Mice
Walls et al., Cell Reports. 2022.
https://www.doi.org/10.1016/j.celrep.2022.111299
Emergence of SARS-CoV-2 variants necessitates real-time evaluation of their impact on serum neutralizing activity, as a proxy for vaccine efficacy, to inform public health policies and guide vaccine development. The investigators report that vaccinated female BALB/c mice do not recapitulate faithfully the breadth and potency of neutralizing antibody responses toward the SARS-CoV-2 Beta and Gamma variants of concern, compared with humans of both sexes and male nonhuman primates (i.e., rhesus and pigtail macaques). This finding was consistent across several vaccine modalities, doses, antigens, and assays, suggesting caution should be exercised when interpreting serum neutralizing data obtained from mice. Supported by ORIP (P51OD010425, U42OD011123) and NIAID.
Sunitinib Inhibits STAT3 Phosphorylation in Cardiac Muscle and Prevents Cardiomyopathy in the mdx Mouse Model of Duchenne Muscular Dystrophy
Oliveira-Santos et al., Human Molecular Genetics. 2022.
https://www.doi.org/10.1093/hmg/ddac042
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy, affecting about 1 in 5,000 boys worldwide. DMD is a fatal X-linked genetic disorder that results from mutations in the dystrophin gene and leads to progressive muscular degeneration. Individuals with DMD often die at a young age from respiratory or heart failure. To date, few studies have examined the basis of cardiac failure associated with DMD, and no effective U.S. Food and Drug Administration (FDA)–approved treatment options are available. Using a mouse model of both sexes, researchers characterized the effectiveness of sunitinib, an FDA-approved small-molecule drug, in preventing DMD-related cardiomyopathy. The treatment reduced STAT3 activation in cardiac muscle and prevented cardiomyopathy disease progression. Inhibition of STAT3 activation in cardiac muscle can reduce inflammation and fibrosis and prevent heart failure. These findings demonstrate sunitinib’s potential as a novel treatment option for skeletal and cardiac muscle dysfunction in patients with DMD. Supported by ORIP (R42OD030543).
Cannabinoid Receptor 1 Antagonist Genistein Attenuates Marijuana-Induced Vascular Inflammation
Wei et al., Cell. 2022.
https://www.doi.org/10.1016/j.cell.2022.04.005
Marijuana use is increasing and is associated with increased risk of cardiovascular disease (CVD); however, the link between marijuana and CVD remains largely unknown. Investigators demonstrated that a psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9‑THC), activates cannabinoid receptor 1 (CB1), causing vascular inflammation, oxidative stress, endothelial dysfunction, and atherosclerosis. This in silico virtual screening study suggested that genistein, a soybean isoflavone, would be a putative CB1 antagonist. Their validation study showed that in male mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. This study for the first time revealed that genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis while preserving clinically useful effects. Supported by ORIP (S10OD030452) and others.
Progression and Resolution of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in Golden Syrian Hamsters
Mulka et al., The American Journal of Pathology. 2022.
https://www.doi.org/10.1016/j.ajpath.2021.10.009
To catalyze SARS-CoV-2 research, disease progression was characterized in a robust model. Male and female golden Syrian hamsters were inoculated intranasally with SARS-CoV-2 to track clinical, pathology, virology, and immunology outcomes. Inoculated animals lost body weight during the first week of infection, had higher lung weights at terminal time points, and developed lung consolidation. At day 7, when the presence of infectious virus was rare, interstitial and alveolar macrophage infiltrates and marked reparative epithelial responses dominated in the lung. These lesions resolved over time. The use of quantitative approaches to measure cellular and morphologic alterations in the lung provides valuable outcome measures for developing therapeutic and preventive interventions for COVID-19. Supported by ORIP (T32OD011089).
AAV5 Delivery of CRISPR-Cas9 Supports Effective Genome Editing in Mouse Lung Airway
Liang et al., Molecular Therapy. 2022.
https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(21)00530-X
Genome editing in the lung has the potential to provide long-term expression of therapeutic protein to treat lung genetic diseases. The authors illustrated that AAV5 can efficiently deliver CRISPR-Cas9 to mouse lung airways and was the first to achieve ∼20% editing efficiency in those airways. Results were confirmed through independent experiments at two different institutes. This highly efficient dual AAV platform will facilitate the study of genome editing in the lung and other tissue types. Supported by ORIP (U42OD026645).