Selected Grantee Publications
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- 172 results found
- Other Animal Models
- Rodent Models
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.
Obesity Alters Pathology and Treatment Response in Inflammatory Disease
Bapat et al., Nature. 2022.
https://www.doi.org/10.1038/s41586-022-04536-0
Obesity and metabolic disease have been shown to affect immunotherapeutic outcomes. By studying classical type 2 T helper cells (TH2) in lean and obese male mouse models for atopic dermatitis, investigators found that the biologic therapies protected lean mice but exacerbated disease in obese mice. RNA sequencing and genome analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells in obese mice when compared to lean mice, indicating that PPARγ is required to prevent aberrant non-TH2 inflammation. Understanding the effects of obesity on immunological disease could inform a potential precision medicine approach to target obesity-induced immune dysregulation. Supported by ORIP (S10OD023689), NIAID, NCI, NIDDK, and NIGMS.
American Alligators Are Capable of West Nile Virus Amplification, Mosquito Infection and Transmission
Byas et al., Virology. 2022.
https://www.doi.org/10.1016/j.virol.2022.01.009
West Nile virus (WNV) overwintering is poorly understood and likely multifactorial. Interest in alligators as a potential amplifying host arose when it was shown that they develop viremias theoretically sufficient to infect mosquitoes. Researchers examined potential ways in which alligators may contribute to the natural ecology of WNV. They experimentally demonstrated that alligators are capable of WNV amplification with subsequent mosquito infection and transmission capability, that WNV-infected mosquitoes readily infect alligators, and that water can serve as a source of infection for alligators but does not easily serve as an intermediate means for transmission between birds and alligators. These findings indicate potential mechanisms for maintenance of WNV outside of the primary bird–mosquito transmission cycle. Supported by ORIP (T32OD010437) and NIAID.
Using the Autofluorescence Finder on the Sony ID7000TM Spectral Cell Analyzer to Identify and Unmix Multiple Highly Autofluorescent Murine Lung Populations
Wanner et al., Frontiers in Bioengineering and Biotechnology. 2022.
https://www.doi.org/10.3389/fbioe.2022.827987
The investigators explored a new imaging approach to detect faint fluorescent signals that are masked in the background of cell types that emit high‑intensity autofluorescence (AF) signals in a flow cytometry panel. Using a novel AF finder tool on the Sony ID7000™ spectral cell analyzer, the investigators studied multiple AF subsets in complex and heterogeneous murine lung single-cell suspensions. Major immune and lung tissue resident cells in a murine model of asthma were easily identified in a multicolor panel using AF subtraction. The findings demonstrate the practicality of the AF finder tool, particularly when analyzing samples with multiple AF populations of varying intensities, to reduce fluorescence background and increase signal resolution in spectral flow cytometry. Supported by ORIP (S10OD025207) and NHLBI.
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).
Expression, Activity, and Regulation of Phosphorylating Enzymes in Tissues and Cells Relevant to HIV-1 Sexual Transmission
Hu et al., AIDS Research and Human Retroviruses. 2022.
https://www.doi.org/10.1089/AID.2020.0250
Phosphorylating enzymes (PEs) are critical for activating nucleoside/nucleotide reverse transcriptase inhibitors (e.g., tenofovir [TFV]), but limited information is available about the expression of PEs in the female genital tract and colon tissue. Investigators compared the mRNA expression of seven PEs involved in metabolism of TFV in cervicovaginal and colon tissues. This work involved human, pigtailed macaque, and rabbit tissues; human cervicovaginal epithelial cell lines; T cell lines; and primary CD4+ T cells. Taken together, this study suggests that TFV activation differs among immune cells and local tissues under varying conditions. Additionally, the variability of PE expression levels found across species provides critical information to assist with the interpretation of data obtained using these animal models. Supported by ORIP (P51OD010425) and NIAID.
AAV Capsid Variants with Brain-Wide Transgene Expression and Decreased Liver Targeting After Intravenous Delivery in Mouse and Marmoset
Goertsen et al., Nature Neuroscience. 2021.
https://www.nature.com/articles/s41593-021-00969-4
Genetic intervention is increasingly being explored as a therapeutic option for debilitating disorders of the central nervous system (CNS). This project focused on organ-specific targeting of adeno-associated virus (AAV) capsids after intravenous delivery. These results constitute an important step forward toward achieving the goal of engineered AAV vectors that can be used to broadly deliver gene therapies to the CNS in humans. Supported by ORIP (U24OD026638), NIMH, and NINDS.
An NR2F1-Specific Agonist Suppresses Metastasis by Inducing Cancer Cell Dormancy
Khalil et al., The Journal of Experimental Medicine. 2021.
Researchers described the discovery of a nuclear receptor NR2F1 antagonist that specifically activates dormancy programs in malignant cells. Agonist treatment resulted in a self-regulated increase in NR2F1 mRNA and protein and downstream transcription of a novel dormancy program. This program led to growth arrest in multiple human cell lines, as well as patient-derived organoids. This effect was lost when NR2F1 was knocked out. In mice, agonist treatment resulted in inhibition of lung metastasis of head and neck squamous cell carcinomas, even after cessation of the treatment. This work provides proof of principle supporting the use of NR2F1 agonists to induce dormancy as a therapeutic strategy to prevent metastasis. Supported by ORIP (S10OD018522 and S10OD026880) and others.
Negative Inotropic Mechanisms of β-cardiotoxin in Cardiomyocytes by Depression of Myofilament ATPase Activity without Activation of the Classical β-Adrenergic Pathway
Lertwanakarn et al., Scientific Reports. 2021.
https://www.nature.com/articles/s41598-021-00282-x
Beta-cardiotoxin (β-CTX) from the king cobra venom (Ophiophagus hannah) was previously proposed as a novel β-adrenergic blocker. However, the involvement of β-adrenergic signaling by this compound has never been elucidated. The objectives of this study were to investigate the underlying mechanisms of β-CTX as a β-blocker and its association with the β-adrenergic pathway. Healthy Sprague Dawley rats were used for cardiomyocytes isolation. In summary, the negative inotropic mechanism of β-CTX was discovered. β-CTX exhibits an atypical β-blocker mechanism. These properties of β-CTX may benefit in developing a novel agent aid to treat hypertrophic cardiomyopathy. Supported by ORIP (P40OD010960) and NHLBI.