Selected Grantee Publications
- 511 results found
Characterizing a Photoacoustic and Fluorescence Imaging Platform for Preclinical Murine Longitudinal Studies
Thompson et al., Journal of Biomedical Optics . 2023.
https://pubmed.ncbi.nlm.nih.gov/36895414/
Preclinical studies using animal models require medical imaging technology with sufficient resolution and sensitivity for anatomical, functional, and molecular assessments. Photoacoustic (PA) tomography provides high resolution and specificity, and fluorescence (FL) molecular tomography provides high sensitivity; the combination of these imaging modalities capitalizes on their strengths and mitigates disadvantages. In this publication, the authors describe TriTom, a preclinical imaging system that integrates PA and FL. They characterized the PA spatial resolution, PA sensitivity, PA spectral accuracy, optical spatial resolution, and FL sensitivity of the platform and demonstrated anatomical imaging in mice. This report demonstrates TriTom’s suitability for biomedical imaging applications. Supported by ORIP (R43OD023029) and NCI.
In-Depth Virological and Immunological Characterization of HIV-1 Cure after CCR5A32/A32 Allogeneic Hematopoietic Stem Cell Transplantation
Jensen et al., Nature Medicine. 2023.
https://pubmed.ncbi.nlm.nih.gov/36807684/
Evidence suggests that CCR5Δ32/Δ32 hematopoietic stem cell transplantation (HSCT) can cure HIV-1, but the immunological and virological correlates are unknown. Investigators performed a longitudinal virological and immunological analysis of the peripheral blood and tissue compartments of a 53-year-old male patient more than 9 years after CCR5Δ32/Δ32 allogeneic HSCT and 48 months after analytical treatment interruption. Sporadic traces of HIV-1 DNA were detected in peripheral T cell subsets and tissue-derived samples, but repeated ex vivo quantitative and in vivo outgrowth assays in humanized mice of both sexes did not reveal replication-competent virus. This case provides new insights that could guide future cure strategies. Supported by ORIP (P51OD011092) and NIAID.
Naturally Occurring Osteochondrosis Latens Lesions Identified by Quantitative and Morphological 10.5 T MRI in Pigs
Armstrong et al., Journal of Orthopaedic Research. 2023.
https://pubmed.ncbi.nlm.nih.gov/35716161/
Juvenile osteochondritis dissecans (JOCD) is a pediatric orthopedic disorder that is associated with pain and gait deficits. JOCD lesions form in the knee, elbow, and ankle joints and can progress to early-onset osteoarthritis. In this study, researchers used a noninvasive magnetic resonance imaging (MRI) method to identify naturally occurring lesions in intact knee and elbow joints of juvenile pigs. This work can be applied to noninvasive identification and monitoring of early JOCD lesions and determination of risk factors that contribute to their progression in children. Supported by ORIP (K01OD021293, T32OD010993), NIAMS, and NIBIB.
Cannabinoids Modulate the Microbiota–Gut–Brain Axis in HIV/SIV Infection by Reducing Neuroinflammation and Dysbiosis while Concurrently Elevating Endocannabinoid and Indole-3-Propionate Levels
McDew-White et al., Journal of Neuroinflammation. 2023.
https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-023-02729-6
Chronic neuroinflammation is thought to be a significant contributor to HIV-associated neurocognitive disorders. Using rhesus macaques of both sexes, researchers investigated the effects of simian immunodeficiency virus (SIV) infection on the microbiota–gut–brain axis (MGBA), as well as the use of low-dose cannabinoids to reverse MGBA dysregulation. They reported that tetrahydrocannabinol reduced neuroinflammation and dysbiosis and increased plasma endocannabinoid, endocannabinoid-like, glycerophospholipid, and indole-3-propionate levels. This study offers a potential strategy to promote brain health in people with HIV. Supported by ORIP (P51OD011104, P51OD011103), NIAID, and NIDA.
A Class of Anti-Inflammatory Lipids Decrease with Aging in the Central Nervous System
Tan et al., Nature Chemical Biology. 2023.
https://doi.org/10.1038/s41589-022-01165-6
Impaired lipid metabolism in the brain has been implicated in neurological disorders of aging, yet analyses of lipid pathway changes with age have been lacking. The researchers examined the brain lipidome of mice of both sexes across the lifespan using untargeted lipidomics. They found that 3-sulfogalactosyl diacylglycerols (SGDGs) are structural components of myelin and decline with age in the central nervous system. The researchers discovered that SGDGs also are present in male human and rhesus macaque brains, demonstrating their evolutionary conservation in mammals. The investigators showed that SGDGs possess anti-inflammatory activity, suggesting a potential role for this lipid class in age-related neurodegenerative diseases. Supported by ORIP (P51OD011092), NIA, NCI, NIDDK, and NINDS.
Pancreatic Cancer Cells Upregulate LPAR4 in Response to Isolation Stress to Promote an ECM-Enriched Niche and Support Tumour Initiation
Wu et al., Nature Cell Biology. 2023.
https://pubmed.ncbi.nlm.nih.gov/36646789/
Understanding drivers of tumor initiation is critical for cancer therapy. Investigators found transient increase of lysophosphatidic acid receptor 4 (LPAR4) in pancreatic cancer cells exposed to environmental stress or chemotherapy. LPAR4 induced tumor initiation, stress tolerance, and drug resistance by downregulating miR-139-5p, a tumor suppressor, and upregulating fibronectin. These results indicate that LPAR4 enhances cell-autonomous production of a fibronectin-rich extracellular matrix (ECM), allowing cells to survive isolation stress and compensate for the absence of stromal-derived factors by creating their own tumor-initiating niche. Supported by ORIP (K01OD030513, T32OD017863), NCI, and NHLBI.
PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS
Hung et al., Cell . 2023.
https://doi.org/10.1016/j.cell.2023.01.005
Investigators showed that pharmacological suppression of PIKFYVE activity reduces pathology and extends survival of animal models and patient-derived motor neurons representing diverse forms of amyotrophic lateral sclerosis (ALS). Upon PIKFYVE inhibition, exocytosis is activated to transport aggregation-prone proteins out of the cells, a process that does not require stimulating macroautophagy or the ubiquitin-proteosome system. These findings suggest therapeutic potential to manage multiple forms of ALS. Supported by ORIP (S10OD021553) and NINDS.
Assessment of Anti-CD20 Antibody Pre-Treatment for Augmentation of CAR-T Cell Therapy in SIV-Infected Rhesus Macaques
Pampusch et al., Frontiers in Immunology. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9941136/
Chronic HIV replication occurs primarily within lymphoid follicles, and investigators hypothesized that temporary disruption of these follicles would create space for chimeric antigen receptor (CAR) T cell engraftment and lead to increased abundance and persistence of CAR T cells. They evaluated CAR T cell abundance and persistence in rhesus macaques of both sexes following simian immunodeficiency virus (SIV) infection and antiretroviral therapy suppression. Their results suggest that CAR T cells expanded to a greater extent in the depleted and CAR T cell–treated animals. Further studies are needed to evaluate strategies for engraftment and the persistence of HIV-specific CAR T cells. Supported by ORIP (P51OD011106, P51RR000167), NIAID, and NIDA.
SIV Infection Regulates Compartmentalization of Circulating Blood Plasma miRNAs within Extracellular Vesicles (EVs) and Extracellular Condensates (ECs) and Decreases EV-Associated miRNA-128
Kopcho et al., Viruses. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10059597/
MicroRNAs (miRNAs) are thought to be involved in HIV pathogenesis, but the effect of HIV on the compartmentalization of miRNAs within extracellular particles is unclear. Researchers sequenced the small RNA population of paired EVs and ECs from male rhesus macaques. They showed that extracellular miRNAs in blood plasma are not restricted to any type of extracellular particles but are associated with lipid‑based carriers, with a significant proportion associated with ECs. Further, simian immunodeficiency virus (SIV) infection altered the miRNAome profile of EVs and revealed miR‑128‑3p as a potential target of infection. This work suggests that EV‑ and EC‑associated miRNAs potentially could serve as biomarkers for various diseases. Supported by ORIP (P51OD011104, P51OD011133), NIAID, and NIDA.
Prolonged Experimental CD4+ T-Cell Depletion Does Not Cause Disease Progression In SIV-Infected African Green Monkeys
Le Hingrat et al., Nature Communications. 2023.
https://www.nature.com/articles/s41467-023-36379-2
Chronically simian immunodeficiency virus (SIV)–infected African green monkeys (AGMs) partially recover mucosal CD4+ T cells, maintain gut integrity, and do not progress to AIDS. Investigators assessed the impact of prolonged, antibody-mediated CD4+ T cell depletion on gut integrity and natural history of SIV infection in AGMs. All circulating CD4+ T cells and more than 90% of mucosal CD4+ T cells were depleted. Plasma viral loads and cell-associated viral RNA in tissues were lower in CD4+-cell-depleted animals. CD4+-cell-depleted AGMs maintained gut integrity, controlled immune activation, and did not progress to AIDS. Therefore, CD4+ T cell depletion is not a determinant of SIV-related gut dysfunction when gastrointestinal tract epithelial damage and inflammation are absent, suggesting that disease progression and resistance to AIDS are independent of CD4+ T cell restoration in SIV-infected AGMs. Supported by ORIP (P40OD028116), NIAID, NIDDK, and NHLBI.