Selected Grantee Publications
A Revamped Rat Reference Genome Improves the Discovery of Genetic Diversity in Laboratory Rats
de Jong, Cell Genomics. 2024.
https://www.cell.com/cell-genomics/fulltext/S2666-979X(24)00069-7
Rattus norvegicus has been used in many fields of study related to human disease; its genome was sequenced shortly after the genomes of Homo sapiens and Mus musculus. Investigators report extensive analyses of the improvements in mRatBN7.2, compared with the previous version. They conducted a broad analysis of a whole-genome sequencing data set of 163 samples from 120 inbred rat strains and substrains. Several additional resources have been created. This new assembly and its associated resources create a more solid platform for research on the many dimensions of physiology, behavior, and pathobiology of rats and can provide more reliable and meaningful translation of findings to human populations. Supported by ORIP (R24OD024617), NHGRI, NHLBI, and NIDA.
Macrophages Derived From Human Induced Pluripotent Stem Cells (iPSCs) Serve As a High-Fidelity Cellular Model for Investigating HIV-1, Dengue, and Influenza viruses
Yang et al., Journal of Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38323811/
Macrophages can be weaponized by viruses to host viral reproduction and support long-term persistence. The most common way of studying these cells is by isolating their precursors from donor blood and differentiating the isolated cells into macrophages. This method is costly and technically challenging, and it produces varying results. In this study, researchers confirmed that macrophages derived from iPSC cell lines—a model that is inexpensive, consistent, and modifiable by genome editing—are a suitable model for experiments involving HIV and other viruses. Macrophages derived from iPSCs are as susceptible to infection as macrophages derived from blood, with similar infection kinetics and phenotypes. This new model offers researchers an unlimited source of cells for studying viral biology. Supported by ORIP (R01OD034046, S10OD021601), NIAID, NIDA, NIGMS, and NHLBI.
Molecular Basis of Human Trace Amine-Associated Receptor 1 Activation
Zilberg et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-023-44601-4
The authors reported the cryogenic electron microscopy structure of human trace amine-associated receptor 1 (hTAAR1, hTA1) signaling complex, a key modulator in monoaminergic neurotransmission, as well as its similarities and differences with other TAAR members and rodent TA1 receptors. This discovery has elucidated hTA1’s molecular mechanisms underlining the strongly divergent pharmacological properties of human and rodent TA1 and therefore will boost the translation of preclinical studies to clinical applications in treating disorders of dopaminergic dysfunction, metabolic disorders, cognitive impairment, and sleep-related dysfunction. Supported by ORIP (S10OD019994, S10OD026880, and S10OD030463), NIDA, NIGMS, NIMH, and NCATS.
GenomeMUSter Mouse Genetic Variation Service Enables Multitrait, Multipopulation Data Integration and Analysis
Ball et al., Genome Research. 2024.
https://genome.cshlp.org/content/34/1/145.long
Advances in genetics, including transcriptome-wide and phenome-wide association analysis methods, create compelling new opportunities for using fully reproducible and widely studied inbred mouse strains to characterize the polygenetic basis for individual differences in disease-related traits. Investigators developed an imputation approach and implemented data service to provide a broad and more comprehensive mouse variant resource. They evaluated the strain-specific imputation accuracy on a “held-out” test set that was not used in the imputation process. The authors present its application to multipopulation and multispecies analyses of complex trait variation in type 2 diabetes and substance use disorders and compare these results to human genetics studies. Supported by ORIP (U42OD010921, P40OD011102, R24OD035408), NCI, NIAAA, NIDA, and NIDCD.
Investigation of Monoclonal Antibody CSX-1004 for Fentanyl Overdose
Bremer et al., Nature Communications. 2023.
https://pubmed.ncbi.nlm.nih.gov/38052779/
The opioid crisis in the United States is primarily driven by the highly potent synthetic opioid fentanyl and has led to more than 70,000 overdose deaths annually; thus, new therapies for fentanyl overdose are urgently needed. Here, the authors present the first clinic-ready, fully human monoclonal antibody CSX-1004 with picomolar affinity for fentanyl and related analogs. In mice, CSX-1004 reverses fentanyl antinociception and the intractable respiratory depression caused by the ultrapotent opioid carfentanil. Using a highly translational nonhuman primate model for respiratory depression, they demonstrate CSX-1004-mediated protection from repeated fentanyl challenges for 3–4 weeks. These data establish the feasibility of CSX-1004 as a promising candidate medication for preventing and reversing fentanyl-induced overdose. Supported by ORIP (P40OD010938) and NIDA.
HIV-1 Remission: Accelerating the Path to Permanent HIV-1 Silencing
Lyons et al., c. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10674359/
Current HIV treatment strategies are focused on forced proviral reactivation and elimination of reactivated cells with immunological or toxin-based technologies. Researchers have proposed the use of a novel “block-lock-stop” approach, which entails the long-term durable silencing of viral expression and permanent transcriptional deactivation of the latent provirus. In the present study, the authors present this approach and its rationale. More research is needed to understand the (1) epigenetic architecture of integrated provirus, (2) cell types and epigenetic cell states that favor viral rebound, (3) molecular functions of Tat (a protein that controls transcription of HIV) and host factors that prevent permanent silencing, (4) human endogenous retrovirus silencing in the genome, and (5) approaches to generate defective proviruses. Additionally, community engagement is crucial for this effort. Supported by ORIP (K01OD031900), NIAID, NCI, NIDA, NIDDK, NHLBI, NIMH, and NINDS.
Timing of Initiation of Anti-Retroviral Therapy Predicts Post-Treatment Control of SIV Replication
Pinkevych et al., PLOS Pathogens. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10558076/
Researchers are interested in approaches to reducing viral rebound following interruption of antiretroviral therapy, but more work is needed to understand major factors that determine the viral “setpoint” level. Researchers previously assessed how timing of treatment can affect the frequency of rebound from latency. In the current study, the authors analyzed data from multiple studies of simian immunodeficiency virus (SIV) infection in rhesus macaques to further explore the dynamics and predictors of post-treatment viral control. They determined that the timing of treatment initiation was a major predictor of both the level and the duration of post-rebound SIV control. These findings could help inform future treatments. Supported by ORIP (U42OD011023, P51OD011132, P51OD011092), NIAID, NCI, NIDA, NIDDK, NHLBI, NIMH, and NINDS
The Eotaxin-1/CCR3 Axis and Matrix Metalloproteinase-9 Are Critical in Anti-NC16A IgE-Induced Bullous Pemphigoid
Jordan et al., Journal of Immunology. 2023.
Bullous pemphigoid is associated with eosinophilic inflammation and circulating and tissue-bound IgG and IgE autoantibodies. Researchers previously established the pathogenicity of anti-NC16A IgE through passive transfer of patient-derived autoantibodies to double-humanized mice. In this study, they characterized the molecular and cellular events that underlie eosinophil recruitment and eosinophil-dependent tissue injury. Their work establishes the eotaxin-1/CCR3 axis and matrix metalloproteinase-9 as key players in the disease and as candidate therapeutic targets for drug development and testing. Supported by ORIP (T32OD011130) and NIAMS.
Lymph-Node-Based CD3+ CD20+ Cells Emerge From Membrane Exchange Between T Follicular Helper Cells and B Cells and Increase Their Frequency Following Simian Immunodeficiency Virus Infection
Samer et al., Journal of Virology. 2023.
https://www.doi.org/10.1128/jvi.01760-22
CD4+ T follicular helper cells are known to persist during antiretroviral therapy (ART) and have been identified as key targets for viral replication and persistence. Researchers identified a lymphocyte population that expresses CD3 (i.e., T cell lineage marker) and CD20 (i.e., B cell lineage marker) on the cellular surface in lymphoid tissues from rhesus macaques of both sexes and humans of male and female sexes. In macaques, the cells increased following simian immunodeficiency virus infection, were reduced with ART, and increased in frequency after ART interruption. These cells represent a potential area for future therapeutic strategies. Supported by ORIP (P51OD011132, U42OD011023), NIAID, NCI, NIDDK, NIDA, NHLBI, and NINDS.
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.