Selected Grantee Publications
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- 13 results found
- nhlbi
- COVID-19/Coronavirus
- Neurological
Establishing the Hybrid Rat Diversity Program: A Resource for Dissecting Complex Traits
Dwinell et al., Mammalian Genome. 2025.
https://pubmed.ncbi.nlm.nih.gov/39907792
Rat models have been extensively used for studying human complex disease mechanisms, behavioral phenotypes, and environmental factors and for discovering and developing drugs. Systems genetics approaches have been used to study the effects of both genetic variation and environmental factors. This approach recognizes the complexity of common disorders and uses intermediate phenotypes to find relationships between genetic variation and clinical traits. This article describes the Hybrid Rat Diversity Program (HDRP) at the Medical College of Wisconsin, which involves 96 inbred rat strains and aims to provide a renewable and reusable resource in terms of the HRDP panel of inbred rat strains, the genomic data derived from the HRDP strains, and banked resources available for additional studies. Supported by ORIP (R24OD024617) and NHLBI.
Peripherally Mediated Opioid Combination Therapy in Mouse and Pig
Peterson et al., The Journal of Pain. 2025.
https://pubmed.ncbi.nlm.nih.gov/39542192
This study evaluates novel opioid combinations for pain relief with reduced side effects. Researchers investigated loperamide (a μ-opioid agonist) with either oxymorphindole or N‑benzyl-oxymorphindole—both δ-opioid receptor partial agonists—in mice (male and female) and pigs (male). These combinations produced synergistic analgesia across species without causing adverse effects or respiratory depression. The therapies significantly reduced hypersensitivity in post-injury models, outperforming morphine alone. These findings suggest that peripherally acting opioid combinations can offer effective, safer alternatives for pain management, potentially lowering opioid misuse and side effects. This approach could improve clinical strategies for treating chronic and acute pain with limited central opioid exposure. Supported by ORIP (T32OD010993), NHLBI, and NIDA.
Plural Molecular and Cellular Mechanisms of Pore Domain KCNQ2 Encephalopathy
Abreo et al., eLife. 2025.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11703504
This study investigates the cellular and molecular mechanisms underlying KCNQ2 encephalopathy, a severe type of early-onset epilepsy caused by mutations in the KCNQ2 gene. Researchers describe a case study of a child with a specific KCNQ2 gene mutation, G256W, and found that it disrupts normal brain activity, leading to seizures and developmental impairments. Male and female Kcnq2G256W/+ mice have reduced KCNQ2 protein levels, epilepsy, brain hyperactivity, and premature deaths. As seen in the patient study, ezogabine treatment rescued seizures in mice, suggesting a potential treatment avenue. These findings provide important insights into KCNQ2-related epilepsy and highlight possible therapeutic strategies. Supported by ORIP (U54OD020351, S10OD026804, U54OD030187), NCI, NHLBI, NICHD, NIGMS, NIMH, and NINDS.
SIV-Specific Antibodies Protect Against Inflammasome-Driven Encephalitis in Untreated Macaques
Castell et al., Cell Reports. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11552693
Viral infections are the most common infectious cause of encephalitis, and simian immunodeficiency virus (SIV)–infected macaques are a well-established model for HIV. Researchers investigated the protective effects of SIV-specific antibodies against inflammation-driven encephalitis in using untreated, SIV-infected, male and female pigtail and rhesus macaques. Findings indicate that these antibodies reduce neuroinflammation and encephalitis, highlighting the importance of antibodies in controlling neuroimmune responses, especially in the absence of antiretroviral therapy. This study provides insight into immune-modulatory approaches to combating inflammation-driven encephalopathies. Supported by ORIP (U42OD013117, T32OD011089), NIDA, NHLBI, NIAID, NINDS, and NIMH.
Impaired Skeletal Development by Disruption of Presenilin-1 in Pigs and Generation of Novel Pig Models for Alzheimer's Disease
Uh et al., Journal of Alzheimer's Disease. 2024.
https://pubmed.ncbi.nlm.nih.gov/39177593/
This study explored the effects of presenilin 1 (PSEN1) disruption on vertebral malformations in male and female PSEN1 mutant pigs. Researchers observed significant skeletal impairments and early deaths in pigs with a PSEN1 null mutation, mirroring phenotypes seen in mouse models of Alzheimer’s disease (AD). This porcine model provides valuable insights into pathological hallmarks of PSEN1 mutations in AD, offering a robust platform of therapeutic exploration. The findings establish pigs as an essential translational model for AD, enabling advanced studies on pathophysiology and treatment development for human skeletal and neurological conditions. Supported by ORIP (U42OD011140), NHLBI, NIA, NIAID.
De Novo Variants in FRYL Are Associated With Developmental Delay, Intellectual Disability, and Dysmorphic Features
Pan et al., The American Journal of Human Genetics. 2024.
https://www.cell.com/ajhg/fulltext/S0002-9297(24)00039-9
FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans, and its functions in mammals are largely unknown. Investigators report 13 individuals who have de novo heterozygous variants in FRYL and one individual with a heterozygous FRYL variant that is not confirmed to be de novo. The individuals present with developmental delay; intellectual disability; dysmorphic features; and other congenital anomalies in cardiovascular, skeletal, gastrointestinal, renal, and urogenital systems. Using fruit flies, investigators provide evidence that haploinsufficiency in FRYL likely underlies a disorder in humans with developmental and neurological symptoms. Supported by ORIP (U54OD030165), NHLBI, NICHD, and NCATS.
Gut Microbiome Dysbiosis in Antibiotic-Treated COVID-19 Patients Is Associated with Microbial Translocation and Bacteremia
Bernard-Raichon et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-33395-6
The investigators demonstrated that SARS-CoV-2 infection induced gut microbiome dysbiosis in male mice. Samples collected from human COVID-19 patients of both sexes also revealed substantial gut microbiome dysbiosis. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicated that bacteria might translocate from the gut into the systemic circulation of COVID-19 patients. These results were consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19. Supported by ORIP (S10OD021747), NCI, NHLBI, NIAID, and NIDDK.
A Potent Myeloid Response Is Rapidly Activated in the Lungs of Premature Rhesus Macaques Exposed to Intra-Uterine Inflammation
Jackson et al., Mucosal Immunology. 2022.
https://www.doi.org/10.1038/s41385-022-00495-x
Up to 40% of preterm births are associated with histological chorioamnionitis (HCA), which can lead to neonatal mortality, sepsis, respiratory disease, and neurodevelopmental problem. Researchers used rhesus macaques to comprehensively describe HCA-induced fetal mucosal immune responses and delineate the individual roles of IL-1β and TNFα in HCA-induced fetal pathology. Their data indicate that the fetal innate immune system can mount a rapid, multifaceted pulmonary immune response to in utero exposure to inflammation. Taken together, this work provides mechanistic insights into the association between HCA and the postnatal lung morbidities of the premature infant and highlights the therapeutic potential of inflammatory blockade in the fetus. Supported by ORIP (P51OD011107), NIEHS, NIDDK, NHLBI, and NICHD.
CAR/CXCR5–T Cell Immunotherapy Is Safe and Potentially Efficacious in Promoting Sustained Remission of SIV Infection
Pampusch et al., PLOS Pathogens. 2022.
https://www.doi.org/10.1371/journal.ppat.1009831
HIV and simian immunodeficiency virus (SIV) replication are concentrated within the B cell follicles of secondary lymphoid tissues. In this study, the researchers developed immunotherapeutic chimeric antigen receptor (CAR) T cells that home to follicles and clear SIV-infected cells in a rhesus macaque model. The CAR T cells localized to the follicle, replicated, and interacted directly with infected cells. Most of the treated animals maintained lower viral loads in the blood and follicles, compared to control animals. These findings demonstrate the safety and potential efficacy of this immunotherapy approach for long-term remission of HIV without requiring the lifelong use of antiretroviral therapy. Supported by ORIP (P51OD011106), NIAID, and NHLBI.
Severely Ill COVID-19 Patients Display Impaired Exhaustion Features in SARS-CoV-2-Reactive CD8+ T Cells
Kusnadi et al., Science Immunology. 2021.
https://immunology.sciencemag.org/content/6/55/eabe4782.long
How CD8+ T cells respond to SARS-CoV-2 infection is not fully known. Investigators reported on the single-cell transcriptomes of >80,000 virus-reactive CD8+ T cells, obtained using a modified Antigen-Reactive T cell Enrichment assay, from 39 COVID-19 patients and 10 healthy subjects. COVID-19 patient cells were segregated into two groups based on whether the dominant CD8+ T cell response to SARS-CoV-2 was “exhausted” or not. SARS-CoV-2-reactive cells in the exhausted subset were increased in frequency and displayed less cytotoxicity and inflammatory features in COVID-19 patients with mild compared to severe illness. In contrast, SARS-CoV-2-reactive cells in the dominant non-exhausted subset from patients with severe disease showed enrichment of transcripts linked to co-stimulation, pro-survival Nuclear Factor κB signaling, and anti-apoptotic pathways, suggesting the generation of robust CD8+ T cell memory responses in patients with severe COVID-19 illness. Overall, this single-cell analysis revealed substantial diversity in the nature of CD8+ T cells responding to SARS-CoV-2. Supported by ORIP (S10RR027366 and S10OD025052), NIAID, NHLBI, and NIGMS.