Selected Grantee Publications
The Role of ATP Citrate Lyase in Myelin Formation and Maintenance
Schneider et al., Glia. 2024.
https://pubmed.ncbi.nlm.nih.gov/39318247/
Myelin formation by Schwann cells is critical for peripheral nervous system development and long-term neuronal function. The study examined how acetyl coenzyme A (acetyl-CoA), essential for lipid synthesis in myelin, is derived, with a focus on mitochondrial ATP citrate lysate (ACLY). By using both sexes in a Schwann cell–specific ACLY knockout mouse model, the authors reported that ACLY plays a role in acetyl-CoA supply for myelin maintenance but not myelin formation. ACLY is necessary for sustaining myelin gene expression and preventing nerve injury pathways. This work highlights a unique dependency on mitochondrial acetyl-CoA for Schwann cell integrity, providing insights into lipid metabolism in neuronal repair. Supported by ORIP (T35OD011078), NICHD, and NINDS.
Cold Atmospheric Plasma Inactivates Aspergillus flavus and Fusarium keratoplasticum Biofilms and Conidia In Vitro
Roberts et al., Journal of Medical Microbiology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38985505
Fungal keratitis (FK) is a severe corneal disease associated with significant morbidity and vision loss that is caused by Aspergillus flavus and Fusarium keratoplasticum. Cold atmospheric plasma (CAP) is a novel nonpharmacologic antimicrobial intervention that has demonstrated potential as a broad-spectrum antifungal treatment. Researchers in this study assessed the efficacy of CAP against clinical FK isolates of A. flavus and F. keratoplasticum grown in vitro. CAP exhibited strong time-dependent inactivation of both fungal species, achieving complete metabolic activity inhibition within 10 minutes of treatment. These results indicate that CAP is an effective broad-spectrum antifungal and a potential treatment strategy for FK. Supported by ORIP (T35OD011070).
Sex-Specific Cardiac Remodeling in Aged Rats After Adolescent Chronic Stress: Associations with Endocrine and Metabolic Factors
Dearing et al., Biology of Sex Differences. 2024.
https://pubmed.ncbi.nlm.nih.gov/39180122
Cardiovascular disease is a leading cause of death in the world. The potential effects of chronic stress on the development and progression of cardiovascular disease in the aged heart are unknown. In this study, researchers investigated sex- and stress-specific effects on left ventricular hypertrophy (LVH) after aging. Male and female rats were exposed to chronic stress during adolescence and then challenged with a swim test and a glucose tolerance test before and after aging 15 months. As a group, female rats showed increased LVH in response to early life stress. Male rats showed individual differences in vulnerability. These results indicate that sex and stress history can interact to determine susceptibility to cardiovascular risks. Supported by ORIP (F30OD032120, T35OD015130) and NHLBI.
A Novel TGFβ Receptor Inhibitor, IPW-5371, Prevents Diet-induced Hepatic Steatosis and Insulin Resistance in Irradiated Mice
Szalanczy et al., Radiation Research. 2024.
https://pubmed.ncbi.nlm.nih.gov/38772553
Radiation damages adipose progenitor cells and increases liver fibrosis, leading to the development of metabolic-associated fatty liver disease (MAFLD) and insulin resistance. As the number of cancer survivors increases and the risk of accidental radiation exposure rises, there is a pressing need to characterize and mitigate the delayed effects of radiation exposure. Some of these effects are mediated by TGFβ pathway signaling, which increases in response to radiation exposure and causes fibrosis. In this study, IPW-5371—a small-molecule inhibitor of a TGFβ receptor called activin receptor-like kinase 5 (ALK5)—was shown to protect mice from the effects of sublethal whole-body irradiation and chronic consumption of a Western diet. Mice treated with IPW-5371 exhibited lower fibrosis and fat accumulation in the liver, were more responsive to insulin, and had lower circulating triglycerides and better muscle endurance. IPW-5371 is a promising treatment for mitigating the metabolic effects of radiation exposure and preventing MAFLD. Supported by ORIP (T35OD010946, T32OD010957).
Acquired Dysfunction of CFTR Underlies Cystic Fibrosis-Like Disease of the Canine Gallbladder
Gookin et al., American Journal of Physiology-Gastrointestinal and Liver Physiology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39041675/
Mucocele formation in dogs is pathologically similar to cystic fibrosis. In this study, researchers investigated the role of cystic fibrosis transmembrane conductance regulator (CFTR) in the pathogenesis of the disease. They determined the location and frequency of disease-associated variants in the coding region of CFTR using whole-genome sequence data from 2,642 dogs representing breeds at low risk, high risk, or with confirmed disease. The authors’ findings establish significant loss of CFTR-dependent anion secretion by mucocele gallbladder mucosa. There were no significant differences in CFTR gene variant frequency, type, or predicted impact comparing low-risk, high-risk, and definitively diagnosed groups of dogs. Their results suggest a disease of the canine gallbladder that is similar to cystic fibrosis and is driven by CFTR dysfunction. Supported by ORIP (T35OD011070, K01OD027058).
Loss of Lymphatic IKKα Disrupts Lung Immune Homeostasis, Drives BALT Formation, and Protects Against Influenza
Cully et al., Immunohorizons. 2024.
https://pubmed.ncbi.nlm.nih.gov/39007717/
Tertiary lymphoid structures (TLS) have context-specific roles, and more work is needed to understand how they function in separate diseases to drive or reduce pathology. Researchers showed previously that lymph node formation is ablated in mice constitutively lacking IκB kinase alpha (IKKα) in lymphatic endothelial cells (LECs). In this study, they demonstrated that loss of IKKα in lymphatic endothelial cells leads to the formation of bronchus-associated lymphoid tissue in the lung. Additionally, they showed that male and female mice challenged with influenza A virus (IAV) exhibited markedly improved survival rates and reduced weight loss, compared with littermate controls. They concluded that ablating IKKα in this tissue reduces the susceptibility of the mice to IAV infection through a decrease in proinflammatory stimuli. This work provides a new model to explore the mechanisms of TLS formation and the immunoregulatory function of lung lymphatics. Supported by ORIP (T35OD010919), NHLBI, NIAID, and NIAMS.
Transcriptome- and Proteome-Wide Effects of a Circular RNA Encompassing Four Early Exons of the Spinal Muscular Atrophy Genes
Luo, Scientific Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/38714739/
Spinal muscular atrophy (SMA) is a leading genetic cause of mortality in infants and often results from a deficiency of deletions of or mutations in the SMN1 gene. In this study, researchers report the transcriptome- and proteome-wide effects of overexpression of C2A‑2B3-4, a circular RNA produced by SMN1 and SMN2, in cells. They report that C2A-2B-3-4 is associated with expression of genes associated with chromatin remodeling, transcription, spliceosome function, ribosome biogenesis, lipid metabolism, cytoskeletal formation, cell proliferation, and neuromuscular junction formation. More work is needed to investigate the role of these genes in processes associated with SMA and other pathological conditions, including cancer and male infertility. Supported by ORIP (T35OD027967) and NINDS.
Epigenetic MLH1 Silencing Concurs With Mismatch Repair Deficiency in Sporadic, Naturally Occurring Colorectal Cancer in Rhesus Macaques
Deycmar et al., Journal of Translational Medicine. 2024.
https://pubmed.ncbi.nlm.nih.gov/38504345
Rhesus macaques serve as a useful model for colorectal cancer (CRC) in humans, but more data are needed to understand the molecular pathogenesis of these cancers. Using male and female rhesus macaques, researchers investigated mismatch repair status, microsatellite instability, genetic mutations, transcriptional differences, and epigenetic alterations associated with CRC. Their data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. This work provides a uniquely informative model for human CRC. Supported by ORIP (P51OD011092, R24OD010947, R24OD021324, P40OD012217, U42OD010426, T35OD010946, T32OD010957), NCATS, and NCI.