Selected Grantee Publications
Senescent-like Microglia Limit Remyelination Through the Senescence Associated Secretory Phenotype
Gross et al., Nature Communications. 2025.
https://www.nature.com/articles/s41467-025-57632-w
Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease in which immune cells infiltrate the central nervous system and promote deterioration of myelin and neurodegeneration. The capacity to regenerate myelin in the central nervous system diminishes with age. In this study, researchers used 2- to 3-month-old (young), 12-month-old (middle-aged), and 18- to 22-month-old (aged) C57BL/6 male and female mice. Results showed an upregulation of the senescence marker P16ink4a (P16) in microglial and macrophage cells within demyelinated lesions. Notably, treatment of senescent cells using genetic and pharmacological senolytic methods leads to enhanced remyelination in young and middle-aged mice but fails to improve remyelination in aged mice. These results suggest that therapeutic targeting of senescence-associated secretory phenotype components may improve remyelination in aging and MS. Supported by ORIP (R24OD036199), NIA, NINDS, and NIMH.
Dysregulation of mTOR Signalling Is a Converging Mechanism in Lissencephaly
Zhang et al., Nature. 2025.
https://pubmed.ncbi.nlm.nih.gov/39743596
Lissencephaly (smooth brain) is a rare genetic condition, with such symptoms as epilepsy and intellectual disability and a median life expectancy of 10 years. This study reveals that reduced activity of the mTOR pathway may be a common cause of lissencephaly. Researchers used laboratory-grown brain models (organoids) and sequencing and spectrometry techniques to identify decreased mTOR activation in two types of lissencephaly disorders: p53-induced death domain protein 1 and Miller–Dieker lissencephaly syndrome. Pharmacological activation of mTOR signaling with a brain-selective mTORC1 activator molecule, NV-5138, prevented and reversed the morphological and functional defects in organoids. These findings suggest that mTOR dysregulation contributes to the development of lissencephaly spectrum disorders and highlight a potential druggable pathway for therapy. Supported by ORIP (S10OD018034, S10OD019967, S10OD030363), NCATS, NHGRI, NICHD, NIDA, NIGMS, NIMH, and NINDS.
Suppression of Viral Rebound by a Rev-Dependent Lentiviral Particle in SIV-Infected Rhesus Macaques
Hetrick et al., Gene Therapy. 2025.
https://pubmed.ncbi.nlm.nih.gov/39025983/
Viral reservoirs are a current major barrier that prevents an effective cure for patients with HIV. Antiretroviral therapy (ART) effectively suppresses viral replication, but ART cessation leads to viral rebound due to the presence of viral reservoirs. Researchers conducted in vivo testing of simian immunodeficiency virus (SIV) Rev-dependent vectors in SIVmac239-infected male and female Indian rhesus macaques, 3–6 years of age, to target viral reservoirs. Treatment with the SIV Rev-dependent vector reduced viral rebound and produced neutralizing antibodies following ART cessation. These results indicate the potential to self-control plasma viremia through a neutralizing antibody-based mechanism elicited by administration of Rev-dependent vectors. This research could guide future studies focused on investigating multiple vector injections and quantifying cell-mediated immune responses. Supported by ORIP (P51OD011104, P40OD028116), NIAID, and NIMH.
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.
Matrikine Stimulation of Equine Synovial Fibroblasts and Chondrocytes Results in an In Vitro Osteoarthritis Phenotype
Gagliardi et al., Journal of Orthopaedic Research. 2025.
https://pubmed.ncbi.nlm.nih.gov/39486895
Advancements in therapy development for osteoarthritis (OA) currently are limited due to a lack of physiologically relevant in vitro models. This study aimed to understand the effect of matrikine stimulation, using human recombinant fibronectin fragment containing domains 7–10 (FN7–10), on equine synovial fibroblasts and chondrocytes. Inflammatory cytokines, chemokines, and matrix degradation genes in equine synovial fibroblasts and chondrocytes were significantly altered in response to FN7–10 stimulation; marked upregulation was observed in interleukin-6 (IL-6), IL-4, IL-10, matrix metalloproteinase 1 (MMP1), MMP3, MMP13, CCL2/MCP1, and CXCL6/GCP-2 gene expression. Only IL-6 protein production was significantly increased in media isolated from cells stimulated with FN7–10. These results support the potential use of equine synovial fibroblasts and chondrocytes—employing FN7–10—as representative in vitro models to study OA. Supported by ORIP (T32OD011130) and NIAMS.
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.
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.
Deep Learning Is Widely Applicable to Phenotyping Embryonic Development and Disease
Naert et al., Development. 2021.
https://pubmed.ncbi.nlm.nih.gov/34739029/
Genome editing simplifies the generation of new animal models for congenital disorders. The authors illustrate how deep learning (U-Net) automates segmentation tasks in various imaging modalities. They demonstrate this approach in embryos with polycystic kidneys (pkd1 and pkd2) and craniofacial dysmorphia (six1). They provide a library of pre-trained networks and detailed instructions for applying deep learning to datasets and demonstrate the versatility, precision, and scalability of deep neural network phenotyping on embryonic disease models. Supported by ORIP (P40OD010997, R24OD030008), NICHD, NIDDK, and NIMH.
The High Affinity Dopamine D2 Receptor Agonist MCL-536: A New Tool for Studying Dopaminergic Contribution to Neurological Disorders
Subburaju et al., ACS Chemical Neuroscience. 2021.
https://pubs.acs.org/doi/full/10.1021/acschemneuro.1c00094
The dopamine D2 receptor exists in two different states, D2high and D2low; the former is the functional form of the D2 receptor and associates with intracellular G-proteins. The D2 agonist [3H]MCL-536 has high affinity for the D2 receptor (Kd 0.8 nM) and potently displaces the binding of (R-(-)-N-n-propylnorapomorphine (NPA; Ki 0.16 nM) and raclopride (Ki 0.9 nM) in competition binding assays. The authors characterized [3H]MCL-536. [3H]MCL-536 as metabolically stable. In vitro autoradiography on transaxial and coronal brain sections showed specific binding of [3H]MCL-536. [3H]MCL-536's unique properties make it a valuable tool for research on neurological disorders like Parkinson's disease or schizophrenia. Supported by ORIP (R43OD020186, R44OD024615) and NIMH.