Selected Grantee Publications
Spatiotemporal Characterization of Cyclooxygenase Pathway Enzymes During Vertebrate Embryonic Development
Leathers et al., Developmental Biology. 2025.
https://pubmed.ncbi.nlm.nih.gov/39581452/
The cyclooxygenase (COX) pathway plays a fundamental role in embryonic development. Disruptions of the COX pathway during pregnancy cause developmental anomalies, including craniofacial clefts, impaired gut innervation, and neural tube defects in the embryo. Researchers used Gallus gallus embryos to study the expression of COX pathway enzymes during neurulation. COX-1 protein expression was upregulated in cells undergoing mitosis, whereas COX-2 protein expression was ubiquitous. This study provides spatiotemporal expression data of COX pathway enzymes at key embryonic development stages in G. gallus and guides future studies focused on defining the role of these enzymes during embryonic development. Supported by ORIP (T35OD010956), NEI, NIDCR, and NIGMS.
Functional Differences Between Rodent and Human PD-1 Linked to Evolutionary Divergence
Masubuchi et al., Science Immunology. 2025.
https://pubmed.ncbi.nlm.nih.gov/39752535/
Programmed cell death protein 1 (PD-1), an immune checkpoint receptor, regulates immunity against cancer. Rodent models (e.g., mice) do not exhibit the same response rates and immune-related adverse effects to PD-1 blocking drugs as patients with cancer. Only 59.6% amino acid sequence identity is conserved in human PD-1 (hu PD-1) and mouse PD-1 (mo PD-1). Researchers used mouse tumor models, coculture assays, and biophysical assays to determine key functional and biochemical differences between hu PD-1 and mo PD-1. HuPD-1 demonstrates stronger suppressive activity of interleukin-2 secretion and CD69 expression than mo PD-1 because of the ectodomain and intracellular domain, but not the transmembrane domain. Analysis of rodent evolution demonstrated that other inhibitory immunoreceptors were positively selected or had selection intensification over PD-1. Understanding the conservation and divergence of PD-1 signaling at the molecular level in humans compared with mice is needed to properly translate preclinical data to clinical therapeutics. Supported by ORIP (S10OD026929), NCI, and NIA.
Immune Gene Regulation Is Associated With Age and Environmental Adversity in a Nonhuman Primate
Watowich et al., Molecular Ecology. 2024.
https://pubmed.ncbi.nlm.nih.gov/39032090
The mammalian aging process involves a decline in physiological function, influenced by molecular mechanisms like epigenetic changes. These processes have been studied in controlled settings, however the role of aging in naturalistic populations remains unclear. This study explored the effects of environmental stressors (i.e., Hurricane Maria) on DNA methylation in free-living male and female rhesus macaques in Cayo Santiago, Puerto Rico. Results showed that environmental adversity accelerated age-related molecular changes, especially in gene transcription regions, while primary aging mainly affected nonregulatory regions. These findings highlight how the biology of aging is influenced by environmental factors. Supported by ORIP (P40OD012217), NIA, and NIMH.
Mechanical Force of Uterine Occupation Enables Large Vesicle Extrusion From Proteostressed Maternal Neurons
Wang et al., eLife. 2024.
https://pubmed.ncbi.nlm.nih.gov/39255003
This study investigates how mechanical forces from uterine occupation influence large vesicle extrusion (exopher production) from proteostressed maternal neurons in Caenorhabditis elegans. Exophers, previously found to remove damaged cellular components, are poorly understood. Researchers demonstrate that mechanical stress significantly increases exopher release from touch receptor neurons (i.e., ALMR) during peak reproductive periods, coinciding with egg production. Genetic disruptions reducing reproductive activity suppress exopher extrusion, whereas interventions promoting egg retention enhance it. These findings reveal that reproductive and mechanical factors modulate neuronal stress responses, providing insight on how systemic physiological changes affect neuronal health and proteostasis, with broader implications for reproductive-neuronal interactions. Supported by ORIP (R24OD010943, P40OD010440), NIA, and NIGMS.
Transcriptomic Analysis of Skeletal Muscle Regeneration Across Mouse Lifespan Identifies Altered Stem Cell States
Walter et al., Nature Aging. 2024.
https://pubmed.ncbi.nlm.nih.gov/39578558
Age-related skeletal muscle regeneration dysfunction is poorly understood. Using single-cell transcriptomics and high-resolution spatial transcriptomics, researchers evaluated factors contributing to age-related decline in skeletal muscle regeneration after injury in young, old, and geriatric male and female mice (5, 20, and 26 months old). Eight immune cell types were identified and associated with age-related dynamics and distinct muscle stem cell states specific to old and geriatric tissue. The findings emphasize the role of extrinsic and intrinsic factors, including cellular senescence, in disrupting muscle repair. This study provides a spatial and molecular framework for understanding regenerative decline and cellular heterogeneity in aging skeletal muscle. Supported by ORIP (F30OD032097), NIA, NIAID, NIAMS, NICHD, and NIDA.
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.
Disruption of Myelin Structure and Oligodendrocyte Maturation in a Macaque Model of Congenital Zika Infection
Tisoncik-Go et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-49524-2
Maternal infection during pregnancy can have severe consequences on fetal development and survival. Using a pigtail macaque model for Zika virus infection, researchers show that in utero exposure of a fetus to Zika virus due to maternal infection results in significantly decreased myelin formation around neurons. Myelin is a protective sheath that forms around neurons and is required for brain processing speed. This study suggests that reduced myelin resulting from Zika infection in utero is likely a contributing factor to severe deficits in brain development and microcephaly. Supported by ORIP (P51OD010425), NEI, and NIAID.
Genetic Diversity of 1,845 Rhesus Macaques Improves Genetic Variation Interpretation and Identifies Disease Models
Wang et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-49922-6
Nonhuman primates are ideal models for certain human diseases, including retinal and neurodevelopmental disorders. Using a reverse genetics approach, researchers profiled the genetic diversity of rhesus macaque populations across eight primate research centers in the United States and uncovered rhesus macaques carrying naturally occurring pathogenic mutations. They identified more than 47,000 single-nucleotide variants in 374 genes that had been previously linked with retinal and neurodevelopmental disorders in humans. These newly identified variants can be used to study human disease pathology and to test novel treatments. Supported by ORIP (P51OD011107, P51OD011106, P40OD012217, S10OD032189), NEI, NIAID, and NIMH.
Potent HPIV3-Neutralizing IGHV5-51 Antibodies Identified from Multiple Individuals Show L Chain and CDRH3 Promiscuity
Abu-Shmais et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38488511/
Human parainfluenza virus 3 fusion glycoprotein (HPIV3 F), responsible for facilitating viral entry into host cells, is a major target of neutralizing antibodies that inhibit infection. More work is needed to understand these dynamics. Researchers characterized the genetic signatures, epitope specificity, neutralization potential, and publicness of HPIV3-specific antibodies identified across multiple individuals. From this work, they identified 12 potently neutralizing antibodies targeting three nonoverlapping epitopes on HPIV3 F. Six of the antibodies used immunoglobulin heavy variable gene, IGHV 5-51. These antibodies used different L chain variable genes (VL) and diverse H chain CDR 3 (CDRH3) sequences. These findings help elucidate the genetic and functional characteristics of HPIV3-neutralizing antibodies and indicate the existence of a reproducible H chain variable–dependent antibody response associated with VL and CDRH3 promiscuity. Supported by ORIP (K01OD036063), NCATS, NCI, NEI, NIAID, and NIDDK.