Selected Grantee Publications
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.
Murine MHC-Deficient Nonobese Diabetic Mice Carrying Human HLA-DQ8 Develop Severe Myocarditis and Myositis in Response to Anti-PD-1 Immune Checkpoint Inhibitor Cancer Therapy
Racine et al., Journal of Immunology. 2024.
Myocarditis has emerged as a relatively rare but often lethal autoimmune complication of checkpoint inhibitor (ICI) cancer therapy, and significant mortality is associated with this phenomenon. Investigators developed a new mouse model system that spontaneously develops myocarditis. These mice are highly susceptible to myocarditis and acute heart failure following anti-PD-1 ICI-induced treatment. Additionally, the treatment accelerates skeletal muscle myositis. The team performed characterization of cardiac and skeletal muscle T cells using histology, flow cytometry, adoptive transfers, and RNA sequencing analyses. This study sheds light on underlying immunological mechanisms in ICI myocarditis and provides the basis for further detailed analyses of diagnostic and therapeutic strategies. Supported by ORIP (U54OD020351, U54OD030187), NCI, NIA, NIDDK, and NIGMS.
Identification of Constrained Sequence Elements Across 239 Primate Genomes
Kuderna et al., Nature. 2024.
https://pubmed.ncbi.nlm.nih.gov/38030727/
Functional genomic elements that have acquired selective constraints specific to the primate order are prime candidates for understanding evolutionary changes in humans, but the selective constraints specific to the phylogenetic branch from which the human species ultimately emerged remain largely unidentified. Researchers constructed a genome-wide multiple sequence alignment of 239 primate species to better characterize constraint at noncoding regulatory sequences in the human genome. Their work reveals noncoding regulatory elements that are under selective constraint in primates but not in other placental mammals and are enriched for variants that affect human gene expression and complex traits in diseases. These findings highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals. Supported by ORIP (P40OD024628), NHGRI, NIA, and NICHD.
Effect of Hormone Replacement Therapy on Amyloid Beta (Aβ) Plaque Density in the Rhesus Macaque Amygdala
Appleman et al., Frontiers in Aging Neuroscience. 2024.
https://www.frontiersin.org/articles/10.3389/fnagi.2023.1326747/full
Amyloid beta plaque density is associated with Alzheimer’s disease. In this study, the authors examined its concentration in aged female nonhuman primates’ cerebrospinal fluid, as well as in the amygdala, an area of the brain involved with emotion and memory. They set out to test the hypothesis that estrogen hormone replacement therapy can beneficially affect amygdala Aβ plaque density in “surgically menopausal” females (i.e., aged rhesus macaques that had undergone ovariectomy). Female rhesus macaques that received estrogen replacement therapy showed fewer amyloid plaques than those that did not receive the hormone. This effect was observed regardless of the type of diet that the animals consumed. These findings suggest that hormone replacement might be a helpful treatment to consider for Alzheimer’s disease. Supported by ORIP (P51OD011092, R24OD011895, S10OD025002) and NIA.
Monoclonal Antibodies Protect Aged Rhesus Macaques From SARS-CoV-2-Induced Immune Activation and Neuroinflammation
Verma et al., Cell Reports. 2021.
https://www.sciencedirect.com/science/article/pii/S2211124721014157?via%3Dihub%C2%A0=
In aged diabetic female rhesus macaques, prophylactic administration of neutralizing monoclonal antibodies (mAbs) effectively limits SARS-CoV-2 replication in both the upper and lower respiratory tract, and decreases immune activation, including reducing interferon-induced chemokines and limiting effector CD4 T cell influx into the cerebrospinal fluid. These protective mechanisms took place in the areas of the body targeted by the virus and may prevent adverse inflammatory consequences of SARS-CoV-2 infection in high-risk populations. Supported by ORIP (P51OD011107), NIAID, and NIA.
Advancing Human Disease Research with Fish Evolutionary Mutant Models
Beck et al., Trends in Genetics. 2021.
https://pubmed.ncbi.nlm.nih.gov/34334238/
Model organism research is essential to understand disease mechanisms. However, laboratory-induced genetic models can lack genetic variation and often fail to mimic disease severity. Evolutionary mutant models (EMMs) are species with evolved phenotypes that mimic human disease. They have improved our understanding of cancer, diabetes, and aging. Fish are the most diverse group of vertebrates, exhibiting a kaleidoscope of specialized phenotypes, many that would be pathogenic in humans but are adaptive in the species' specialized habitat. Evolved compensations can suggest avenues for novel disease therapies. This review summarizes current research using fish EMMs to advance our understanding of human disease. Supported by ORIP (R01OD011116), NIA, NIDA, and NIGMS.
Innate Immunity Stimulation via CpG Oligodeoxynucleotides Ameliorates Alzheimer’s Disease Pathology in Aged Squirrel Monkeys
Patel et al., Brain: A Journal of Neurology. 2021.
https://pubmed.ncbi.nlm.nih.gov/34128045/
Alzheimer's disease is the only illness among the top 10 causes of death for which there is no disease-modifying therapy. The authors have shown in transgenic Alzheimer's disease mouse models that harnessing innate immunity via TLR9 agonist CpG oligodeoxynucleotides (ODNs) modulates age-related defects associated with immune cells and safely reduces amyloid plaques, oligomeric amyloid-β, tau pathology, and cerebral amyloid angiopathy (CAA). They used a nonhuman primate model for sporadic Alzheimer's disease pathology that develops extensive CAA-elderly squirrel monkeys. They demonstrate that long-term use of Class B CpG ODN 2006 induces a favorable degree of innate immunity stimulation. CpG ODN 2006 has been well established in numerous human trials for a variety of diseases. This evidence together with their earlier research validates the beneficial therapeutic outcomes and safety of this innovative immunomodulatory approach. Supported by ORIP (P40OD010938), NINDS, NIA, and NCI.
Rhesus Macaques Build New Social Connections After a Natural Disaster
Testard et al., Current Biology. 2021.
https://www.sciencedirect.com/science/article/pii/S0960982221003687
Climate change has increased the frequency and intensity of weather-related disasters such as hurricanes and floods. In 2017, Puerto Rico suffered its worst natural disaster, Hurricane Maria, leaving 3,000 dead and provoking a mental health crisis. Cayo Santiago Island, home to a population of rhesus macaques (Macaca mulatta), was devastated by this storm. Testard et al. compared social networks of two groups of macaques before and after the hurricane and found an increase in affiliative social connections, driven largely by monkeys most socially isolated before Hurricane Maria. Further analysis revealed monkeys invested in building new relationships rather than strengthening existing ones. Supported by ORIP (P40OD012217), NIA, and NIMH.