Selected Grantee Publications
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- 310 results found
- Infectious Diseases
- Neurological
- Pediatrics
Multimodal Analysis of Dysregulated Heme Metabolism, Hypoxic Signaling, and Stress Erythropoiesis in Down Syndrome
Donovan et al., Cell Reports. 2024.
https://pubmed.ncbi.nlm.nih.gov/39120971
Down syndrome (DS), a genetic condition caused by the presence of an extra copy of chromosome 21, is characterized by intellectual and developmental disability. Infants with DS often suffer from low oxygen saturation, and DS is associated with obstructive sleep apnea. Investigators assessed the role that hypoxia plays in driving health conditions that are comorbid with DS. A multiomic analysis showed that people with DS exhibit elevated heme metabolism and activated stress erythropoiesis, which are indicators of chronic hypoxia; these results were recapitulated in a mouse model for DS. This study identified hypoxia as a possible mechanism underlying several conditions that co-occur with DS, including congenital heart defects, seizure disorders, autoimmune disorders, several leukemias, and Alzheimer's disease. Supported by ORIP (R24OD035579), NCATS, NCI, and NIAID.
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.
Stat3 Mediates Fyn Kinase-Driven Dopaminergic Neurodegeneration and Microglia Activation
Siddiqui et al., Disease Models & Mechanisms. 2024.
https://pubmed.ncbi.nlm.nih.gov/39641161
The FYN gene is a risk locus for Alzheimer’s disease and several other neurodegenerative disorders. FYN encodes Fyn kinase, and previous studies have shown that Fyn signaling in dopaminergic neurons and microglia plays a role during neurodegeneration. This study investigated Fyn signaling using zebrafish that express a constitutively active Fyn Y531F mutant in neural cells. Activated neural Fyn signaling in the mutant animals resulted in dopaminergic neuron loss and induced inflammatory cytokine expression when compared with controls. Transcriptomic and chemical inhibition analyses revealed that Fyn-driven changes were dependent on the Stat3 and NF-κB signaling pathways, which work synergistically to activate neuronal inflammation and degeneration. This study provides insight into the mechanisms underlying neurodegeneration, identifying Stat3 as a novel effector of Fyn signaling and a potential translational target. Supported by ORIP (R24OD020166).
A Comparative Review of Cytokines and Cytokine Targeting in Sepsis: From Humans to Horses
Hobbs et al., Cells. 2024.
https://pubmed.ncbi.nlm.nih.gov/39273060
Bacterial infections resulting in endotoxin or exotoxin exposure can lead to sepsis because of dysregulated host responses. Sepsis causes organ dysfunction that can lead to death if not treated immediately, yet no proven pharmacological treatments exist. Horses can serve as a comparative and translational model for sepsis in humans because both species share mechanisms of immune response, including severe neutropenia, cytokine storms, formation of neutrophil extracellular traps, and decreased perfusion. Research on sepsis has focused on the pathophysiological role of interleukin-6, interleukin-1β, tumor necrosis factor-α, and interleukin10. Research on novel sepsis therapies has focused on monoclonal antibodies, cytokine antagonists, and cytokine removal through extracorporeal hemoperfusion. Future sepsis research should focus on optimizing therapeutic strategies of cytokine modulation and analyzing the underlying mechanisms of cytokine dysregulation. Supported by ORIP (T32OD011130).
A Single-Dose Intranasal Live-Attenuated Codon Deoptimized Vaccine Provides Broad Protection Against SARS-CoV-2 and Its Variants
Liu et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/39187479
Researchers developed an intranasal, single-dose, live-attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) vaccine (CDO-7N-1) using codon deoptimization. This vaccine demonstrates broad protection against SARS-CoV-2 variants, with highly attenuated replication and minimal lung pathology across multiple in vivo passages. The vaccine induced robust mucosal and systemic neutralizing antibodies, as well as T-cell responses, in male and female hamsters, female K18-hACE2 mice, and male HFH4-hACE2 mice. In male and female cynomolgus macaques, CDO-7N-1 effectively prevented infection, reduced severe disease, and limited transmission of SARS-CoV-2 variants. This innovative approach offers potential advantages over traditional spike-protein vaccines by providing durable protection and targeting emerging variants to curb virus transmission. Supported by ORIP (K01OD026529).
Temperature-Dependent Alterations in the Proteome of the Emergent Fish Pathogen Edwardsiella piscicida
Jacobsen et al., Journal of Fish Diseases. 2024.
https://pubmed.ncbi.nlm.nih.gov/39304982
Reported outbreaks of Edwardsiella piscicida, a bacterial pathogen among cultured and wild fish, have been steadily increasing over the past decade in tandem with climate change–mediated increases in water temperatures. The capacity for this increasingly prevalent fish pathogen to infect and cause disease in mammals is important to understand. Researchers examined the role of temperature on the virulence of E. piscicida to understand its pathogenesis in the context of climate warming trends and better understand its zoonotic potential. Findings revealed downregulation of virulence-related proteins, such as flagellar and Type VI secretion system proteins, at colder temperatures. These findings highlight the potential environmental factors influencing the pathogen’s threat to aquaculture and public health. Supported by ORIP (S10OD026918, T32OD011147).