Selected Grantee Publications
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).
Extracted Plasma Cell-Free DNA Concentrations Are Elevated in Colic Patients With Systemic Inflammation
Bayless et al., Veterinary Sciences. 2024.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11435807
Researchers investigated cell-free DNA (cfDNA) as a potential biomarker to detect colic in humans. In horses, colic is a life-threatening gastrointestinal (GI) condition. Measurements of cfDNA released from damaged or dying cells in the blood of male and female horses with colic were compared across groups based on GI disease type, signs of inflammation, and survival status. Elevated cfDNA levels were prominent in horses with systemic inflammation, but did not significantly differ by GI disease type or survival. This study suggests that cfDNA may be linked to inflammatory responses in colic conditions. Supported by ORIP (T32OD011130).