Project description:C. elegans exhibit an age-dependent mechanical stress response to blunt force injury. Stress responses are often defined in part by an elicited cellular transcriptional response. We find in C. elegans that mechanical stress by blunt trauma induces a distinct and age-dependent transcriptional program.
Project description:The selective vulnerability of dopaminergic neurons to trauma-induced neurodegeneration is a conserved phenomenon across species, extending from nematodes to humans. However, the molecular mechanisms contributing to this hypersensitivity to blunt force injury remain poorly understood. We find that dopamine oxidation, a key driver of Parkinson’s Disease, extends its toxic role to the acute challenges of blunt force trauma. Ectopic synthesis of dopamine in serotonergic neurons alone proves sufficient in determining neuronal subtype sensitivity to trauma-induced death. While dopaminergic neurons maintain this neurotransmitter in a functional and benign state, trauma-induced subcellular redox imbalances elicit dopamine-dependent cytotoxicity. Perturbing dopamine synthesis and its packaging into synaptic vesicles further demonstrate how cytosolic dopamine is both necessary and sufficient to drive cell loss upon mechanical stress and during aging. Additionally, trauma activates the B-Zip transcription factor, fos-1, which exacerbates this toxic cascade by transcriptionally upregulating the rate-limiting enzyme in dopamine synthesis, cat-2. In summary, our study unravels the molecular intricacies that render dopaminergic neurons uniquely prone to physical perturbation, highlighting a shared vulnerability across different evolutionary lines.
Project description:The selective vulnerability of dopaminergic neurons to trauma-induced neurodegeneration is a conserved phenomenon across species, extending from nematodes to humans. However, the molecular mechanisms contributing to this hypersensitivity to blunt force injury remain poorly understood. We find that dopamine oxidation, a key driver of Parkinson’s Disease, extends its toxic role to the acute challenges of blunt force trauma. Ectopic synthesis of dopamine in serotonergic neurons alone proves sufficient in determining neuronal subtype sensitivity to trauma-induced death. While dopaminergic neurons maintain this neurotransmitter in a functional and benign state, trauma-induced subcellular redox imbalances elicit dopamine-dependent cytotoxicity. Perturbing dopamine synthesis and its packaging into synaptic vesicles further demonstrate how cytosolic dopamine is both necessary and sufficient to drive cell loss upon mechanical stress and during aging. Additionally, trauma activates the B-Zip transcription factor, fos-1, which exacerbates this toxic cascade by transcriptionally upregulating the rate-limiting enzyme in dopamine synthesis, cat-2. In summary, our study unravels the molecular intricacies that render dopaminergic neurons uniquely prone to physical perturbation, highlighting a shared vulnerability across different evolutionary lines.
Project description:Mechanical stress by blunt force trauma elicits a distinct and reproducible transcriptional response in C. elegans. Vhp-1, a MAPK phosphatase, regulates a significant portion of these stress-inducible transcripts.
Project description:Does the adoptive transfer of MDSCs modulate lymphocyte (T cell) functions? Microarray expression analysis of T cells from MDSC-treated mice after Blunt chest trauma (TxT)
Project description:Trauma induces a “genomic storm” of gene expression in circulating leukocytes. We hypothesized that the neutrophil contribution to this response after blunt trauma varies with the magnitude of physiologic insult and with exposure to additional and subsequent inflammatory stimuli.