Dante Rivera
Predoctoral trainee (Tahmasebi Lab)
Department of Pharmacology & Regenerative Medicine
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About
Advisor: Soroush Tahmasebi
Co-mentor: Ki-Wook Kim
Project Title:
"Role of GCN2-eIF2 in Regulating Tissue Resident Macrophages in an Experimental Autoimmune Encephalomyelitis (EAE) Disease Model"
Project Summary/Abstract:
General control nonderepressible 2 (GCN2)-eIF2a signaling is a branch of the integrated stress response (ISR) activated in response to various environmental stressors, including amino acid deprivation and UV irradiation. GCN2 is a serine-threonine kinase that is responsible for the phosphorylation of a key translation initiation factor, eIF2. Phosphorylation of the alpha subunit of eIF2 (P-eIF2a) at a single residue, serine 51, has an inhibitory effect on global protein synthesis, with the exception of the translation of stress-related proteins like Activating transcription factor 4 (ATF4).
The activation of the GCN2-eIF2a pathway has been associated with neurodegenerative diseases such as Huntington’s Disease and Multiple Sclerosis (MS). Integrated Stress Response Inhibitor (ISRIB), a compound that blocks P-eIF2a’s effect on translation, has shown promise in its capacity to ameliorate neurodegenerative symptoms in murine models of MS, making it an attractive candidate for the treatment of this disease. Monocyte-macrophages play a critical role in the pathogenesis of neurodegenerative diseases, including MS.
However, the modulation of the ISR in monocyte-macrophages remains unclear. In addition to monocyte-macrophages, endothelial cells (ECs) and their crosstalk with monocyte-macrophages play a crucial role in defining the outcome of inflammation-induced tissue damage.
One of the aims of this project is to understand the role of the GCN2-eIF2a pathway in the context of monocyte-macrophage and EC communications. To overcome this gap in scholarship, our proposed project aims to utilize tamoxifen-inducible macrophage or EC-specific phosphorylation-resistant eIF2α or GCN2 knockout (KO) mouse lines to investigate the interplay between macrophages and vasculature via the GCN2-EIF2α pathway in a mouse model of MS.