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Molecular mechanisms of protein aggregation and unconventional secretion in the context of inflammation and neurodegenerative disorders

Molecular mechanisms of protein aggregation and unconventional secretion in the context of inflammation and neurodegenerative disorders 2021-2023
Acronym: AggrInflam
Budget: 431.900 RON
Project director: Mari Chiritoiu

Background: Inflammation is a hallmark of many pathologies such as autoimmune and neurodegenerative disorders, diabetes and atherosclerosis. Cytokines of the IL-1 family are primary mediators of inflammation. These are cytoplasmic proteins exported from macrophages and monocytes via the unconventional secretory pathway (UPS). I have previously shown that interleukin-1β (IL-1β) secretion form activated primary macrophages is regulated by the GRASP55-IRE1α axis and disrupting this pathway leads to intracellular aggregation of IL-1β, hampers its secretion and causes general proteome instability. 
Hypothesis: Intracellular aggregation of cytoplasmic proteins (such IL-1β, α-synuclein and other) might be correlated with cargo availability for unconventional secretion, therefore modulating this process could provide potential methods to control pathological outcomes for inflammation and neurodegeneration. 
Aim: Dissect the molecular mechanism and identify intracellular factors modulating aggregation and secretion of UPS cargoes. For this purpose we will use as model cargo IL-1β, produced by cells of the immune system and further corroborate the functional conservation of the identified factors for α-synuclein physiology in neurons and C. elegans model for Parkinson’s disease. 
Expected results: This project should facilitate the understanding of signaling pathways and identify the intermediates transducing the information for the stress sensing machinery to induce cytoplasmic proteome instability. Also we estimate to indentify key proteins involved in UPS cargo aggregation, which could be used as targets to control the secretion of cytoplasmic proteins in the context of inflammation and neurodegeneration.

Mari Chiritoiu, PhD
Mari Chiritoiu, PhD

Senior Reseacher III

Mari Chiritoiu graduated from Faculty of Chemistry, University of Bucharest (2004-2008) and received her Ph.D. in Biology from the Institute of Biochemistry of the Romanian Academy in 2014, under the supervision of dr. Stefana Petrescu. She was a posdoctoral fellow in the lab of prof. Vivek Malhotra, at CRG-Centre for Genomic Regulation, Barcelona, Spain (2016-2019) where she investigated the process of unconventional protein secretion using as model cargo the pro-inflammatory cytokine interleukin-1β. In the future, dr. Chiritoiu aims to understand key aspects of the molecular mechanism of leaderless protein export, such as interleukin-1β and α-synuclein, More...