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Identification of pathways signaling for autophagy involved in macrophage senescence using CRISPR-Cas9 genome wide screening

Grant number: 17/07863-5
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): July 10, 2017
Effective date (End): March 29, 2018
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Thiago Mattar Cunha
Grantee:Nerry Tatiana Cecilio
Supervisor abroad: Daniel Vicent Ebner
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : University of Oxford, England  
Associated to the scholarship:16/17773-0 - Validation of new pharmacological hits for the treatment of inflammatory diseases and pain, BP.PD

Abstract

Autophagy is an important homeostatic cellular process, responsible for the lysosomal degradation of non-functional proteins and organelles. Moreover, recently it is well accepted that autophagy has multiple effects on immune system. Interestingly, genetic ablation and pharmacological inhibition of autophagic machinery have been described to induce phenotypic modifications in immune cells related to enhancement of inflammation. Notably, these modifications also have been associated with aging. In fact, aging has been described to exhibit a reduced autophagic capacity and appear of chronic inflammatory condition. This state is currently designed as inflammaging. In addition, it is described that monocytes and macrophages have a pivotal role in triggering the inflammaging by the fact that autophagy capacity can interfere in the amounts of cytosolical and endosomal pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs), modulating indirectly the activation of pattern recognition receptors (PRRs). Moreover, in the autophagy absence occur an excessive cellular damage accumulation, leading cells to senescence, acquiring a senescence-associated secretory phenotype and reinforcing the inflammation. Although findings of multiple aging-like phenotypes of autophagy-deficient macrophages suggest that an impaired autophagy contributes to macrophage dysfunction, the genes and signalling pathways involved in this process remain unclear. Therefore, this project will investigate the mechanisms involved in the molecular link between autophagy and macrophage-aging phenotype. We propose to perform pooled CRISPR/Cas9 based screens aiming: (i) to describe the relationship between autophagy genes and macrophages aging; (ii) to evaluate this relationship during macrophage activation. Finally, the identified mechanisms here may be further approached to develop novel therapeutics for the chronic inflammatory diseases.

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