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Endoplasmic reticulum-plasma membrane contacts as hubs for NOx NADPH oxidase-dependent cellular redox signaling

Grant number: 18/07511-4
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): September 01, 2018
Effective date (End): December 02, 2023
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Francisco Rafael Martins Laurindo
Grantee:Tiphany Coralie de Bessa
Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated research grant:13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID
Associated scholarship(s):21/13257-6 - Molecular mechanisms involved in redox-dependent regulation of endoplasmic reticulum-plasma membrane contacts, BE.EP.PD

Abstract

Redox processes emerged as major regulatory mechanisms of cell signaling and strongly regulate (patho)physiological processes, but several fundamental underlying mechanisms remain unclear, including in particular the associated subcellular compartmentalization. This remains a fundamental problem in cell biology, essential to clarify the implications of redox processes in health and disease. Our group identified the endoplasmic reticulum (ER) chaperone protein disulfide isomerase A1 (PDIA1) as a strong regulator of Nox family NADPH oxidases, a major cell signaling-related source of reactive oxygen species (ROS). ER-plasma membrane (PM) contacts are major sites for calcium signaling and regulate protein secretion and ER stress. We hypothesized that ER-PM contacts are preferential sites for the organization of redox-mediated signaling processes, particularly those associated with Noxes and PDIA1, as well as a potential hub for convergence between calcium signaling and redox processes. Since formation and stabilization of ER-PM contacts is highly dynamic, it is possible that ER-PM contacts help support oxidant generation and Nox assembling, while ER-PM contacts could also be redox / Nox signaling targets themselves, so that Nox activation might influence the number and extent of ER-PM contacts in cells. The central aim of our project focuses on the hypothesis of a mutual convergence - physical as well as functional - between Nox(es) and the formation/stabilization of dynamic ER-PM contacts. The specific aims are: 1) To map the extent of ER-PM contacts in wild-type vascular smooth muscle cells (VSMC) and in VSMC overexpressing synaptotagmin-3 (E-Syt3), a structural marker of ER-PM contacts; 2) To perform in those VSMC a combined approach to calcium/ROS imaging; 3) To investigate through imaging tools and loss-of-function approaches the roles of Nox4, Nox1 and PDIA1 on the extent of ER-PM contacts and calcium/ROS imaging. This project will be developed in collaboration with the King's College London (Prof. Ajay Shah's group) which are expert in calcium and ROS imaging. These results can provide entirely novel and original mechanisms of cellular redox signaling.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SANTOS DE OLIVEIRA, PERCILLIA VICTORIA; GARCIA-ROSA, SHEILA; AZEVEDO SACHETTO, ANA TERESA; SOARES MORETTI, ANA IOCHABEL; DEBBAS, VICTOR; DE BESSA, TIPHANY CORALIE; SILVA, NATHALIA TENGUAN; PEREIRA, ALEXANDRE DA COSTA; MARTINS-DE-SOUZA, DANIEL; SANTORO, MARCELO LARAMI; et al. Protein disulfide isomerase plasma levels in healthy humans reveal proteomic signatures involved in contrasting endothelial phenotypes. REDOX BIOLOGY, v. 22, . (17/25588-1, 18/07511-4, 17/19866-9, 14/20595-1, 13/08711-3, 13/25177-0, 14/10068-4, 13/07937-8)

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