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Protein Disulfide Isomerase A1 (PDIA1) as integrative pathway of cell differentiation and mitochondrial function

Grant number: 20/03838-9
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2020
Effective date (End): August 31, 2022
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Francisco Rafael Martins Laurindo
Grantee:Lívia Teixeira
Home 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

Abstract

Our group has described several effects of PDIA1 (Protein Disulfide Isomerase) on the regulation of vascular redox signaling. These include production of oxidants by NADPH oxidases (Nox), regulation of the cytoskeleton, cell migration and differentiation. Increases in PDIA1expression are observed in the arterial wall in vascular diseases. However, the temporal evolution of the effects and possible mechanisms associated with increased expression of PDIA1 are unknown. The aim of this project is to investigate the effect of the gradual and sustained overexpression of PDIA1 in Vascular Smooth Muscle Cells (VSMC), induced by an inducible viral vector, in markers of VSMC differentiation and in the mitochondria dynamics and function. The planned approach includes the study, in the different stages of induced expression of PDIA1, of: expression of mitochondrial mass marker enzymes, mitophagy markers, mitochondrial DNA, electron microscopy for morphological analysis, production of mitochondrial superoxide, expression of enzymes related to mitochondrial fission and fusion and mitochondrial dynamics. The redox status of Drp1 will also be assessed. As an additional molecular mechanism, the expression and activity of Rho GTPases Rac1 and RhoA, in addition to Ras, will be investigated, considering that these proteins have the potential to remodel the cell cytoskeleton and mitochondrial dynamics. In particular, we will investigate the interaction of PDIA1 with Miro1 (and Miro2), which are mitochondrial Rho GTPases strongly involved in mitochondrial dynamics. In parallel, measurements of mitochondrial respiration, acidification of the medium and consumption of fatty acids will be performed. Finally, the in vivo relevance of this model will be evaluated in vascular injury and repair models. These data should provide important advances in the understanding of a new interaction pathway between PDIA1, a canonically located protein in the endoplasmic reticulum, and mitochondria in the regulation of the VSMC phenotype, an important determinant of vascular diseases. (AU)

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