The endoplasmic reticulum stress-induced gene CHOP: orchestrating the cross talk between er stress, apoptosis and inflammation in type 1 Diabetes

• Grant number: 15/01237-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: May 01, 2015
• End date: April 30, 2016
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: José Roberto Bosqueiro
• Grantee: Natalia Moretti Violato
• Supervisor: Alessandra Kupper Cardozo
• Host Institution: Faculdade de Ciências (FC). Universidade Estadual Paulista (UNESP). Campus de Bauru. Bauru , SP, Brazil
• Institution abroad: Université Libre de Bruxelles (ULB), Belgium
• Associated to the scholarship: 12/23603-0 - The role of cytokine activated NFkB and STAT1 pathways in impairment of insulin secretion of cachectic solid Ehrlich carcinoma-bearing mice., BP.DR

Abstract

Type 1 diabetes (T1D) is a severe chronic disease of childhood and adolescence resulting from an autoimmune destruction of the pancreatic beta-cells. Endoplasmic reticulum (ER) stress contributes to beta-cell dysfunction and death in type 1 diabetes. CHOP is an important pro-apoptotic transcription factor induced by ER stress. Dr. Cardozo's group have previously shown that pro-inflammatory cytokines induce CHOP in rat and human beta-cells and that knockdown of CHOP decreases cytokine-induced apoptosis. Moreover, they showed that knocking down CHOP using specific siRNAs decrease cytokine-induced apoptosis in both rodent beta-cells and human islets. Importantly, current data from their laboratory showed an increase in CHOP expression in islets from T1D patients as compared to control subjects. Overall, these recent data establish an important role for CHOP expression in ²-cell apoptosis in T1D. Although it is well known that CHOP is a pro-apoptotic protein, it is still unclear how this transcription factor exerts its pro-apoptotic effects. Therefore, Dr. Cardozo's group presently performed a proteome analysis of insulin-producing beta-cells exposed to cytokines in the presence or absence of CHOP inhibition by specific siRNAs. Proteomics data was analyzed in an unbiased manner using the Ingenuity Pathway Analysis (IPA) software. IPA analysis showed that CHOP knockdown leads to upregulation of a series of proteins downstream the transcription factor XBP-1. In addition, downregulation of several proteins downstream the STAT-1 pathway was also observed. Against this background the aims of the present project are: 1. Characterize the molecular mechanisms by which CHOP regulates beta-cell apoptosis, focusing on its negative regulation of the transcription factors XBP-1; 2. Characterize the molecular mechanisms by which CHOP regulate beta-cell pro-inflammatory responses, focusing on its positive regulation of the transcription factors STAT-1. The present project is innovative and will provide the basis for the design of novel interventions to prevent beta-cell destruction in T1D. (AU)

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)

MEYEROVICH, KIRA; VIOLATO, NATALIA M.; FUKAYA, MAKIKO; DIRIX, VIOLETTE; PACHERA, NATHALIE; MARSELLI, LORELLA; MARCHETTI, PIERO; STRASSER, ANDREAS; EIZIRIK, DECIO L.; CARDOZO, ALESSANDRA K.. MCL-1 Is a Key Antiapoptotic Protein in Human and Rodent Pancreatic beta-Cells. Diabetes, v. 66, n. 9, p. 2446-2458, SEP 1 2017. (15/01237-0)