Identification of novel IRE-1alpha interacting proteins and their role in pancreatic beta cells ER stress and inflammation

• Grant number: 13/25835-8
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: April 10, 2014
• End date: April 09, 2015
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Antonio Carlos Boschiero
• Grantee: Tarlliza Romanna Nardelli
• Supervisor: Décio L. Eizirik
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Université Libre de Bruxelles (ULB), Belgium
• Associated to the scholarship: 11/22852-3 - Involvement of prolactin in the prevention of beta cells dysfunction and death induced by endoplasmic reticulum stress, BP.DD

Abstract

Type I diabetes (T1D) is triggered by an autoimmune assault with a strong inflammatory component. Recent findings by the host laboratory suggest that components of unfolded protein response (UPR) are present in islets of T1D patients and contribute to trigger diabetes in mouse models. The UPR is activated to upgrade the functional capacity of the endoplasmic reticulum (ER) when this organelle faces increased demand for protein translation and folding. The UPR amplifies beta cell inflammation by increasing the expression of the pro-inflammatory transcription factor nuclear factor-kappaB (NF-kappaB) and its downstream pro-inflammatory molecules. One of the key components of the UPR is the ER membrane protein IRE-1alpha. This protein is regulated by the accumulation of unfolded proteins inside the ER and by interactions with cytosolic regulatory proteins that remain to be identified in pancreatic beta cell. Experiments carried out by the host laboratory suggest that IRE-1alpha, and its downstream target X-box binding protein 1 spliced, are the key regulatory molecules in the cross-talk between ER stress and beta cell pro-inflammatory responses. Therefore, in this study we intent to determine and characterize new IRE-1alpha-interacting proteins in pancreatic beta cells and to investigate their role in cytokine-dependent IRE-1alpha activation and UPR modulation, and in the amplification of the inflammatory response. (AU)