The role of cytokine activated NFkB and STAT1 pathways in impairment of insulin secretion of cachectic solid Ehrlich carcinoma-bearing mice.

• Grant number: 12/23603-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: May 01, 2013
• End date: February 28, 2017
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: José Roberto Bosqueiro
• Grantee: Natalia Moretti Violato
• Host Institution: Faculdade de Ciências (FC). Universidade Estadual Paulista (UNESP). Campus de Bauru. Bauru , SP, Brazil
• Associated scholarship(s): 15/01237-0 - The endoplasmic reticulum stress-induced gene CHOP: orchestrating the cross talk between er stress, apoptosis and inflammation in type 1 Diabetes, BE.EP.DR

Abstract

Cachexia is a common syndrome that affects malignant tumor-bearing patients, and is characterized by a severe imbalance in metabolic homeostasis, acting especially in glycemic homeostatic mechanisms. In previous studies, we demonstrate that solid Ehrlich tumor bearing mice (SET) showed diminished insulin secretion and higher insulin sensitivity when compared to control group. Furthermore, there was a significant increase in cytokines levels in pancreatic islets, as IL-1², TNF-±, IFN-³, IL-6 and IL-8 associated with lymphocyte infiltrate. The establishment of systemic inflammation seems to play a pivotal role in cachexia progression, mainly by cytokine presence. However, there are no studies that clarify the mechanisms responsible for alterations in insulin secretion in cancer cachexia or correlate these alterations with inflammatory islet status. Considering the importance of insulin secretion to metabolic homeostasis control, to identify mechanisms involved in this process became important. Thus, in this study we propose to investigate the effects of high cytokine levels in pancreatic islets of solid Ehrlich carcinoma-bearing mice in the activity of important inflammatory pathways, notably apoptotic pathways, searching for evidence that could indicate the involvement of inflammatory status in diminished insulin secretion capacity. For that, islets isolated from Swiss mice (CTL) and tumor-bearing mice (SET) with 14 days of tumor inoculation will be analyzed to evaluate protein expression of NFºB and STAT1 pathways, expression of apoptotic genes and measurement of insulin secretion with NFºB and STAT1specific blockers. Furthermore, we will accomplish morphometric and morphological analysis like growth, proliferation and beta cell mass.