Study of pancreatic beta cell demise: role of NF-kB, HNF4a and IL6 in the Diabetes mellitus development

• Grant number: 17/04580-2
• Support Opportunities: Regular Research Grants
• Duration: July 01, 2017 - June 30, 2019
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Fernanda Ortis
• Grantee: Fernanda Ortis
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Alex Rafacho ; Angelo Rafael Carpinelli ; Antonio Carlos Boschiero ; Fernando Rodrigues de Moraes Abdulkader ; Gustavo Jorge dos Santos ; José Maria Costa Júnior ; Sandra Mara Ferreira

Abstract

Diabetes Mellitus (DM) is a disease characterized by chronic hyperglycemia and alteration in the metabolism of carbohydrate, lipids and protein. There are different forms of the disease, that differ on its etiology, however they have in common the induction of dysfunction and cell death of the pancreatic beta cells. Thus, it is of extreme importance a better understanding of the molecular mechanisms involved in the this demise of the pancreatic beta cells during the development of the DM in order to design effective therapies against this disease. The two main forms of this disease are the type 1 (DM1), autoimmune, and the type 2 (DM2), related with insulin resistance. The mechanisms leading to cell death and dysfunction are different between these two forms of DM, however they present common features, such as activation of the endoplasmic reticulum (ER) stress and of key transcriptional factors involved in the regulation of beta cell viability and function. Recently another type of DM, maturity-onset diabetes of the young (MODY) has being described; this DM is characterized by an autosomal dominant mode of inheritance that leads to an unpaired insulin secretion. There are different types of MODY, depending on the gene affected, the MODY1 highlight the role of the transcription factor HNF4± in the maintenance of beta cells function and viability, and also in the regulation of the ER homeostasis.Thus, the present project aim to analyze the pathways related the induction of beta cell death and dysfunction, such as the expression and regulation of transcription factors (NF-kB, HNF4±) and pathways involved in the regulation of cell homeostasis (ERK1/2, JNK and ER stress) in animal and cellular models that mimic the conditions during the development of DM1 and DM2. Besides we intend also to analyze the modulation of these pathways during treatments described as beneficial for the maintenance of beta cell function and viability, such as the IL-6 produced during physical exercise. (AU)

Scientific publications

(4)

(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; ORTIS, FERNANDA; CARDOZO, ALESSANDRA K.. The non-canonical NF-kappa B pathway and its contribution to beta-cell failure in diabetes. JOURNAL OF MOLECULAR ENDOCRINOLOGY, v. 61, n. 2, p. F1-F6, AUG 2018. (17/04580-2)

VILAS-BOAS, ELOISA A.; CARLEIN, CHRISTOPHER; NALBACH, LISA; ALMEIDA, DAVIDSON C.; AMPOFO, EMMANUEL; CARPINELLI, ANGELO R.; ROMA, LETICIA P.; ORTIS, FERNANDA. Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts beta-Cell Function and Survival. ANTIOXIDANTS, v. 10, n. 8, AUG 2021. (17/26339-5, 20/06184-0, 17/04580-2, 13/08769-1)

VILAS-BOAS, ELOISA APARECIDA; ALMEIDA, DAVIDSON CORREA; ROMA, LETICIA PRATES; ORTIS, FERNANDA; CARPINELLI, ANGELO RAFAEL. Lipotoxicity and beta-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress. CELLS, v. 10, n. 12, DEC 2021. (17/26339-5, 17/04580-2, 19/26062-9, 14/50867-3, 20/06184-0)

PIMENTEL VILLACA, CATHARINA DE BARROS; DE PAULA, CAROLINA CAVALCANTE; DE OLIVEIRA, CAROLINE CRUZ; VILAS-BOAS, ELOISA APARECIDA; DOS SANTOS-SILVA, JUNIA CAROLINA; DE OLIVEIRA, SERGIO FERREIRA; ABDULKADER, FERNANDO; FERREIRA, SANDRA MARA; ORTIS, FERNANDA. Beneficial effects of physical exercise for beta-cell maintenance in a type 1 diabetes mellitus animal model. Experimental Physiology, v. 106, n. 7, p. 1482-1497, JUL 2021. (14/50867-3, 17/04580-2, 19/26062-9)