Characterization of the interaction of nuclear receptor PPAR³ with the deacetylase SIRT1 under influence of its phosphorylation in the context of metabolic homeostasis regulation

• Grant number: 20/08366-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2021
• End date: August 14, 2025
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Ana Carolina Migliorini Figueira
• Grantee: Caique Camargo Malospirito
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Associated scholarship(s): 22/11624-4 - Structural characterization of PPAR³:SIRT1 protein complex in the context of obesity and insulin resistance, BE.EP.DR

Abstract

The Metabolic Syndrome is a cluster of conditions that happens together. These conditions disrupt the body glycose levels homeostasis, which leads to a resistance to respond to insulin. The thiazolidinediones (TZDs) are the main drug for the treatment of Metabolic Syndrome. It targets the ligate-dependent nuclear receptor (RN) PPAR³ where it acts as a strong agonist. The PPAR³ is a key player in improving insulin sensitivity once activated. It acts as a transcriptional factor changing the level of expression in a subset of genes related to insulin resistance. However, the long-term administration of TZDs in comorbid patients has been in intense discussion. Besides its beneficial effects of PPAR³ activation, the TZDs also cause adverse effects to the patients, worsening this clinical condition. Its already know that the balance between PPAR³ posttranscriptional modifications (MPT) as phosphorylation at Lis293 and Lis268 for CDK5 and the acetylation/deacetylation at Lis293 and Lis268 p300/SIRT1 drive to benefits effects to the organism. Based on this, this project aims (1) to characterize in vitro the molecular basis of PPAR³:SIRT complex and (2) investigate the influence of phosphorylation from CDK5 in that relationship. In addition, we will search for new potential molecular that could act as a partial agonist of PPAR³, activating it without causing any damage to the patient. In this investigation, we intend to determine the affinity between PPAR³:SIRT1 by biophysical techniques and the structure of the complex as well. Furthermore, a screening for new molecules able to act as a partial agonist also we shall perform. In parallel, colleagues also will execute in vivo characterization for a robust and multi multidisciplinary approach towards a better understanding of proposed goals. (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)

DE OLIVEIRA, VINICIUS M.; MALOSPIRITO, CAIQUE C.; DA SILVA, FERNANDO B.; VIDEIRA, NATALIA B.; DIAS, MARIELI M. G.; SANCHES, MURILO N.; LEITE, VITOR B. P.; FIGUEIRA, ANA CAROLINA M.. Exploring the molecular pathways of the activation process in PPARγ recurrent bladder cancer mutants. Journal of Chemical Physics, v. 161, n. 16, p. 10-pg., 2024-10-28. (23/02219-1, 19/14465-1, 16/02348-2, 18/11614-3, 20/08366-8, 21/15028-4, 19/22540-3, 19/10274-7, 22/07231-7, 16/19766-1)