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Role of the interaction between HIF-1 and the short chain fatty acids in the colon in physiological and pathologycal conditions (intestinal inflammation)

Grant number: 17/16280-3
Support type:Regular Research Grants
Duration: January 01, 2018 - December 31, 2019
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Marco Aurélio Ramirez Vinolo
Grantee:Marco Aurélio Ramirez Vinolo
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Short chain fatty acids (SCFAs) are products derived from the intestinal microbiota, which are produced mainly by the fermentation of dietary fibers. Found in high concentrations in the colon, SCFAs exert important functions for the maintainance of intestinal homeostasis including providing energy for intestinal epithelial cells (IECs), regulating their proliferation and apoptosis and modulating the immune system. Recent studies described that SCFAs can indirectly activate the transcription factor HIF-1 in IECs. However, the physiologycal relevance of this effect and the involvement of other molecular mechanisms of SCFAs action (epigenetic modifications and FFAR2 activation) were not investigated. The aim of this study is to investigate the relevance of HIF-1 expression in IECs for the effects of SCFAs produced under physiological (diets with different amounts of fibers) and pathological conditions (C.difficile-induced colitis). In addition, we intend to analyze additional mechanisms of interaction between SCFAs and HIF-1 including epigenetic modifications and the participation of the SCFA receptor, FFAR2. For this, we will use in vivo models (animals with deletion of HIF-1± and/or Vhl in specifically in IECs and knockouts for FFAR2) and in vitro (intestinal organoids), in which we will perform molecular analyzes including Western blotting, immunofluorescence, RT-PCR, analysis 16S, RNA sequencing, ChIP-Seq, tests with HDAC inhibitors, and intestinal immunohistological analyzes following C. difficile-induced colitis. (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)
FACHI, JOSE LUIS; SECCA, CRISTIANE; RODRIGUES, PATRICIA BRITO; PINHEIRO DE MATO, FELIPE CEZAR; DI LUCCIA, BLANDA; FELIPE, JAQUELINE DE SOUZA; PRAL, LAIS PASSARIELLO; RUNGUE, MARCELLA; ROCHA, VICTOR DE MELO; SATO, FABIO TAKEO; SAMPAIO, ULLIANA; PEDROSA SILVA CLERICI, MARIA TERESA; RODRIGUES, HOSANA GOMES; SARAIVA CAMARA, NIELS OLSEN; CONSONNI, SILVIO ROBERTO; VIEIRA, ANGELICA THOMAZ; OLIVEIRA, SERGIO COSTA; MACKAY, CHARLES REAY; LAYDEN, BRIAN T.; BORTOLUCI, KARINA RAMALHO; COLONNA, MARCO; RAMIREZ VINOLO, MARCO AURELIO. Acetate coordinates neutrophil and ILC3 responses against C. difficile through FFAR2. JOURNAL OF EXPERIMENTAL MEDICINE, v. 217, n. 3 MAR 2020. Web of Science Citations: 0.
FACHI, JOSE LUIS; FELIPE, JAQUELINE DE SOUZA; PRAL, LAIS PASSARIELLO; DA SILVA, BRUNA KARADI; CORREA, RENAN OLIVEIRA; PEREIRA DE ANDRADE, MIRELLA CRISTINY; DA FONSECA, DENISE MORAIS; BASSO, PAULO JOSE; SARAIVA CAMARA, NIELS OLSEN; DE SALES E SOUZA, ERICKA LORENNA; MARTINS, FLAVIANO DOS SANTOS; SATO GUIMA, SUZANA EIKO; THOMAS, ANDREW MALTEZ; SETUBAL, JOAO CARLOS; MAGALHAES, YULI THAMIRES; FORTI, FABIO LUIS; CANDREVA, THAMIRIS; RODRIGUES, HOSANA GOMES; DE JESUS, MARCELO BISPO; CONSONNI, SILVIO ROBERTO; FARIAS, ALESSANDRO DOS SANTOS; VARGA-WEISZ, PATRICK; RAMIREZ VINOLO, MARCO AURELIO. Butyrate Protects Mice from Clostridium difficile-Induced Colitis through an HIF-1-Dependent Mechanism. CELL REPORTS, v. 27, n. 3, p. 750+, APR 16 2019. Web of Science Citations: 3.

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