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Neural, hormonal and nutritional control of autophagy

Grant number: 18/10089-2
Support type:Research Projects - Thematic Grants
Duration: April 01, 2019 - March 31, 2024
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Isis Do Carmo Kettelhut
Grantee:Isis Do Carmo Kettelhut
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto, SP, Brazil
Co-Principal Investigators:Luciane Carla Alberici ; Luiz Carlos Carvalho Navegantes
Assoc. researchers:Amanda Martins Baviera ; Fernando Silva Ramalho ; Marc R. Montminy ; Mariana Kiomy Osako ; Rubens Fazan Júnior ; Rüdiger Rudolf

Abstract

Autophagy is a ubiquitous catabolic process that causes intracellular degradation through vesicular engulfment of dysfunctional, damaged, or harmful cytoplasmic components. Although it is well established that autophagy and the Ub-proteasome system regulate cellular homeostasis, the exacerbation of these processes leads to muscle atrophy and several pathologies. Previous work from our laboratory has demonstrated that activation of cAMP signaling plays an important role in the inhibition of proteolytic processes in different tissues including skeletal muscle, heart, brown adipose tissue as well as in the neuromuscular junction (NMJ) of rodents. The present project aims to investigate the mechanisms (transmission signals, transcription factors, degradation pathways and protein synthesis, etc.) through which the CNS, via the sympathetic nerves, hormones (glucocorticoids, glucagon, adrenaline and angiotensin II), peptides (CGRP) and dietary factors control autophagy in the setting of basal and energy demanding situations like fasting, exercise and cold. Moreover, we aim to investigate the effects of muscle transfection with Urocortin 2, a peptide that acts through cAMP, in the attenuation of muscle atrophy and loss of cholinergic receptors at the NMJ of denervated muscles and insulin sensitivity in obese animals. To this end, we will use biochemical, molecular and imaging methods for the evaluation of autophagic flow and protein metabolism turnover in tissues and cells. Also, we propose to use transgenic and mutant Drosophila melanogaster models of proteins of interest and carriers of fluorescent markers to estimate autophagy. The better understanding of the regulatory control of autophagy may contribute to the development of therapeutic strategies for metabolic and neuromuscular diseases. (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)
GONCALVES, DAWIT A.; SILVEIRA, WILIAN A.; MANFREDI, LEANDRO H.; GRACA, FLAVIA A.; ARMANI, ANDREA; BERTAGGIA, ENRICO; O'NEILL, BRIAN T.; LAUTHERBACH, NATALIA; MACHADO, JULIANO; NOGARA, LEONARDO; PEREIRA, MARCELO G.; ARCIDIACONO, DILETTA; REALDON, STEFANO; KAHN, C. RONALD; SANDRI, MARCO; KETTELHUT, ISIS C.; NAVEGANTES, LUIZ CARLOS C. Insulin/IGF1 signalling mediates the effects of beta(2)-adrenergic agonist on muscle proteostasis and growth. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, v. 10, n. 2, p. 455-475, APR 2019. Web of Science Citations: 0.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.