Unveiling HSPB1's role in prolactin-induced modulation of the unfolded protein response in type 1 Diabetes models

• Grant number: 17/03618-6
• Support Opportunities: Regular Research Grants
• Duration: October 01, 2017 - March 31, 2020
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Leticia Labriola
• Grantee: Leticia Labriola
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia resulting from deficiency in insulin secretion, action thereof, or both. Islet transplantation is a promising therapy for the treatment of type 1 diabetes mellitus (T1DM). However, the islet grafts are subjected to rejection by the immune system of the receptor patients. Thus, in order to optimize the success rate of the procedure, it is necessary to develop efficient strategies leading to beta-cell cytoprotection. Previous results from our laboratory have shown that the hormone prolactin (PRL) inhibits apoptosis triggered by pro-inflammatory cytokines in beta cells and that this process depends, at least in part on the presence of HSPB1, a protein family of the Heat Shock Proteins (HSPs). HSPs inhibit the formation and/or ER accumulation of poorly folded polypeptides. This increase of misfolded proteins in the ER may cause the so-called endoplasmic reticulum stress (ER stress) which is responsible for the Unfolded Protein Response activation (UPR) designed to lead to cell proteostasis but, depending on the extent and duration of the stress conditions can also induce apoptosis. It has been shown that during T1DM development, beta cells undergo ER stress that also contributes to trigger cell death. Recent results from our group have not only shown that PRL was able to protect beta cells against ER stress-induced beta-cell death but also that HSPB1 is an essential mediator of this cytoprotective effect. Since there are no molecular mechanisms describing the role HSPB1 in PRL-induced inhibition of ER stress-mediated beta-cell death, we set out to study the role of HSPB1 in PRL modulation of UPR in DM1 models. Since there is a direct link between UPR activation and induction of intrinsic apoptosis, we also plan to complete our previous studies in order to better understand the role of HSPB1 on beta-cell mitochondrial function. The knowledge generated by this project will contribute to generate efficient strategies leading to increase beta cell viability and thus to an optimization of islet transplantation's success rate in DM1 patients. (AU)

Scientific publications

(5)

(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)

DOS SANTOS, ANCELY F.; DE ALMEIDA, DARIA RAQUEL Q.; TERRA, LETICIA F.; WAILEMANN, ROSANGELA A. M.; GOMES, VINICIUS M.; ARINI, GABRIEL S.; RAVAGNANI, FELIPE G.; BAPTISTA, MAURICIO S.; LABRIOLA, LETICIA. Fluence Rate Determines PDT Efficiency in Breast Cancer Cells Displaying Different GSH Levels. Photochemistry and Photobiology, v. 96, n. 3, SI, DEC 2019. (13/07937-8, 16/04676-7, 17/03618-6, 19/09517-2)

WAILEMANN, ROSANGELA A. M.; TERRA, LETICIA F.; OLIVEIRA, TALITA C.; DOS SANTOS, ANCELY F.; GOMES, VINICIUS M.; LABRIOLA, LETICIA. Heat shock protein B1 is required for the prolactin-induced cytoprotective effects on pancreatic islets. Molecular and Cellular Endocrinology, v. 477, p. 39-47, DEC 5 2018. (14/17974-0, 14/02745-6, 13/13914-0, 13/07029-4, 16/04676-7, 17/03618-6)

TERRA, LETICIA F.; WAILEMANN, ROSANGELA A. M.; DOS SANTOS, ANCELY F.; GOMES, VINICIUS M.; SILVA, RAILMARA P.; LAPORTE, ANNA; MEOTTI, FLAVIA C.; TERRA, WALTER R.; PALMISANO, GIUSEPPE; LORTZ, STEPHAN; et al. Heat shock protein B1 is a key mediator of prolactin-induced beta-cell cytoprotection against oxidative stress. Free Radical Biology and Medicine, v. 134, p. 394-405, APR 2019. (16/02881-2, 14/17974-0, 13/07029-4, 17/03618-6, 14/02745-6, 13/13914-0)

MULE, SIMON NGAO; GOMES, VINICIUS DE MORAIS; WAILEMANN, ROSANGELA A. M.; MACEDO-DA-SILVA, JANAINA; ROSA-FERNANDES, LIVIA; LARSEN, MARTIN R.; LABRIOLA, LETICIA; PALMISANO, GIUSEPPE. HSPB1 influences mitochondrial respiration in ER-stressed beta cells. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, v. 1869, n. 9, SEP 2021. (17/04032-5, 14/02745-6, 17/03618-6, 18/18257-1, 16/04676-7, 20/04923-0, 16/14845-0, 13/07937-8, 18/15549-1, 21/00507-4)

DOS SANTOS, ANCELY F.; INAGUE, ALEX; ARINI, GABRIEL S.; TERRA, LETICIA F.; WAILEMANN, ROSANGELA A. M.; PIMENTEL, ANDRE C.; YOSHINAGA, MARCOS Y.; SILVA, RICARDO R.; SEVERINO, DIVINOMAR; DE ALMEIDA, DARIA RAQUEL Q.; et al. Distinct photo-oxidation-induced cell death pathways lead to selective killing of human breast cancer cells. CELL DEATH & DISEASE, v. 11, n. 12, DEC 14 2020. (19/09517-2, 17/13804-1, 19/05026-4, 16/04676-7, 17/23914-9, 17/18922-2, 17/03618-6, 15/02654-3, 13/07937-8)