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Control of the transcriptome in diabetes mellitus

Abstract

Molecular genetic studies will be performed on type-1 (T1-D), type-2 (T2-D) and gestational (GD) diabetes, evaluating the large scale gene expression profiles (transcriptome level). T1-D is an autoimmune disorder caused by the immunological destruction of pancreatic β- cells, leading to insulin dependence. Although several susceptibility loci have been described in association with T1-D, the major genetic component has been associated with MHC located at chromosome 6 (HLA) in humans and 17 in mouse. A counterpart of T1-D in experimental models has been reproduced in the non obese mouse (NOD), in which syntenic regions mouse/human have been described. T2-D and GD are characterized by glucose homeostasis unbalance primarily determined by environmental factors, including diet and life style in T2-0, predisposing to obesity (non-autoimmune diabetes), or during pregnancy (GD). Overall, these diseases reflect the contribution of genetic and environmental factors. According to our hypothesis, the study of distinct presentation forms of diabetes mellitus may answer questions about autoimmunity molecular genetics (T1-D), as well as questions referring to the consequences of metabolic alterations (T2-D and GD). The susceptibility loci of these complex diseases, including T1-D and T2-D, have been identified on the basis of linkage studies, which allow the association of specific chromosome regions with particular phenotypes. Therefore, several questions were addressed: firstly, whether such chromosome regions are in fact transcribed into mRNAs. Our approach to this subject relies on functional genomics, by using the microarray technology and bioinformatic analysis. This kind of approach may explore gene expression profiles at large scale encompassing several reported and unreported diabetes mellitus susceptibility regions. In addition, the meta-analysis of gene expression data may identify shared modulated genes in the three variants of diabetes. Secondly, whether or not gene expression profiles in humans may exhibit syntheny with those observed in mouse. To reach this goal, we will study NOD (non obese diabetic) mouse that reproduces T1-D, attempting to establish a parallel between human and mouse gene expression profiles relatively to susceptibility chromosome regions. Thirdly, evaluate regulators of gene expression that has been reported to be associated with autoimmune disorders, including the autoimmune regulator gene Aire (autoimmune regulatory in the context of T1-D and NOD; the consequences of the modulation of Aire expression will be studied using the RNAi (interference RNA) strategy. The regulatory role of microRNAs will further be studied in the context of T1-D, T2-D and GD. Finally, considering that the glucose metabolism is impAired in diabetes, yielding reactive oxygen species, gene expression profiles exhibited by the T1-D, T2-D and GD will be studied in response to the oxidative stress. In addition, for some particular genes, the effects of oxidative agents, including glucose and hydrogen peroxide, will be evaluated in terms of transcription (mRNA) and translation (protein) in lymphocytes obtained from healthy individuals. This approach may permit the validation of the microarray data. (AU)

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Scientific publications (10)
(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)
OLIVEIRA, ERNNA H.; MACEDO, CLAUDIA; COLLARES, CRISTHIANNA V.; FREITAS, ANA CAROLINA; DONATE, PAULA BARBIM; SAKAMOTO-HOJO, ELZA T.; DONADI, EDUARDO A.; PASSOS, GERALDO A. Aire Downregulation Is Associated with Changes in the Posttranscriptional Control of Peripheral Tissue Antigens in Medullary Thymic Epithelial Cells. FRONTIERS IN IMMUNOLOGY, v. 7, NOV 23 2016. Web of Science Citations: 4.
FORNARI, THAIS A.; DONATE, PAULA B.; ASSIS, AMANDA F.; MACEDO, CLAUDIA; SAKAMOTO-HOJO, ELZA T.; DONADI, EDUARDO A.; PASSOS, GERALDO A. Comprehensive Survey of miRNA-mRNA Interactions Reveals That Ccr7 and Cd247 (CD3 zeta) are Posttranscriptionally Controlled in Pancreas Infiltrating T Lymphocytes of Non-Obese Diabetic (NOD) Mice. PLoS One, v. 10, n. 11 NOV 25 2015. Web of Science Citations: 11.
XAVIER, DANILO J.; TAKAHASHI, PAULA; EVANGELISTA, ADRIANE F.; FOSS-FREITAS, MARIA C.; FOSS, MILTON C.; DONADI, EDUARDO A.; PASSOS, GERALDO A.; SAKAMOTO-HOJO, ELZA T. Assessment of DNA damage and mRNA/miRNA transcriptional expression profiles in hyperglycemic versus non-hyperglycemic patients with type 2 diabetes mellitus. MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS, v. 776, n. SI, p. 98-110, JUN 2015. Web of Science Citations: 11.
MACEDO, CLAUDIA; OLIVEIRA, ERNNA H.; ALMEIDA, RENATA S.; DONATE, PAULA B.; FORNARI, THAIS A.; PEZZI, NICOLE; SAKAMOTO-HOJO, ELZA T.; DONADI, EDUARDO A.; PASSOS, GERALDO A. Aire-dependent peripheral tissue antigen mRNAs in mTEC cells feature networking refractoriness to microRNA interaction. Immunobiology, v. 220, n. 1, p. 93-102, JAN 2015. Web of Science Citations: 10.
XAVIER, DANILO J.; TAKAHASHI, PAULA; MANOEL-CAETANO, FERNANDA S.; FOSS-FREITAS, MARIA C.; FOSS, MILTON C.; DONADI, EDUARDO A.; PASSOS, GERALDO A.; SAKAMOTO-HOJO, ELZA T. One-week intervention period led to improvements in glycemic control and reduction in DNA damage levels in patients with type 2 diabetes mellitus. Diabetes Research and Clinical Practice, v. 105, n. 3, p. 356-363, SEP 2014. Web of Science Citations: 6.
EVANGELISTA, ADRIANE F.; COLLARES, CRISTHIANNA V. A.; XAVIER, DANILO J.; MACEDO, CLAUDIA; MANOEL-CAETANO, FERNANDA S.; RASSI, DIANE M.; FOSS-FREITAS, MARIA C.; FOSS, MILTON C.; SAKAMOTO-HOJO, ELZA T.; NGUYEN, CATHERINE; PUTHIER, DENIS; PASSOS, GERALDO A.; DONADI, EDUARDO A. Integrative analysis of the transcriptome profiles observed in type 1, type 2 and gestational diabetes mellitus reveals the role of inflammation. BMC MEDICAL GENOMICS, v. 7, MAY 23 2014. Web of Science Citations: 16.
TAKAHASHI, PAULA; XAVIER, DANILO J.; EVANGELISTA, ADRIANE F.; MANOEL-CAETANO, FERNANDA S.; MACEDO, CLAUDIA; COLLARES, CRISTHIANNA V. A.; FOSS-FREITAS, MARIA C.; FOSS, MILTON C.; RASSI, DIANE M.; DONADI, EDUARDO A.; PASSOS, GERALDO A.; SAKAMOTO-HOJO, ELZA T. MicroRNA expression profiling and functional annotation analysis of their targets in patients with type 1 diabetes mellitus. Gene, v. 539, n. 2, p. 213-223, APR 15 2014. Web of Science Citations: 30.
COLLARES, C. V. A.; EVANGELISTA, A. F.; XAVIER, D. J.; TAKAHASHI, P.; ALMEIDA, R.; MACEDO, C.; MANOEL-CAETANO, F.; FOSS, M. C.; FOSS-FREITAS, M. C.; RASSI, D. M.; SAKAMOTO-HOJO, E. T.; PASSOS, G. A.; DONADI, E. A. Transcriptome meta-analysis of peripheral lymphomononuclear cells indicates that gestational diabetes is closer to type 1 diabetes than to type 2 diabetes mellitus. MOLECULAR BIOLOGY REPORTS, v. 40, n. 9, p. 5351-5358, SEP 2013. Web of Science Citations: 10.
DONATE, PAULA B.; FORNARI, THAIS A.; MACEDO, CLAUDIA; CUNHA, THIAGO M.; NASCIMENTO, DANIELE C. B.; SAKAMOTO-HOJO, ELZA T.; DONADI, EDUARDO A.; CUNHA, FERNANDO Q.; PASSOS, GERALDO A. T Cell Post-Transcriptional miRNA-mRNA Interaction Networks Identify Targets Associated with Susceptibility/Resistance to Collagen-induced Arthritis. PLoS One, v. 8, n. 1 JAN 24 2013. Web of Science Citations: 14.
MANOEL-CAETANO, FERNANDA S.; XAVIER, DANILO J.; EVANGELISTA, ADRIANE F.; TAKAHASHI, PAULA; COLLARES, CRISTHIANNA V.; PUTHIER, DENIS; FOSS-FREITAS, MARIA C.; FOSS, MILTON C.; DONADI, EDUARDO A.; PASSOS, GERALDO A.; SAKAMOTO-HOJO, ELZA T. Gene expression profiles displayed by peripheral blood mononuclear cells from patients with type 2 diabetes mellitus focusing on biological processes implicated on the pathogenesis of the disease. Gene, v. 511, n. 2, p. 151-160, DEC 15 2012. Web of Science Citations: 26.

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