Genetic modularity of protein disulfide isomerase and guanine dissociation inhibitor families: computational and molecular studies and cloning of the regulatory region

• Grant number: 12/10203-3
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2012
• End date: August 31, 2016
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Francisco Rafael Martins Laurindo
• Grantee: Jéssyca Cristine Pavanelli
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Understanding mechanisms of redox processes is important in pathophysiology. The redox chaperone protein disulfide isomerase (PDI) functionally modulates the NADPH oxidase complex, a main source of reactive oxygen species in vascular cells. The question addressed in this project has to do with the mechanism of this effect. By means of computational and systems biology methods, PDI interactome algorithms show convergence between Rho family GTPases (involved in cell signaling and activation of NADPH oxidase, including Rac1 and RhoA), and the GTPase regulator RhoGDI. Databases analysis indicate that the chromosomal mapping of PDI (s) and GDI genes shows synteny, i.e., occupation of adjacent chromosomal loci. Syntenic genes may function in coordination, sharing regulatory regions and binding sites for transcription factors. Such synteny was observed at distinct evolutive scale levels in eukaryotes, from fish to humans. In particular, synteny was observed in chromosomes bearing different isoforms of those two families: ie, PDIA1 (PDI P4HB) PDIA2 (PDIP) and PDIA8 (Erp27) are syntenic, respectively, to RhoGDI1, RhoGDI3 and RHOGDI2. The broad objective of our study is to locate and to identify regulatory elements and sites for transcription factor binding in the sequences of such gene paris from PDI and GDI families. This analysis will be done by computer techniques and make functional correlations in cellular model. Our specific objectives are: to evaluate by computational techniques the interaction between PDI (s) and RhoGDI (s) genes with respect to: (1) Genomic structure, (2) Information mapping, (3) gene expression profiles to assess coexpression and (4) Structures of genomic regulatory blocks, looking for conserved regions in different species, (5) In the same genomic blocks, mapping sites of transcription factors (TFBS), and from these sites, definition of the elements in trans (6) Correlation between regulatory structures in these genomic blocks and gene expression (7) From the data obtained above, to clone conserved blocks common to PDI and RhoGDI and develop experimental models for this study. The understanding of a possible co-regulation and analysis of the promoter region of these genes in evolutionary perspective and with the desired functional correlations will clarify the ontogeny and functional regulation of these genes, with potential implications for elucidating redox signaling associated with NADPH oxidase. (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)

MORETTI, ANA I. S.; PAVANELLI, JESSYCA C.; NOLASCO, PATRICIA; LEISEGANG, MATTHIAS S.; TANAKA, LEONARDO Y.; FERNANDES, CAROLINA G.; WOSNIAK, JR., JOAO; KAJIHARA, DANIELA; DIAS, MATHEUS H.; FERNANDES, DENISE C.; et al. Conserved Gene Microsynteny Unveils Functional Interaction Between Protein Disulfide Isomerase and Rho Guanine-Dissociation Inhibitor Families. SCIENTIFIC REPORTS, v. 7, DEC 8 2017. (09/54764-6, 15/15281-0, 12/10203-3, 14/24511-7, 13/07937-8)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

PAVANELLI, Jéssyca Cristine. Genetic modularity of families of protein disulphide isomerase and guanine dissociation inhibitor: computational, molecular and functional studies. 2016. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) São Paulo.