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Global expression profile of long non-coding RNAs (lncRNAs) in the ventral prostate of rats submitted to Maternal Protein Restriction: Characterization and functional validation

Grant number: 21/00340-2
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): November 01, 2023
Effective date (End): July 31, 2025
Field of knowledge:Biological Sciences - Morphology - Histology
Principal Investigator:Luis Antonio Justulin Junior
Grantee:Luiz Marcos Frediani Portela
Host Institution: Instituto de Biociências (IBB). Universidade Estadual Paulista (UNESP). Campus de Botucatu. Botucatu , SP, Brazil
Associated scholarship(s):23/17519-0 - Integrative analysis of the multi-omic profile of the prostate of rats subjected to maternal protein restriction: identification of potential biomarkers of the developmental origin of prostate cancer (PCa), BE.EP.DR

Abstract

The approach Developmental Origins of Health and Disease (DOHaD) seeks to establish the correlation of diseases in adult life with events that occurred during intrauterine development and/or early childhood. One of the models used for DOHaD studies is the submission of rodents to Maternal low protein diet (MLPD). MLPD is responsible for the delay in the normal development of the prostate, in addition to increasing the incidence of Prostate Cancer (PCa) with the aging of the offspring. One of the main consequences of DOHaD is the epigenetic changes that accompany the offspring throughout life. In addition to changes in chromatin, epigenetics encompasses the expression of non-coding RNAs (ncRNA), and in recent years, long non-coding RNAs (lncRNAs) have gained prominence, since they control several molecular mechanisms, such as regulation of mRNA translation, inhibiting miRNA activity, interfering with protein-protein interaction, and they can also modulate transcription factors, and consequently, gene expression. In recent years, our research group has been dedicated to globally understanding the molecular mechanisms that cause prostatic changes, from the perspective of omic data, however, the elucidation of the participation of lncRNA in these prostatic changes is not yet established. Thus, the objective of this work will be to analyze the global expression profile of lncRNA in the ventral prostate (PV) of the offspring of rats submitted to RPM during pregnancy and lactation. In addition to comparing the expression of lncRNA in PCa, and to draw a network of interaction between lncRNA to the protein, transcriptomic and microRNomic profile of these animals. For this, we will use data from the sequencing of mRNA, miRNA and PV proteins from Sprague Dawley rats that underwent RPM. These animals were divided into two experimental groups: CTR group (control, with 17% protein feed offer, n = 6) and RPGL (protein restriction during pregnancy and lactation, 6% feed offer during pregnancy and lactation, n = 6), and that were euthanized in PND 21 and 540, these data are part of the database of our research group. From the mRNA sequencing data, we will identify the differentially expressed (DE) lncRNA at each age, we will compare with the data of the patients with CaP, and through them, we will perform integrative analyzes, prediction of interaction with the mRNA, miRNA and proteins DE. With enrichment analyzes of molecular and ontological pathways, we will identify the main pathways regulated by lncRNA in PV and select a lncRNA to validate its functional role in cell culture. The validations will take place through RT-qPCR in the PV of the animals and we will perform functional tests with inhibition of the expression of lncRNAs in benign prostatic cells (PNT2) and in tumoral lineage, as well as the tests of cell viability, proliferation, healing and migration. We hope to identify the lncRNA DE in the PV of these animals submitted to MLPD, establish their role in the regulation of mRNA, miRNA and proteins and the consequences for prostatic changes. In addition, we will describe the functional role of these lncRNAs in benign and tumoral prostate cells.

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