Multiomic analysis (RNAseq and ATACseq) in single-cell nuclei of the hypothalamus of normal mice and during pre-eclamptic gestation

• Grant number: 21/14426-6
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: February 01, 2022
• Status: Discontinued
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Andre de Souza Mecawi
• Grantee: Victor Jardim Duque
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 19/27581-0 - Control of vasopressin secretion in pregnancy and its implications in pathophysiology of Preeclampsia, AP.JP
• Associated scholarship(s): 24/14265-0 - Multispecies single-cell transcriptomic atlas of the hypothalamus: tracking the evolutive pathways taken by the peptidergic neurons, BE.EP.DD

Abstract

Pregnancy is a period of extreme changes in the physiology of the female, adapting the mother's organism to ensure the healthy development of the embryo or fetus. Preeclampsia (PE) is a disease characteristic of gestation and defined by the development of hypertension in the second half of pregnancy, associated with proteinuria and/or dysfunction of target organs. It affects between 3 and 5% of pregnant women in the world and 8% in the poorest regions of Brazil, making it one of the main causes of maternal and fetal death. It has long been known that there is a reduction in the osmotic threshold for activation of vasopressin (AVP) producing neurons during pregnancy, but only in this decade has the hypersecretion of this vasoactive hormone been involved in the induction of PE. Despite this recent finding, the mechanisms responsible for increased AVP secretion and consequent PE induction are not known. The overall objective of this project is to study the mechanisms responsible for changing the osmosensitivity of the AVP-producing neurons during pregnancy, as well as to understand the consequences of their hypersecretion for the development of PE. We will apply the sequencing technique of RNA and decompressed chromatin regions (ATACseq) in the single nuclei of hypothalamus cells to identify new genes regulating the exacerbated secretion of AVP during gestation and their participation in the development of preeclampsia. After identifying the candidate genes and validating the alteration of their expression at the levels of mRNA and protein, we will use the Cre-loxP technology to delete at least one of these in the AVP-producing neurons, making it possible to assess their implication in the process of synthesis, excitation, and secretion of AVP during physiological and pre-eclamptic gestation. We hope to contribute to the understanding of the changes in the secretion of AVP during pregnancy and their implication in the induction of PE, enabling the development of new strategies for prevention, diagnosis, and treatment of this disease. (AU)