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Analysis of the Notch signaling pathway in endothelial-to mesenchymal transition and their consequences in chronic kidney disease in zebrafish model

Grant number: 16/07343-9
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): November 26, 2016
Effective date (End): November 25, 2017
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Roberto Zatz
Grantee:Clarice Silvia Taemi Origassa
Supervisor abroad: Joseph Vincent Bonventre
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Local de pesquisa : Brigham and Women's Hospital (BWH), United States  

Abstract

Fibroblasts are key mediators of fibrosis in the kidney and other organs but their origin during fibrosis is still not completely clear. Activated fibroblasts likely arise from resident quiescent cells via epithelial-to-mesenchymal transition (EMT) and directly from bone marrow. We have studying a third origin of fibroblasts in renal fibrosis: the endothelial-to-mesenchymal transition (EndMT). Moreover, the signaling pathways involved in this recruitment and differentiation are not fully elucidated. Recently, Notch signaling pathway has gained interest due to its influence on intercellular communication during cellular organization, coordinating the growth of blood vessels. Indeed, subtle changes in Notch activity are sufficient to cause differences in behavior of endothelium and blood vessel formation. Therefore, we hypothesize that Notch signaling is a crucial hint for EndMT. Here, we will examine the contribution of Notch signaling in EndMT, and ultimately, its contribution to renal fibrosis in a zebrafish model of chronic kidney disease (CKD), by taking advantage of the model and the possibility to visualize the process in vivo. To corroborate this strategy, a murine model of CKD will also be established to study the Notch pathway. Endothelial lineage tracing using pTol-cdh5:Notch1-RFP transgenic zebrafish and Cdh5creNotch1lox/lox-GFP mice will be subjected to renal injury and used to further confirm the presence of EndMT in renal fibrosis. We will use different strategies of image, pharmacological inhibition and cell/molecular biology to demonstrate the presence and role of Notch in EndMT. EndMT could contribute to the accumulation of activated fibroblasts and myofibroblasts in renal fibrosis and any attempt to uncover new mechanisms will be implicated in therapeutic potential.