GENERATION OF ANIMAL MODELS AND STUDY OF MOLECULAR MECHANISMS INVOLVED IN THE TUMORIGENESIS OF CORTICOTROPH TUMORS AND ADRENOCORTICAL CARCINOMAS

• Grant number: 22/09929-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date until: April 01, 2023
• End date until: November 30, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Margaret de Castro
• Grantee: Gabriel Henrique Marques Gonçalves
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 14/03989-6 - Uncovering pathophysiological and molecular mechanisms involved in tumorigenesis by platforms for next-generation sequencing (NGS), AP.TEM

Abstract

Corticotroph tumors and adrenorcotical carcinomas are important pathologies of the hypothalamus-pituitary-adrenal axis with molecular mechanisms involved in their pathogenesis still poorly elucidated. Recently, it was described an important association between the genetic variant of USP8 and corticotroph tumors, however the relationship between this mutation as a driver mutation for the tumoral development remains uncertain. Regarding adrenocortical carcinomas, evidence shows that the pathogenic variant of TP53 pR337H, widely present in the Brazilian population, has a low penetrance related with the tumoral development. Based on this and by using gene editing methodologies cre-lox and crispr we aim to generate genetic modified mice with gain of function mutation of Usp8 (subproject 1) as well with the point mutation Trp53 R334H (subproject 2) to study the molecular and metabolic mechanisms associated with tumoral development and also the response to specific therapies in these pathologies of difficult clinical management.