Development of Blood-Brain Barrier (BBB)-on-a-chip in vitro models to study Zika Virus oncolytic activity and drug permeability in Brain Cancer treatment

• Grant number: 22/02212-4
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): September 01, 2022
• Effective date (End): August 31, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Mayana Zatz
• Grantee: Ma Hui Ling
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center, AP.CEPID

Abstract

Challenges in developing therapeutics for Brain Cancer and Central Nervous System (CNS) diseases remain chiefly ascribed to the Blood-Brain Barrier (BBB) since its complex cellular interactions restrict the drug penetration, leading to low treatment effectiveness. Zika Virus (ZIKV) is an oncolytic virus used in virotherapy to selectively target and kill brain Cancer stem-like cells, including high-grade glioblastoma (GBM), medulloblastomas and CNS embryonal tumors (MB). ZIKV infection can cross the BBB to reach the CNS through the upregulation of cellular adhesion molecules triggering local neuro inflammation. However, a comprehensive view about BBB penetration mechanism by ZIKV remain poorly understood. The existing animal and in vitro BBB models present limitations in mimicking human brain complexity and specificity by different viral entry receptors that hampered conducting a mechanistic study on the human neural receptors and their interactions with therapeutic and viruses at molecular and cellular levels. The current project aims to develop BBB-on-a-chip as a micro physiological platform composed of BBB cells differentiated from human-induced Pluripotent Stem Cells (iPSCs). Combining tridimensional (3D) bioprinting with microfluidic technologies allows recapitulating the structure and function of BBB and brain tumors for 3D mapping of ZIKV and other therapeutic distributions in the vascular and perivascular regions. Hence, this high-fidelity in vitro human BBB models may increase drug screening efficiency and boost new therapeutics research for CNS disorders. (AU)