Vascular MAPs

Project Summary

A major objective of our research is to delineate the cell autonomous mechanisms that are responsible for adverse cellular dysfunction in response to various stress conditions, which contribute to neurovascular toxicity and tissue pathogenesis. To further delineate the role of cell-cell interactions and study of paracrine mechanisms which maintains the retinal neurovascular integrity, 3D organotypic models that represent the in vivo tissue architecture and organization are essential. Here we propose to develop an organotypic culture of neurovascular system using human induce pluripotent stem cells. These cells will be differentiated to various cellular components of the neurovasculature including endothelial cells, pericytes, and astrocytes. Using defined synthetic matrices from the Synthetic Matrices Core, which allow for “biologically driven assembly” of these cells into a neurovascular unit, we will generate organotypic neurovascular culture systems.

These cultures will be adapted for high throughput screening of chemicals with unknown toxicity to identify those with adverse effect on formation of capillary networks. Our hypothesis is that these compounds will have adverse effects on developmental processes, which depend on angiogenesis. Using our knowledge regarding the intracellular pathways that contribute to neurovascular dysfunction, we will utilize a high content automated imaging system and the Pathway Analysis Core for further analysis of hit compounds identified in a primary toxicity screen. This knowledge will advance our understanding of the cellular and molecular mechanisms and pathways which contribute to neurovascular dysfunction under adverse conditions, and better risk assessment and management of compounds with unknown toxic effects.