Vascular MAPs: Vascular and Neurovascular Tissue Models

EPA Grant Number: R835737C004
Subproject: this is subproject number 004 , established and managed by the Center Director under grant R835737
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Human Models for Analysis of Pathways (H–MAPs) Center
Center Director: Murphy, William L
Title: Vascular MAPs: Vascular and Neurovascular Tissue Models
Investigators: Sheibani, Nader
Institution: University of Wisconsin - Madison
EPA Project Officer: Klieforth, Barbara I
Project Period: December 1, 2014 through November 30, 2018
Project Amount: Refer to main center abstract for funding details.
RFA: Organotypic Culture Models for Predictive Toxicology Center (2013) RFA Text |  Recipients Lists
Research Category: Safer Chemicals , Health , Human Health

Objective:

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. 

Approach:

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 component of the neurovasculature including endothelial cells, pericytes, and astrocytes. Using defined synthetic matrices, which allow for “biologically driven assembly” of these cells to 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. 

Expected Results:

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 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. 

Publications and Presentations:

Publications have been submitted on this subproject: View all 14 publications for this subprojectView all 25 publications for this center

Journal Articles:

Journal Articles have been submitted on this subproject: View all 14 journal articles for this subprojectView all 24 journal articles for this center

Supplemental Keywords:

Capillary Morphogenesis, Oxidative Stress, Cellular Permeability, Inflammation, Inflammatory Mediators, Diabetic Retinopathy, Vascular Endothelial Growth Factor, Platelet Derived Growth Factor, MAPK Pathways

Progress and Final Reports:

2015 Progress Report
2016 Progress Report


Main Center Abstract and Reports:

R835737    Human Models for Analysis of Pathways (H–MAPs) Center

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R835737C001 Liver MAPs
R835737C002 Brain MAPs
R835737C003 Cancer MAPs: A 3D Organotypic Microfluidic Culture System to Identify Chemicals that Impact Progression and Development of Breast Cancer
R835737C004 Vascular MAPs: Vascular and Neurovascular Tissue Models
R835737C005 Pathway Analysis Core