University of Wisconsin–Madison

Welcome to the Human Models for Analysis of Pathways (HMAPs) Center

Introduction

The Human Models for Analysis of Pathways (HMAPs) Center, is an EPA sponsored Science to Achieve Results (STAR) center, based in University of Wisconsin Madison, that addresses the need for human, organotypic culture models (/ micro-physiological systems / human tissue on a chip) that comply with the requirements of contemporary toxin screening and drug discovery (i.e. reproducibility, high throughput, transferability of data, clear mechanisms of action, defined adverse outcomes).

These technologies will provide a suitable alternative and reduce the number of animals required for in vivo studies reducing the overreliance on animal studies. Current in vivo animal models do not capture the biological diversity and complexity of human tissues and it is not possible to screen the tens of thousands of compounds that are present in our environment in animal models. Similarly, there is a need for human models to validate drug efficacy and avoid drug induced toxicity, as greater than 90% of new drug candidates fail even after passing through the majority of the drug development pipeline.

The H-MAPs Center is committed to transforming chemical toxicity testing and drug discovery by taking advantage of advances in biology, biotechnology, and computer modeling. The overall objective of the center is to create transformative organotypic human models in formats that offer unique practical capabilities for toxin screening and pathway analysis.

The Human MAPs Center Objectives are to:

  • Generate human pluripotent stem cell-derived cells that properly represent the diverse phenotypic characteristics of developing or mature human somatic cells;
  • Generate organotypic cell culture models that are robust and reproducible;
  • Translate organotypic cell culture models to microscale systems for HTS;
  • Combine genomic/epigenomic analyses with bioinformatics to gain molecular level insights into organotypic model assembly and the pathways influenced by toxins.

The H-MAPs Center brings together leading experts in human pluripotent stem cell biology, human development, and microscale tissue engineering to develop organotypic human models. The Center will also form organotypic human models in robust, innovative high throughput screening systems and identify mechanisms of action associated with toxicity using bioinformatics-based pathway analysis.

Innovative Technology Cores


The HMAPs Center activities are supported by three Innovative Technology Cores (ITCs). The Synthetic Matrices ITC provides defined synthetic hydrogels, thin films and synthetic microparticles for use across center projects. These matrices provide the building blocks for the biologically driven assembly in the organotypic culture models being generated in the HMAPs Center. The Microscale Systems ITC provides innovative microfluidic technologies that can transform the organotypic culture models from standard assay formats to high throughput screening formats. The Pathway Analysis ITC provides the ability to identify which specific cell phenotypes are influenced by a drug or toxin, and identifies which gene regulatory networks are affected by the compound exposure. Forming the human tissues in a dish offers the potential to capture the complexity associated with human tissue development and function. However, the increased complexity and phenotypic diversity in organotypic models makes it difficult to understand which cell types a toxin is affecting, and by which specific signaling mechanisms. Bioinformatics and computational tools are required to extract mechanistic information. This Core provides the full suite of bioinformatics tools needed to support the H-MAPs Center objectives.

Research Highlights