High-throughput Hazard, Dose-response and Population Variability Assessment of Cardiotoxicity in a Human Induced Pluripotent Stem Cell (iPSC)-derived in vitro Culture Model

EPA Grant Number: R835802C001
Subproject: this is subproject number 001 , established and managed by the Center Director under grant R835802
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).

Center: Organotypic Culture Models For Predictive Toxicology Center
Center Director: Rusyn, Ivan
Title: High-throughput Hazard, Dose-response and Population Variability Assessment of Cardiotoxicity in a Human Induced Pluripotent Stem Cell (iPSC)-derived in vitro Culture Model
Investigators: Rusyn, Ivan , Threadgill, David W. , Wright, Fred A.
Institution: Texas A & M University
Current Institution: Texas A & M University , North Carolina State University , University of North Carolina at Chapel Hill
EPA Project Officer: Klieforth, Barbara I
Project Period: June 1, 2015 through May 31, 2019
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: Human Health , Health , Safer Chemicals

Objective:

The long-term objective of the Center is to advance chemical risk assessment by establishing and validating effective, accurate and fiscally responsible means for identifying/characterizing cardiac chemical hazards. 

Approach:

Recent advances in stem cell research and establishment of robust protocols for culturing, distribution and phenotyping holds promise for development of a functional cardiac OCM for modeling cardiovascular disease and testing for chemical hazards. The central hypotheses of this proposal are that: (i) stem cell-derived cardiomyocyte cultures constitute an effective organotypic culture model for predictive toxicity screening of environmental chemicals; (ii) a population-based experimental design utilizing a panel of human iPSCs and mouse Collaborative Cross (CC) can assess variation in toxicity to better characterize uncertainties; and (iii) integration of dosimetry with screening provides an in vivo context to in vitro data and improves human health assessments. Project 1 will conduct population-based concentration-response high-content/-throughput in vitro screening of up to 200 ToxCast chemicals in iPSC-derived cardiomyocytes from 100 humans, and will collect pharmacokinetic data using hepatocytes. Project 2 will conduct mouse population-based in vitro screening of these chemicals in CC-derived cardiomyocytes followed by in vivo validation in the CC strains. Project 3 will conduct dose-response modeling to establish appropriate point of departure, genome-wide association analyses and in vitro-to-in vivo extrapolation modeling. 

Rationale:

The WHO estimates that up to 23% of the global burden of cardiovascular diseases, a leading cause of death, is attributable to environmental chemicals. The WHO estimates that up to 23% of the global burden of cardiovascular diseases, a leading cause of death, is attributable to environmental chemicals. However, methods for assessment of cardiac safety of non-pharmaceutical agents are lagging behind the traditional health hazards of concern to human health (carcinogenicity, mutagenicity, reproductive toxicity, etc.). Recent advances in the development of organotypic beating cardiomyocyte models (OCM), most notably derived from human/rodent embryonic or induced pluripotent (iPSC) stem cells, open new prospects for simulating complex chemical-perturbed adverse outcome pathways in the heart.

Expected Results:

This project will develop and validate a population-based human and mouse cardiac organotypic culture model for characterizing susceptibility and variability in response to chemical hazards. In addition, we will map human iPSC-derived phenotypes onto an adverse outcome pathway for cardiotoxicity.  

Publications and Presentations:

Publications have been submitted on this subproject: View all 7 publications for this subprojectView all 55 publications for this center

Journal Articles:

Journal Articles have been submitted on this subproject: View all 3 journal articles for this subprojectView all 13 journal articles for this center

Supplemental Keywords:

cardiovascular, stem cells, toxicity pathway, variability, pharmacokinetic model, tissue mimetics, microphysiological systems

Progress and Final Reports:

2015 Progress Report


Main Center Abstract and Reports:

R835802    Organotypic Culture Models For Predictive Toxicology Center

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R835802C001 High-throughput Hazard, Dose-response and Population Variability Assessment of Cardiotoxicity in a Human Induced Pluripotent Stem Cell (iPSC)-derived in vitro Culture Model
R835802C002 Linking in vitro-to-in vivoToxicity Testing Using Genetically-matched Organoids and Mice from a Novel Genetic Reference Population
R835802C003 A Pipeline for in vitro-to-in vivo Extrapolation, Population Modeling, & Prioritization