In Vitro Cardiotoxicity Screening Approaches
Postdoctoral Positions Available
FDA is accepting applications for postdoctoral fellows to develop human cell- and protein-based assays for assessing cardiotoxicity of new drugs. Candidates should have received Ph.D. or equivalent degrees in computer sciences or life/health/medical sciences within the last five years, and must have resided in the United States for at least three of the past five years. Work will be done at NIEHS in Research Triangle Park, NC.
Cardiotoxicity, or toxicity to the heart, is a major cause of failure of new drugs in mid- to late-stage development. Most cardiotoxicity testing is currently done in animals; these animal-based tests are expensive and time-consuming, and can fail to fully predict effects in humans.
NICEATM is supporting an initiative to design, build, and test new non-animal approaches to assess cardiotoxicity hazard. The goal is to develop human cell- and protein-based assays to more efficiently screen drugs and chemicals for their potential to be toxic to the heart or circulatory system. The initiative is supported jointly by NTP (Biomolecular Screening Branch and NICEATM), the FDA Center for Drug Evaluation and Research, and the Health and Environment Sciences Institute (HESI).
Two NTP projects within this initiative focus on in silico screening approaches for assessing cardiovascular safety.
Leveraging Existing Mechanistic In Vitro Cardiovascular Data
This project will mine public data sources to compile a structured cardiotoxicity database. Activities will include:
- Collate and curate mechanistic in vitro cardiovascular data from public data sources and peer-reviewed literature
- Annotate performance standards for relevant endpoints
- Map the available data and testing platforms to cardiovascular failure modes defined by the HESI Cardiac Safety Technical Committee
- Develop in silico methods to apply quantitative structure activity relationship analyses and in vitro to in vivo extrapolation
- Propose integrated testing strategies that cover cardiovascular failure modes and provide human-relevant mechanistic information
Human-relevant data will be used to build and test the capabilities of the developed models and integrated testing strategies.
Pathway-based Modeling of Cardiovascular Hazards
This project will use a whole-genome co-expressed network analysis (WGCNA) approach to characterize chemical effects that are potentially relevant to cardiotoxicity. Activities will include:
- Extract, collate and curate cardiac-relevant transcriptomics data from DrugMatrix, and other sources
- Apply WGCNA approaches to construct cardiac-relevant modules from both in vivo (rat heart) and in vitro (rat and human cardiomyocyte) model systems
- Map associations between WGCNA module effects and pathological manifestations observed in the DrugMatrix data
- Identify modules that exhibit conservation across model systems/species to understand where in vitro systems best model toxicological response
Findings of this project will guide the use of cardiac-related in vitro systems for testing and identify areas for further model development.