Grantee Research Project Results
2023 Progress Report: Integrated blood brain barrier computational model development to predict doses of concern for compound linked neurotoxicity
EPA Grant Number: R840027Title: Integrated blood brain barrier computational model development to predict doses of concern for compound linked neurotoxicity
Investigators: Knipp, Gregory , Sluka, James
Institution: Purdue University
EPA Project Officer: Chung, Serena
Project Period: August 1, 2020 through May 8, 2025
Project Period Covered by this Report: August 1, 2022 through July 31,2023
Project Amount: $790,441
RFA: Advancing Toxicokinetics for Efficient and Robust Chemical Evaluations (2019) RFA Text | Recipients Lists
Research Category: Chemical Safety for Sustainability
Objective:
Investigate the bidirectional permeability of marker compounds to determine the permeation of 50 known or purported environmental neurotoxicants across a human cell-based model of the Blood-Brain Barrier. Permeability data will be integrated to rank order neurotoxicant exposure in reference to established BBB marker compounds. The development of physiological-based pharmacokinetic (PBPK) models based on the neurotoxicant permeation rates across the BBB cell-based assays will then be performed to improve accuracy in predicting doses of concern of chemicals that have been implicated in causing perturbations in brain function.
Progress Summary:
We have completed investigating the bidirectional permeability of marker compounds to determine the permeation of 50 known or purported environmental neurotoxicants across a human cell-based triculture model of the Blood-Brain Barrier. Permeability data has been integrated to rank order neurotoxicant exposure in reference to established BBB marker compounds at steady state plasma concentrations. We have also begun to develop an in vitro Neurovascular Unit model by co-culturing the BBB model for three days with SH-SY5Y cells to provide a more direct way of assessing permeability-linked neurotoxicity in a single assay. Collaborative efforts have led to developing physiological-based High Throughput Toxicokinetic brain model (HTTK-R). We are now focused on validation and testing the HTTK-R brain model utilizing the neurotoxicant permeation rates across the BBB cell-based assays to improve accuracy in predicting doses of concern of chemicals that have been implicated in causing perturbations in brain function.
Future Activities:
We are currently in the process of expanding the BBB direct contact triculture model to include neurons in the basal chamber of the TranswellTM in an effort to mimic the in vivo neurovascular unit (NVU). Our goal will be to optimize the NVU culture conditions based on changes in permeability rates and then characterize changes in proteins involved in the tight junctions, efflux transporters, and cytoskeleton as indices of the barrier properties. Upon completion, we will perform permeability studies with selected neurotoxicants to further validate the HTTK-brain model.
Journal Articles on this Report : 1 Displayed | Download in RIS Format
| Other project views: | All 10 publications | 6 publications in selected types | All 6 journal articles |
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Lubin K, Xu Z, Sluka J, Knipp G. Development of an in vitro model of the neurovascular unit for BBB permeability-linked neuroactivity screening. Medicinal Chemistry Research 2024;33:1450-1463. |
R840027 (2023) R840027 (2024) |
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Supplemental Keywords:
Neurovascular Unit, Blood-Brain Barrier, High Throughput Toxicokinetics HTTK-R, bidirectional permeability screeningProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.