Grantee Research Project Results

2024 Progress Report: Integrated blood brain barrier computational model development to predict doses of concern for compound linked neurotoxicity

EPA Grant Number: R840027
Title: 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: Spatz, Kyle
Project Period: August 1, 2020 through May 8, 2025
Project Period Covered by this Report: August 1, 2023 through July 31,2024
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:

The overall objective is to develop an in vitro Blood-Brain Barrier direct contact screening model to assess the exposure

Objective 1: Adapt a presently available low throughput triculture model of the human BBB to a higher throughput screen that will measure bi-directional compound permeability.
Objective 2: Integrate permeability measures with human-based physiological parameters and compound properties relevant to their disposition in the brain to predict C_ss,brain of compounds.

Progress Summary:

We have investigated the bidirectional permeability of marker compounds to determine the permeation of over 60 compounds including 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. 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 Transwell 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 : 5 Displayed | Download in RIS Format

Publications Views
Other project views:	All 10 publications	6 publications in selected types	All 6 journal articles

Publications
Type	Citation	Project	Document Sources
Journal Article	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)	Full-text: Springer Link - Full Text HTML Exit
Journal Article	Lubin KE, Knipp GT. Design of experiment based optimization of an in vitro direct contact triculture blood brain barrier model for permeability screening. Pharmacy and Pharmacology International Journal 2021;9(4):143-158.	R840027 (2024)	Abstract: Abstract HTML Exit
Journal Article	Sego TJ, Sluka JP, Sauro HM, Glazier JA. Tissue forge:interactive biological and biophysics simulation environment. PLOS Computational Biology 2023;19(10):e1010768.	R840027 (2024)	Full-text: Abstract and Full Text HTML
Journal Article	Zha L, Matsu-Ura T, Sluka JP, Murakawa T, Tsuta K. Morphological basis of the lung adenocarcinoma subtypes. IScience 2024;27(5).	R840027 (2024)	Full-text: Abstract and Full Text HTML
Journal Article	Wittner R, Holub P, Mascia C, Frexia F, Müller H, Plass M, Allocca C, Betsou F, Burdett T, Cancio I, Chapman A. Toward a common standard for data and specimen provenance in life sciences. Learning Health Systems 2024;8(1):e10365.	R840027 (2024)	Full-text: Abstract and Full Text HTML

Supplemental Keywords:

Neurovascular Unit, Blood-Brain Barrier, HTTK-R Brain Model, bidirectional permeability screening, toxicokinetics

Progress and Final Reports:

Original Abstract

The 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.