RUI: Mathematical Modeling of Microglia

Cal Poly Humboldt Sponsored Programs Foundation, Arcata CA

Investigators

Abstract

Microglia are a special type of immune cell found only in the central nervous system. These multifaceted cells fight infections, repair damage, remove debris, and are central to maintaining brain health. However, these cells can go rogue and contribute to neurodegenerative pathologies such as Alzheimer's Disease. This is linked to a shift in their cellular metabolism, but how and why this metabolic reprogramming occurs and its impact on disease progression remains unknown. This project will develop and analyze multi-scale mathematical models to better understand the role of various molecular mechanisms in microglia behavior and how this behavior influences and orchestrates further cellular activity in the brain. This project will incorporate and train undergraduate students in interdisciplinary research techniques. Additionally, the project will assess the impact of an undergraduate research experience on students' science identity and persistence in STEM. This project aims to accomplish three specific goals: 1) Modeling microglia metabolism in a single healthy cell and understanding how the metabolism corresponds to phenotype commitment and behavior through ordinary differential equation modeling and analysis; 2) Incorporating crosstalk between microglia and other cell types and mathematically describing a potential lactate shuttle which may occur under inflammatory conditions through ordinary differential equation modeling and analysis; and 3) Incorporating a spatial component and cell heterogeneity by using agent-based models. The primary tools to be used for this project include numerical simulation, global sensitivity analysis, and parameterizing models by using data from biological experiments conducted by collaborators in parallel with the mathematical work. Cross-talk and agent-based models will specifically consider pathways linked to Alzheimer's Disease. The project will also evaluate the impact of the undergraduate research experience with a mixed method study to assess changes in students' sense of belonging, science self-efficacy, and science identity. This project is jointly funded by the MPS Division of Mathematical Sciences (DMS) through the Mathematical Biology Program, and the BIO Division of Molecular and Cellular Biosciences through the System and Synthetic Biology Cluster. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.