Design and Testing of Math Models of Iron Trafficking and Regulation in Eukaryotes
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Iron is an essential micronutrient of eukaryotic cells. It is required to generate most of the chemical energy in our bodies. Iron-bound enzymes catalyze hundreds of reactions in cells, including processes as fundamental as DNA replication and repair. In this project, the principal investigator''s aim is to develop mathematical models that simulate the movement of iron in eukaryotic cells and to investigate how that iron is regulated by cells. Like cars driving into a city at rush-hour, iron "traffic" occurs on different pathways in the main cytosol region of the cell, and different iron species end up at different locations in the cell such as in mitochondria, the nucleus, or other organelles. The cell regulates these traffic patterns so it can survive and prosper under various environmental situations (too much iron or too little iron). However, the details of this regulation - at the level of molecules - are poorly understood. In this project, the investigator''s main objective is to develop a comprehensive math model that accounts for all of the iron-containing species in the cell that will help explain complex iron "traffic" within cells. As part of the broader impacts of the project, the PI will engage graduate and undergraduate students, including members of underrepresented groups in science, in interdisciplinary research training. The PI will also develop a website offering free downloads, sample data and video tutorials related to the project.The overall objective of this project is to develop molecular-level mechanistically-based math models of iron trafficking and regulation that can simulate the comprehensive iron content and iron-based reactivity of a yeast cell. The PI will construct a model that accounts for iron in the cytosol, mitochondria, vacuoles, ER/Golgi, nuclei, and cell wall. The ordinary-differential-equations-based models will reflect all of the ca. 120 iron-containing species in yeast cells, with species being represented as groups of aggregated components. Models will share "housekeeping" processes but each model will have a unique emphasis that will be expanded in detail. In developing the models, the investigator will focus on: a) respiration and reactive oxygen species; b) cytosolic iron metabolism (involving the cytosolic iron sulfur cluster assembly (CIA) and iron-related chemistry in the nucleus; c) mitochondrial iron-sulfur and heme chemistry; d) nutrient iron import and metabolism; e) iron homeostasis and regulation. Each model will be optimized in terms of kinetic parameters against experimental data obtained in the PI''s lab or elsewhere. Models will be tested by determining whether predictions made by the model (e.g. the effects of deleting or overexpressing a gene related to iron metabolism) are realized experimentally. Models will also guide the design of new experiments, generating a unique synergy between experiments and modeling that will advance our understanding of the cell biology of iron metabolism.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.