Design and Testing of Math Models of Iron Trafficking and Regulation in Eukaryotes

铁是真核细胞必需的微量营养素。它需要产生我们体内大部分的化学能。铁结合酶催化细胞中的数百种反应，包括DNA复制和修复等基本过程。在这个项目中，主要研究者的目标是开发数学模型，模拟铁在真核细胞中的运动，并研究铁是如何被细胞调节的。就像汽车在高峰时段驶入城市一样，铁“交通”发生在细胞主要胞质溶胶区域的不同途径上，不同的铁物质最终出现在细胞的不同位置，如线粒体、细胞核或其他细胞器中。细胞调节这些交通模式，因此它可以在各种环境条件下生存和繁荣（铁太多或太少）。然而，这种调节的细节-在分子水平上-知之甚少。在这个项目中，研究人员的主要目标是开发一个全面的数学模型，解释细胞中所有含铁物质，这将有助于解释细胞内复杂的铁“交通”。作为该项目更广泛影响的一部分，PI将让研究生和本科生，包括科学中代表性不足的群体的成员，参与跨学科研究培训。 PI还将开发一个网站，提供与该项目有关的免费下载、样本数据和视频教程。该项目的总体目标是开发分子水平的基于机械的铁运输和调节的数学模型，可以模拟酵母细胞的综合铁含量和铁基反应性。PI将构建一个模型，解释细胞溶质、线粒体、空泡、ER/高尔基体、细胞核和细胞壁中的铁。基于常微分方程的模型将反映所有的情况。酵母细胞中的120种含铁物质，其中物质表示为聚集组分的组。模型将共享“内务处理”过程，但每个模型将有一个独特的重点，将详细扩展。在开发模型时，研究者将重点关注：a）呼吸和活性氧; B）细胞溶质铁代谢（涉及细胞溶质铁硫簇组装（CIA）和细胞核中的铁相关化学; c）线粒体铁硫和血红素化学; d）营养铁输入和代谢; e）铁稳态和调节。每个模型将根据PI实验室或其他地方获得的实验数据在动力学参数方面进行优化。将通过确定模型所做的预测（例如，删除或过度表达与铁代谢相关的基因的影响）是否在实验中实现来测试模型。模型还将指导新实验的设计，在实验和建模之间产生独特的协同作用，这将促进我们对铁代谢细胞生物学的理解。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.