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。它是我们体内产生大部分化学能量所必需的。铁结合的酶在细胞中催化数百种反应，包括DNA复制和修复这样的基本过程。在这个项目中，主要研究人员的目标是开发数学模型，模拟铁在真核细胞中的运动，并研究细胞如何调节铁。就像在高峰时间开车进入城市的汽车一样，铁“交通”发生在细胞主要胞浆区域的不同路径上，不同的铁物种最终到达细胞中的不同位置，如线粒体、细胞核或其他细胞器。细胞调节这些交通模式，因此它可以在各种环境情况下生存和繁荣(铁过多或铁过少)。然而，这一调控的细节--在分子水平上--却鲜为人知。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，该模型可以解释细胞中所有的含铁物种，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，包括科学领域代表性不足的群体的成员，参加跨学科研究培训。国际和平研究所还将开发一个网站，提供与该项目有关的免费下载、样本数据和视频教程。这个项目的总体目标是开发基于分子水平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基于铁的反应性。PI将构建一个模型，说明胞浆、线粒体、液泡、内质网/高尔基体、细胞核和细胞壁中的铁。基于常微分方程式的模型将反映酵母细胞中大约120种含铁物种，这些物种被表示为一组聚集的成分。模型将共享“内务”流程，但每个模型都将有一个独特的重点，并将详细展开。在建立模型时，研究人员将重点放在：a)呼吸和活性氧物种；b)胞质铁代谢(涉及胞质铁硫簇组装(CIA)和细胞核中与铁相关的化学；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。根据PI实验室或其他地方获得的实验数据，每个模型都将在动力学参数方面进行优化。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效果)是否在实验上实现，将对模型进行测试。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，将促进我们对铁代谢的细胞生物学的理解。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.