Collaborative Research: Living on the Edge - Quantitative Systems Physiology of Iron Homeostasis

该项目将描述BRUTUS（BTS），一种局限于植物脉管系统的铁结合蛋白，如何控制整个植物的铁（Fe）处理-通过调节能够通过植物根和芽移动的其他蛋白质来动态响应Fe水平的变化。在哺乳动物中，铁是一种重要的营养素，对几种细胞过程至关重要。不幸的是，它对细胞也有潜在的毒性。因此，细胞必须严格调节Fe的可用性。通过揭示BTS如何作为植物中Fe状态的主要调节剂，这项工作将为产生具有增加的营养含量或对普遍存在的碱性土壤的耐受性的作物提供新的分子靶点，其中Fe的可用性很差。在这个项目的过程中，研究人员将与NC和TN 4-H青年发展计划合作，为农村和少数民族社区的青年创建体验式学习模块，通过旨在促进系统思考的活动来提高对植物生物学基础的认识。在模式植物拟南芥中，铁结合泛素连接酶BRUTUS（BTS）的缺失导致系统性Fe过量。虽然它会导致促进铁吸收的转录因子的降解，但BTS及其转录因子靶点都在转录上上调以响应铁缺乏。目前还不清楚如何同时激活铁反应激活剂和它们的拮抗剂解决系统性缺乏。本项目的长期目标是阐明拟南芥系统铁稳态的分子规律。在迭代完善的模型衍生假设的指导下，将使用分子生物学、成像、生物化学和系统生物学方法的组合来1）表征BTS及其在根中响应于Fe可用性的靶标的分子和细胞内动力学，2）确定寡聚化在调节缺陷响应性转录因子的迁移率和活性中的作用，和3）鉴定一种芽特异性网络基序，该基序允许BTS充当一种传感器，该传感器既响应于系统性Fe缺乏信号又负责调节系统性Fe缺乏信号。拟议的工作将提供关于多细胞生物中营养感测如何以组织和细胞特异性方式协调蛋白质-蛋白质相互作用变化的新观点，并展示复杂的细节，多尺度调节现象可以通过采用模型来更有效地揭示-该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识产权进行评估来支持。优点和更广泛的影响审查标准。

This project will delineate how BRUTUS (BTS), an iron-binding protein confined to the plant vasculature, controls iron (Fe) handling throughout the plant – dynamically responding to changes in Fe levels by regulating other proteins that are able to move through the plant root and shoot. As in mammals, Fe is a critical nutrient and essential for several cellular processes. Unfortunately, it is also potentially toxic to cells. Thus, cells must tightly regulate Fe availability. By revealing how BTS acts as a master regulator of Fe status in plants, this work will provide new molecular targets for generating crops with increased nutrient content or tolerance to pervasive alkaline soils, in which Fe is poorly available. Over the course of this project, the investigators will collaborate with NC and TN 4-H Youth Development programs to create experiential learning modules for youth in rural and minority communities to gain awareness of plant biology fundamentals through activities designed to promote systems thinking.E3 ubiquitin ligases are central to Fe homeostasis in both mammals and plants. In the model plant Arabidopsis thaliana, the absence of the iron-binding ubiquitin ligase, BRUTUS (BTS), leads to systemic Fe excess. Although it causes the degradation of transcription factors that promote Fe uptake, BTS and its transcription factor targets are both transcriptionally upregulated in response to Fe deficiency. It is unclear how the concurrent activation of Fe response activators and their antagonists resolves systemic deficiency. The long-term goal of this project is to delineate the molecular rules underlying systemic Fe homeostasis in Arabidopsis. Guided by iteratively refined, model-derived hypotheses, a combination of molecular biology, imaging, biochemical, and systems biology approaches will be used to 1) characterize the molecular and intracellular dynamics of BTS and its targets in the root in response to Fe availability, 2) determine the role of oligomerization in regulating mobility and activity of deficiency responsive transcription factors, and 3) identify a shoot-specific network motif that allows BTS to act as a sensor that is both responsive to and responsible for the regulation of systemic Fe deficiency signals. The proposed work will provide new perspectives on how nutrient sensing in a multicellular organism orchestrates changes in protein-protein interactions in a tissue- and cell-specific manner and demonstrate how the details of a complex, multiscale regulatory phenomenon can be uncovered more efficiently by adopting a model-driven research strategy.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.