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

该项目将描述Brutus(BTS)是如何控制整个植物的铁(Fe)处理的，它是一种局限于植物维管系统的铁结合蛋白-通过调节能够通过植物根和地上部分移动的其他蛋白质来动态地响应铁水平的变化。正如在哺乳动物中一样，铁是一种关键的营养物质，对许多细胞过程都是必不可少的。不幸的是，它对细胞也有潜在的毒性。因此，细胞必须严格控制铁的利用率。通过揭示BTS如何作为植物中铁状态的主要调节者，这项工作将为培育营养含量增加或对铁缺乏有效性的普遍碱性土壤耐受性更高的作物提供新的分子靶标。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，为农村和少数族裔社区的青年创建体验式学习模块，通过旨在促进系统思维的活动获得对植物生物学基础的认识。E3泛素连接酶对哺乳动物和植物中的铁平衡至关重要。在模式植物拟南芥中，铁结合泛素连接酶Brutus(BTS)的缺失导致了系统铁的过剩。虽然它导致促进铁摄取的转录因子的降解，但BTS及其转录因子靶标都在转录水平上上调，以响应铁缺乏。目前尚不清楚铁反应激活剂及其拮抗剂的同时激活如何解决系统性缺陷。该项目的长期目标是描述拟南芥系统铁稳态的分子规律。在不断改进的模型假说的指导下，分子生物学、成像、生化和系统生物学方法的组合将被用来1)表征BTS及其在根中的靶标对铁有效性的分子和细胞内动力学，2)确定寡聚在调节缺铁响应转录因子的迁移性和活性中的作用，以及3)确定一个地上部特异的网络基序，使BTS作为传感器对系统性缺铁信号做出反应并负责调节。这项拟议的工作将为多细胞生物体中的营养感应如何以组织和细胞特有的方式协调蛋白质-蛋白质相互作用的变化提供新的视角，并展示如何通过采用模型驱动的研究策略更有效地揭示复杂、多尺度调控现象的细节。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。

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.