NSF-BSF: Regulating iron homeostasis by controlling the fate of intracellular ferritin

铁是几乎所有活着的有机体所必需的微量营养素，也是许多生物过程的关键成分。然而，铁过多或过少都会带来问题，是导致人类疾病的重要因素。没有被细胞立即利用的铁储存在铁蛋白中，铁蛋白是一种普遍存在的24亚单位纳米结构，在细胞和全身铁稳态中发挥关键作用，是细胞内代谢铁的主要储存库。这个项目的目标是了解铁蛋白在细胞内外的运输和调节机制，以及这些过程是如何控制的。该项目将为美国和以色列四所不同机构的本科生和研究生以及博士后研究员提供强大的跨学科培训经验，从而为这些学员及其教师导师提供合作和创新的独特机会。铁的稳态是一个严格调控的过程，通过调节细胞铁的输入、输出和储存。不同的蛋白质和铁调节剂，包括多肽激素海普西丁、铁调节蛋白Irp1和IRP2、低氧诱导因子(HIF)、铁伴侣蛋白PCBP1、核受体辅活化子NCOA4和铁储存蛋白Ferritin在铁稳态的调节中发挥重要作用。尽管在过去的几十年里进行了大量的研究和铁稳态的生理意义，但对细胞和全身铁稳态背后的分子机制缺乏充分的了解。利用结构和分子生物学、光谱学、荧光显微镜、定量蛋白质组学以及分析和生物物理工具的组合，该团队将解决铁代谢的基本问题，并将描绘决定细胞铁蛋白命运的机制及其从蛋白质-蛋白质分子水平到细胞水平的运输路线。研究人员将首次探索以前未知的NCOA4/PCBP1/铁蛋白相互作用的生化、生物物理、结构和细胞阐明。拟议研究的背景和跨学科性质将为促进本科生和研究生，特别是历史上代表性不足和经济困难的学生的STEM研究和教育创造独特的机会。此外，所有受训人员和高级研究人员将接触到不同的技术、科学社区和研究机会，目标是在日益全球化的社会中加强创新、科学培训和公民身份。这一美国/以色列合作项目得到了美国国家科学基金会和以色列双国科学基金会的支持。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 for virtually all living organisms and a crucial component of many biological processes. However, too much or too little iron can be problematic and a significant contributor to human diseases. Iron not immediately utilized by cells is stored in ferritin, a ubiquitous 24-subunit-nanostructure that plays a critical role in cellular and systemic iron homeostasis and serves as the principal reservoir of metabolic iron within the cell. The goals of this project are to understand the mechanisms of ferritin trafficking and regulation within and out of the cell and how these processes are controlled. This project will provide a strong interdisciplinary training experience for undergraduate and graduate students and for postdoctoral fellows at four different institutions in the US and Israel and thus extend unique opportunities for these trainees and their faculty mentors to work together and innovate. Iron homeostasis is a tightly regulated process through the tuning of cellular iron import, export, and storage. Different proteins and iron regulators including the peptide hormone hepcidin, the iron regulatory proteins IRP1 and IRP2, the hypoxia inducible factor (HIF), the iron chaperone protein PCBP1, the nuclear receptor coactivator NCOA4, and the iron storage protein ferritin play important roles in the regulation of iron homeostasis. Despite intense research over the past decades and the physiological significance of iron homeostasis, there is a lack of full understanding of the molecular mechanisms underlying both cellular and systemic iron homeostasis. Using a combination of structural and molecular biology, spectroscopy, fluorescence microscopy, quantitative proteomics, and analytical and biophysical tools, the team will address fundamental questions in iron metabolism and will delineate the mechanisms that determine the fate of cellular ferritin and its trafficking route, from the protein-protein molecular level to the cellular level. For the first time, the investigators will explore biochemical, biophysical, structural, and cellular elucidation of previously uncharacterized NCOA4/PCBP1/ferritin interactions. The background and interdisciplinary nature of the proposed research will create unique opportunities to promote STEM research and education for undergraduate and graduate students, particularly historically underrepresented and economically disadvantaged students. Additionally, all trainees and senior research personnel will be exposed to different technologies, scientific communities, and research opportunities with the goal of enhancing innovation, scientific training, and citizenship in an increasingly global society.This collaborative US/Israel project is supported by the US National Science Foundation and the Israeli Binational Science Foundation.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.