Regulation of Mitochondrial Functions by Iron and Ceramides in C. elegans

线虫中铁和神经酰胺对线粒体功能的调节

• 批准号: 1557787
• 负责人: Pamela Padilla
• 金额: $ 99.27万
• 依托单位: University of North Texas
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1557787&HistoricalAwards=false
• 关键词: Regulation; Mitochondrial; Functions; Iron; Ceramides

Biological processes such as responses to stress, cell death and lifespan depend on maintaining a balance among levels of various compounds such as fats (lipids), iron and sugars. Although substantial research efforts have revealed how the levels of fats and sugars are controlled by different hormones, such as insulin, the connection of these processes to processes that regulate iron levels is poorly understood. Recently, the investigators identified cellular processes that potentially integrate the ways that iron and lipid levels are maintained. The investigators will determine the dynamics and interaction between iron homeostasis and synthesis of specific lipids (ceramides), and how these interactions impact organismal functions such as metabolism, cell death and responses to stress. A genetic model system will be used to identify novel genes involved with cellular iron and lipid homeostasis. Additionally, the investigators will incorporate their research with education by providing research opportunities and mentoring to graduate and undergraduate students. Furthermore, an outreach-based learning module will be incorporated into the existing and successful UNT Elm Fork Education Center. This science education center reaches over 20,000 visitors per year (majority are K-8th graders). By collaborating with the Elm Fork Education Center students will be exposed to the field of genetic modeling and the cellular responses to environmental stress in animals. Completion of this project will elucidate novel mechanisms regulating mitochondrial function relative to whole animal biology. The goals of this project are to dissect the pathways controlling sphingolipid/ceramide metabolism and iron regulation and to determine if sphingolipid/ceramide metabolism and iron regulation are mechanistically linked. The approach is to use the genetic model system Caenorhabditis elegans to conduct cellular, molecular and genetic analysis on mutants with altered sphingolipid/ceramide metabolism and iron regulation. The investigators will test the hypothesis that 1) central features of mitochondrial function and the response to oxygen deprivation in an intact whole organism are sphingolipid/ceramide metabolism and iron regulation; and 2) sphingolipid/ceramide metabolism and iron regulation are mechanistically linked in mitochondrial functions. To test these hypothesis the following Specific Aims will be conducted: Aim 1: Determine how ceramide biosynthesis and iron regulation impact mitochondria functions and whole organism stress responses; Aim 2: Conduct genetic suppression analyses to identify signaling pathways that interact with ceramide biosynthesis and iron regulation; Aim 3. Utilize genetic analysis to determine if neet-1 and ceramide biosynthesis mechanistically interact to regulate mitochondrial functions. The proposed research could have a transformative impact on the way sphingolipid/ceramide metabolism and iron regulation is viewed in the context of mitochondrial homeostasis. The project provides research training for graduate and undergraduate students. Furthermore, an outreach-based learning module that focuses on the genetic model system C. elegans will be offered through a program at the UNT Elm Fork Education center. This outreach program will have a broad impact since it reaches over 20,000 visitors per year.

对压力、细胞死亡和寿命的反应等生物过程取决于维持脂肪（脂质）、铁和糖等各种化合物水平的平衡。尽管大量研究工作已经揭示了不同激素（例如胰岛素）如何控制脂肪和糖的水平，但人们对这些过程与调节铁水平的过程之间的联系知之甚少。最近，研究人员发现了可能整合铁和脂质水平维持方式的细胞过程。研究人员将确定铁稳态和特定脂质（神经酰胺）合成之间的动态和相互作用，以及这些相互作用如何影响新陈代谢、细胞死亡和应激反应等机体功能。遗传模型系统将用于识别与细胞铁和脂质稳态有关的新基因。此外，研究人员将通过为研究生和本科生提供研究机会和指导，将他们的研究与教育结合起来。此外，基于外展的学习模块将被纳入现有且成功的 UNT Elm Fork 教育中心。该科学教育中心每年接待超过 20,000 名游客（大多数是 K-8 年级学生）。通过与 Elm Fork 教育中心合作，学生将接触到遗传模型和动物细胞对环境压力的反应领域。该项目的完成将阐明与整个动物生物学相关的调节线粒体功能的新机制。该项目的目标是剖析控制鞘脂/神经酰胺代谢和铁调节的途径，并确定鞘脂/神经酰胺代谢和铁调节是否存在机械联系。该方法是利用遗传模型系统秀丽隐杆线虫对鞘脂/神经酰胺代谢和铁调节发生改变的突变体进行细胞、分子和遗传分析。研究人员将检验以下假设：1）完整的整个生物体中线粒体功能和对缺氧反应的核心特征是鞘脂/神经酰胺代谢和铁调节； 2) 鞘脂/神经酰胺代谢和铁调节在线粒体功能中存在机械联系。为了检验这些假设，将进行以下具体目标： 目标 1：确定神经酰胺生物合成和铁调节如何影响线粒体功能和整个生物体应激反应；目标 2：进行基因抑制分析，以确定与神经酰胺生物合成和铁调节相互作用的信号通路；目标 3. 利用遗传分析确定 neet-1 和神经酰胺生物合成是否通过机制相互作用来调节线粒体功能。拟议的研究可能会对在线粒体稳态背景下看待鞘脂/神经酰胺代谢和铁调节的方式产生变革性影响。该项目为研究生和本科生提供研究培训。此外，UNT Elm Fork 教育中心的一个项目将提供一个以线虫遗传模型系统为重点的外展学习模块。该推广计划每年吸引超过 20,000 名访客，因此将产生广泛影响。