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

对压力的反应、细胞死亡和寿命等生物过程依赖于各种化合物（如脂肪（脂质）、铁和糖）水平的平衡。尽管大量的研究工作已经揭示了脂肪和糖的水平是如何由不同的激素（如胰岛素）控制的，但这些过程与调节铁水平的过程之间的联系却知之甚少。最近，研究人员发现细胞过程可能整合维持铁和脂质水平的方式。研究人员将确定铁稳态与特定脂质（神经酰胺）合成之间的动力学和相互作用，以及这些相互作用如何影响机体功能，如代谢、细胞死亡和应激反应。一个遗传模型系统将用于鉴定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，一个基于外展的学习模块将被纳入现有的和成功的UNT榆树福克教育中心。这个科学教育中心每年接待超过2万名游客（大多数是k -8年级的学生）。通过与Elm Fork教育中心的合作，学生将接触到遗传建模和动物对环境压力的细胞反应领域。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。本项目的目的是剖析神经鞘脂/神经酰胺代谢和铁调控的调控途径，并确定神经鞘脂/神经酰胺代谢和铁调控是否存在机制联系。方法是利用秀丽隐杆线虫遗传模型系统，对鞘脂/神经酰胺代谢和铁调控发生改变的突变体进行细胞、分子和遗传分析。研究人员将验证以下假设：1)完整生物体中线粒体功能和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有机制联系。为了验证这些假设，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的应激反应；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。利用遗传分析来确定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。拟议的研究可能对鞘脂/神经酰胺代谢和铁调节在线粒体稳态背景下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训练。此外，将通过UNT Elm Fork教育中心的一个项目提供一个以遗传模型系统秀丽隐杆线虫为重点的外展式学习模块。这项外展计划将产生广泛的影响，因为它每年将吸引超过20,000名游客。

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.