Lifespan Regulation by Inter-Organellar Heme Signaling

细胞间血红素信号传导的寿命调节

• 批准号: 10722824
• 负责人: Iqbal Hamza
• 金额: $ 38.22万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722824
• 关键词: Address; Age; Aging; Animal Model; Animals; Binding; Biochemical; Biochemical Genetics; Biological; Biological Availability; Biophysics; Caenorhabditis elegans; Catalysis; Cell Aging; Cell model; Cells; Cellular biology; Chelating Agents; Collaborations; Communication; Data; Dietary Iron; Disease; Dissociation; Electron Transport; Endowment; Enterocytes; Exhibits; Funding; Gases; Gene Deletion; Genes; Genetic; Heme; Heme Iron; Homeostasis; Hydrophobicity; Ion Channel; Iron; Laboratories; Lipids; Location; Longevity; Mass Spectrum Analysis; Mediating; Membrane; Metabolic; Microbe; Mitochondria; Modeling; Molecular; Molecular Genetics; Neurons; Nucleic Acids; Nutrient; Organ; Organelles; Oxidative Stress; Pathway interactions; Phosphotransferases; Process; Property; Proteins; Proteomics; Publishing; RNA Interference; Regulation; Respiration; Role; Saccharomyces cerevisiae; Signal Transduction; Signaling Molecule; Site; Source; Testing; Therapeutic Intervention; Tissues; Transition Elements; Yeasts; cofactor; cytotoxic; extracellular; genetic approach; healthspan; inhibitor; mitochondrial dysfunction; mitochondrial metabolism; mutant; novel; novel therapeutics; proteostasis; receptor; response; sensor; trafficking; transcription factor; transmission process

PROJECT SUMMARY The long-term objectives of this proposal are to elucidate heme signaling networks that regulate the metabolic adaption to aging and control lifespan. The canonical function of heme in cell biology is as a protein cofactor. More recent studies indicate that heme may act as a dynamic signaling molecule. Previous studies have shown that there is a decline in heme concentration in several cell and animal models of aging, and this decline is associated with various hallmarks of aging, including mitochondrial dysfunction, oxidative stress, and diminished lifespan. In our recent unpublished studies, we found that limiting cellular heme dramatically increases lifespan in cell (Saccharomyces cerevisiae) and animal (Caenorhabditis elegans) models of aging. However, the mechanisms by which heme regulates lifespan are not known. The current proposal integrates genetically encoded heme sensors, heme chelators, mass spectrometry approaches, and molecular genetics, to probe the role of heme in aging and the mechanisms it acts through to control lifespan. In particular, we seek to identify the targets of heme signaling that control lifespan, the mechanisms that mediate inter-organelle and inter-organ heme transfer to regulate lifespan, and the subcellular and tissue/organ locations where heme signaling operates to respond to aging and control lifespan. Two specific aims are proposed in which the role of heme in cellular and animal aging will be probed in Saccharomyces cerevisiae, a cell model, (Aim 1) and in Caenorhabditis elegans, an animal model (Aim 2). In Aim 1, to elucidate the mechanisms of inter-organelle heme signaling in a yeast cell model of aging, we will (a) identify the targets of heme signaling using complementary genetic and hemoproteomics approaches, (b) determine the subcellular location where heme is sourced for heme signaling, and elucidate inter-organellar heme trafficking pathways using gene-deletion and proteomics screens. In Aim 2, to elucidate the mechanisms of inter-organ heme signaling in a worm animal model of aging, we will (a) determine the role of heme and heme responsive genes (hrgs) in modifying lifespan in long-lived [daf-2] and short-lived [daf-16] worm mutants, (b) identify the sender and receiver cells of heme signaling in control of lifespan using tissue-restricted genetically encoded heme sensors in long-lived and short-lived mutants, (c) assess organ and subcellular labile heme pools that control lifespan, and deploy hemoproteomics to identify novel targets of heme signaling that could control lifespan and assess the impact of these candidate interactors on heme signaling The current proposal will be the first to comprehensively decipher the role of heme in aging and may lead to new heme-based therapeutic interventions that can be used to slow aging or treat age associated diseases.

项目概要 该提案的长期目标是阐明调节代谢的血红素信号网络 适应衰老和控制寿命。血红素在细胞生物学中的典型功能是作为蛋白质辅因子。 最近的研究表明，血红素可能充当动态信号分子。之前的研究有 研究表明，在几种衰老细胞和动物模型中，血红素浓度有所下降，这 衰老与多种衰老特征有关，包括线粒体功能障碍、氧化应激和 寿命缩短。在我们最近未发表的研究中，我们发现显着限制细胞血红素 延长细胞（酿酒酵母）和动物（秀丽隐杆线虫）衰老模型的寿命。 然而，血红素调节寿命的机制尚不清楚。目前的提案整合了 基因编码的血红素传感器、血红素螯合剂、质谱方法和分子遗传学， 探讨血红素在衰老中的作用及其控制寿命的机制。特别是，我们 寻求确定控制寿命的血红素信号传导的目标以及介导细胞器间的机制 和器官间血红素转移以调节寿命，以及血红素所在的亚细胞和组织/器官位置 信号传导的作用是响应衰老和控制寿命。 提出了两个具体目标，其中将探讨血红素在细胞和动物衰老中的作用 酿酒酵母，一种细胞模型（目标 1），以及秀丽隐杆线虫，一种动物模型（目标 2）。在 目标 1，为了阐明衰老酵母细胞模型中细胞器间血红素信号传导的机制，我们将 (a) 使用互补的遗传和血液蛋白质组学方法确定血红素信号转导的靶标，(b) 确定血红素信号来源的亚细胞位置，并阐明细胞器间的关系 使用基因删除和蛋白质组学筛选的血红素贩运途径。目标 2：阐明机制 为了研究蠕虫动物衰老模型中器官间血红素信号传导的研究，我们将 (a) 确定血红素的作用和 血红素反应基因 (hrgs) 改变长寿命 [daf-2] 和短寿命 [daf-16] 蠕虫突变体的寿命， (b) 使用组织限制识别控制寿命的血红素信号传导的发送细胞和接收细胞 长寿命和短寿命突变体中的基因编码血红素传感器，(c) 评估器官和亚细胞 控制寿命的不稳定血红素池，并部署血液蛋白质组学来识别血红素信号传导的新靶标 可以控制寿命并评估这些候选相互作用者对血红素信号传导的影响 目前的提案将首次全面破译血红素在衰老中的作用，并可能导致 新的基于血红素的治疗干预措施可用于延缓衰老或治疗与年龄相关的疾病。