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 In our recent unpublished studies, we found that limiting cellular heme dramatically increases lifespan in cell (Saccharomyces cerevisiae) and animal (Caenorhabditis elegans) models of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.

项目摘要 该提案的长期目标是阐明调节代谢的血红素信号网络 适应老化和控制寿命。血红素在细胞生物学中的规范功能是蛋白质辅因子。 最近的研究表明，血红素可以充当动态信号分子。先前的研究已有 表明几个细胞和动物衰老模型的血红素浓度下降，这 下降与衰老的各种标志有关，包括线粒体功能障碍，氧化应激和 寿命减少。在我们最近未发表的研究中，我们发现细胞血红素极大地限制了 增加细胞（酿酒酵母）和动物（秀丽隐杆线虫）衰老模型的寿命。 但是，尚不清楚血红素调节寿命的机制。当前的建议集成 遗传编码的血红素传感器，血红素螯合剂，质谱法和分子遗传学， 探测血红素在衰老中的作用及其对控制寿命的作用。特别是我们 寻求确定控制寿命的血红素信号传导的靶标，这是介导轨道间的机制 和器官血红素转移到调节寿命，以及细胞和组织/器官的位置 信号传导可以响应衰老和控制寿命。 提出了两个具体目的，其中血红素在细胞和动物衰老中的作用将在 酿酒酵母的葡萄球菌模型（AIM 1）和秀丽隐杆线虫（AIM 2）。在 目的1，为了阐明衰老的酵母细胞模型中的轨道间血红素信号传导的机制，我们将（a） 使用互补的遗传和血蛋白组学方法来确定血红素信号传导的靶标，（b） 确定血红素以用于血红素信号传导的亚细胞位置，并阐明孔间层 使用基因脱落和蛋白质组学筛选的血红素运输途径。在AIM 2中，阐明机制 在衰老的蠕虫动物模型中，Organ Heme信号传导的作用，我们将（a）确定血红素和血红素的作用 血红素反应性基因（HRGS）在长寿[DAF-2]和短生[DAF-16]蠕虫突变体中修饰寿命中， （b）使用组织限制 长寿命和短寿命突变体中的遗传编码的血红素传感器，（c）评估器官和亚细胞 不稳定的血红素池，可以控制寿命和部署血蛋白组学，以识别血红素信号的新靶 可以控制寿命并评估这些候选者相互作用者对血红素信号的影响 当前的提案将是第一个全面破译血红素在衰老中的作用的提案，并可能导致 新的基于血红素的治疗干预措施，可用于减慢衰老或治疗与年龄相关的疾病。