Aging regulation by non-autonomous signaling from Drosophila gut enteroendocrine cells

果蝇肠道内分泌细胞非自主信号传导的衰老调节

• 批准号: 10392963
• 负责人: MARC TATAR
• 金额: $ 39.26万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392963
• 关键词: Adult; Affect; Age; Aging; Animals; Behavior; Biological Assay; Biological Models; Brain; Cell Communication; Cells; Chest; Coculture Techniques; Corpora Allata; Data; Diet; Digestion; Distant; Drosophila genus; Enteroendocrine Cell; Fat Body; G-Protein-Coupled Receptors; Goals; Growth; Hormones; Human; Individual; Insulin; Intestines; Juvenile Hormones; Lipids; Longevity; Mammals; Measures; Metabolism; Modeling; Muscle; Neuropeptides; Nutrient; Organism; Peptide Receptor; Peptides; Performance; Peripheral; Physiology; Production; Proteins; Regulation; Reproduction; Signal Transduction; Signaling Molecule; Source; System; Testing; Tissues; Transcriptional Regulation; Work; age related; cytokine; dietary restriction; fly; genetic approach; genetic manipulation; gut microbiome; hormonal signals; insulin-like peptide; mortality; novel; peptide hormone; response; stem cells; transcription factor

Signals produced by a few cells within a single tissue can regulate lifespan and functional aging throughout an animal. These signaling molecules may exert nonautonomous effects at target tissues to induce their protective mechanisms against age-dependent degeneration. Conversely, nonautonomous signals such as insulin/IGF-like hormones may promote somatic functions that favor growth and reproduction, but while being permissive to somatic degeneration. While nonautonomous signaling in aging regulation has been best characterized in terms of centrally produced hormones, and more recently with cytokines and SASP, provocative data from several model systems suggest there are critical, nonautonomous regulators of aging yet to be described. Accordingly, this proposal focuses on small neuropeptide like molecules secreted from specialized cells of the intestine – gut peptides. Enteroendocrine cells of animal guts, including those of Drosophila and humans, produce many gut peptides that have system-wide impacts on behavior, digestion and metabolism. Working with Drosophila, we propose that gut peptides can also affect lifespan and somatic functional aging by nonautonomous signaling across the organism. In Drosophila, gut peptide production appears change with age, some increasing and others decreasing. We also found that depleting a nutrient sensitive transcription factor in fly enteroendocrine cells was sufficient to block longevity extension by dietary restriction, while inducing this factor appears to increase the ability of dietary restriction to slow aging. We propose that gut peptides secreted from these cells provides a mechanism to regulate aging and in particular in response to diet. The work has three objectives. First is to fully characterize changes in the secretion of gut peptides from fly intestines with age and in response to dietary restriction, and to assay their transcriptional controls. From our identified age-dynamic gut peptides, we will use genetic manipulations to robustly infer which gut have the capacity to nonautonomously control life span and functional aging at target tissues. The second goal is to determine if gut peptides modulate aging through direct signaling at target tissues, and notably through G-Protein Coupled Receptors at these tissues. The third aim explores if gut peptides nonautonomously modulate aging by affecting production of a secondary, relay hormone, such as insulin/IGF or juvenile hormone, which in turn control systemic functional aging. Together these aims will describe a novel tissue function for the intestine in aging control through systemic signaling, and provide a model to explore these highly conserved gut peptides in mammals during aging and in response to dietary restriction.

由单个组织中的几个细胞产生的信号可以在整个过程中调节寿命和功能老化。 动物这些信号分子可能在靶组织中发挥非自主作用，诱导其保护作用。 对抗年龄依赖性退化的机制。相反，非自主信号，如胰岛素/IGF-样 激素可以促进有利于生长和繁殖的躯体功能，但同时允许 躯体退化虽然非自主信号在老化调节中的最佳特征是 中枢产生的激素，最近与细胞因子和SASP，挑衅性的数据，从几个 模型系统表明，还有一些关键的、非自主的老化调节器有待描述。因此，委员会认为， 这项建议集中于从肠的特化细胞分泌的小神经肽样分子。 缩氨酸动物肠道的肠内分泌细胞，包括果蝇和人类的肠内分泌细胞， 对行为、消化和代谢具有系统性影响的肽。通过研究果蝇， 我认为肠道肽也可以通过非自主信号传导影响寿命和躯体功能老化 在整个有机体中。在果蝇中，肠道肽的产生随着年龄的增长而变化，有些增加， 其他人减少。我们还发现，在果蝇肠内分泌系统中， 细胞足以阻止通过饮食限制延长寿命，而诱导这种因素似乎 增加饮食限制延缓衰老的能力。我们认为这些细胞分泌的肠肽 提供了一种调节衰老的机制，特别是对饮食的反应。这项工作有三个目标。 首先是充分表征苍蝇肠道分泌的肠道肽随年龄的变化和响应 饮食限制，并测定其转录控制。从我们确定的年龄动态肠道肽， 我们将使用基因操作来有力地推断哪种肠道具有非自主控制生命的能力 靶组织的跨度和功能老化。第二个目标是确定肠道肽是否调节衰老 通过靶组织的直接信号传导，特别是通过这些组织的G蛋白偶联受体。 第三个目的是探索肠道肽是否通过影响次级代谢产物的产生来非自主地调节衰老， 中继激素，如胰岛素/IGF或保幼激素，其反过来控制系统功能性衰老。一起 这些目的将描述通过系统信号传导在衰老控制中肠的新组织功能， 提供了一个模型，以探索这些高度保守的肠道肽在哺乳动物在衰老过程中，并在响应 饮食限制