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

基本信息

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
项目类别：
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

项目摘要

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.

单个组织中的几个细胞产生的信号可以调节整个整个寿命和功能衰老动物。这些信号分子可能会在目标时间内执行非自主效应以诱导其受保护针对年龄依赖性变性的机制。相反，非自主信号，例如胰岛素/IGF样骑马可能会促进有利于生长和繁殖的躯体功能，但在允许的同时躯体变性。虽然衰老调节中的非自主信号传导最佳地表征了在中央产生的恐怖片，最近有几个细胞因子和SASP的挑衅性数据模型系统表明，尚待描述尚有关键的非自主调节剂。根据，该提案的重点是小神经肽，例如从肠道的专用细胞分泌的分子 - 肠肽。动物肠道的肠内分泌细胞，包括果蝇和人类的肠细胞，产生许多肠对行为，消化和新陈代谢产生影响的肽。与果蝇一起工作，我们提议肠道辣椒也会通过非自主信号影响寿命和躯体功能衰老遍及整个生物体。在果蝇中，肠道肽的产生随着年龄的增长而发生变化，有些会增加，并且其他人减少。我们还发现，在蝇肠肠分泌中耗尽营养敏感的转录因子细胞足以通过饮食限制阻止寿命延长，而诱导的因素似乎提高饮食限制缓慢衰老的能力。我们建议从这些细胞分泌的肠辣椒提供了一种调节衰老的机制，尤其是响应饮食。这项工作有三个目标。首先是充分表征随着年龄的增长和回应的肠道肠道分泌的变化饮食限制，并主张其转录控制。从我们确定的年龄动态肠意中，我们将使用遗传操作来鲁棒推断哪种肠道具有非自治的能力目标组织的跨度和功能衰老。第二个目标是确定肠肽是否调节衰老通过在目标时机处的直接信号传导，尤其是通过G蛋白耦合受体在这些时机上进行。第三个目标探讨了肠道是否通过影响次级的产生，非自主来调节衰老。继电器马酮，例如胰岛素/IGF或少年马酮，进而控制全身功能性衰老。一起这些目的将描述通过全身信号传导衰老控制肠的新型组织功能，以及提供一个模型来探索这些高度构成的肠辣椒在衰老期间的哺乳动物中饮食限制。