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Mechanisms of the cell non-autonomous dietary restriction pathway

细胞非自主饮食限制途径的机制

基本信息

批准号：
10406885
负责人：
SCOTT F LEISER
金额：
$ 38.32万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2018-08-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406885
关键词：
Aging Caenorhabditis elegans Cells ChIP-seq Clinical Communication Data Disease Drug Antagonism Environment Esthesia Event Excision FMO2 Fasting Food Future Genes Genetic Genetic Screening Genetic Transcription Goals Health Health Benefit Human Hypoxia Individual Intervention Intestines Invertebrates Knowledge Lead Longevity Longevity Pathway Mammals Maps Mediating Medical Metabolic Modeling Molecular Molecular Genetics Nematoda Nervous system structure Neurons Neuropeptides Organism Pathway interactions Patients Peptides Perception Peripheral Physiological Process Proteins Publications Publishing RNA Interference Research Design Resistance Role Sensory Serotonin Serotonin Antagonists Signal Pathway Signal Transduction Signaling Molecule Smell Perception Stress Synapses System Techniques Testing Time Tissues Work base dietary restriction environmental change food restriction healthspan improved innovation insight neural circuit neural network neuronal circuitry neurotransmission novel receptor response therapy development tool transcription factor

项目摘要

PROJECT SUMMARY/ABSTRACT Our understanding of the molecular and genetic mechanisms of aging has grown exponentially in the past 25 years. Groundbreaking studies in invertebrate models such as the nematode Caenorhabditis elegans have been at the forefront of many breakthroughs, including the discovery of the first genes that control longevity. Despite these important studies, there are many aspects of the genetic and molecular mechanisms of aging that are still not well understood. One of these mechanisms is the cell non-autonomous control of aging by small subsets of cells (frequently neurons) in an organism. Multiple highly regarded publications have identified individual genes and neurons at the origin of signaling pathways that eventually modify genetic and metabolic responses in peripheral tissues. These studies provide substantial evidence that cell non- autonomous control of aging is common to multiple longevity pathways, but they lack in detail as to the specific signals, receptors, neural circuits, and downstream effectors involved. Our preliminary data show that the most well-studied longevity intervention, dietary restriction (DR), acts in part through a cell non-autonomous signaling pathway that is inhibited by the smell of food in C. elegans. We further find that DR and fasting each lead to induction of an intestinal protein, flavin-containing monooxygenase-2 (fmo-2), that is both necessary and sufficient to improve healthspan, stress resistance, and longevity. We also observe that induction of fmo-2 and extension of lifespan both depend on the serotonergic signaling and can be recapitulated by the serotonin antagonist drug, mianserin. This project will map the cell non-autonomous pathway initiated by removal of food that eventually leads to intestinal fmo-2 induction and extension of lifespan. Aim 1 will identify and epistatically relate the neurons involved in this neural circuit, answering important questions about which specific cell(s) initiate the signal, which cell(s) propagate the signal, and ultimately, which cell(s) integrate the signal into a system-wide response. The results will define a neural circuit led by food sensing and utilizing serotonin that may overlap with other longevity pathways. The second aim will focus on the signals involved in inter-neuronal and tissue to tissue communication by identifying small peptides, synaptic transport mechanisms, and receptors involved in the pathway. The resulting data will fill out the neural circuit model from aim 1 with the key signals and receptors beyond serotonin, and could lead to future studies designed to mimic/block these signals. The third aim will identify the major receptors and transcription factors necessary to induce fmo-2 in the intestine. We will use a forward genetic screen, a targeted RNAi approach, and existing ChIP-SEQ data to define the major intestinal genes involved with DR-mediated fmo-2 induction. Together, these aims will act independently and synergistically to provide an understanding of a major signaling network that modifies aging. Our ultimate goal is to exploit this knowledge of control mechanisms of aging to develop approaches that promote human health.

项目总结/摘要在过去的25年里，我们对衰老的分子和遗传机制的理解呈指数级增长。年在无脊椎动物模型中的开创性研究，如线虫秀丽隐杆线虫，在许多突破性进展中处于领先地位，包括发现了第一个控制寿命的基因。尽管有这些重要的研究，衰老的遗传和分子机制仍有许多方面这些仍然没有得到很好的理解。这些机制之一是细胞非自主控制老化，生物体中细胞（通常是神经元）的小子集。多个备受推崇的出版物确定了信号通路起源处的单个基因和神经元，这些信号通路最终改变了遗传和外周组织的代谢反应。这些研究提供了大量证据表明，细胞非- 衰老的自主控制在多种长寿途径中是常见的，但他们缺乏具体的细节，信号、受体、神经回路和下游效应器。初步数据显示，研究得最多的长寿干预措施，饮食限制（DR），部分是通过细胞非自主性发挥作用的。在C.优美的我们进一步发现，DR和禁食导致诱导肠蛋白，含黄素单加氧酶-2（FMO-2），其是必需的并且足以改善健康寿命、抗压性和寿命。我们还观察到fmo-2的诱导和延长寿命都依赖于肾上腺素能信号，拮抗药米安色林。本项目将绘制细胞非自主途径，最终导致肠道FMO-2诱导和寿命延长的食物。目标1将确定和上位性地将参与这个神经回路的神经元联系起来，回答了关于这些神经元的重要问题。特定的细胞启动信号，哪个细胞传播信号，并且最终哪个细胞整合信号。信号转化为全系统响应。结果将定义由食物感知和利用主导的神经回路 5-羟色胺可能与其他长寿途径重叠。第二个目标将集中在涉及的信号，通过识别小肽、突触转运、神经元间和组织间通讯机制和参与该途径的受体。产生的数据将填充神经电路模型从aim 1中提取的关键信号和受体超过5-羟色胺，并可能导致未来的研究，模拟/阻止这些信号。第三个目标将确定主要的受体和转录因子，在肠道中诱导FMO-2。我们将使用正向遗传筛选，靶向RNAi方法，以及现有的 ChIP-SEQ数据，以定义参与DR介导的fmo-2诱导的主要肠道基因。在一起，这些目标将独立地和协同地发挥作用，以提供对主要信令网络的理解可以改变衰老我们的最终目标是利用这些关于衰老控制机制的知识，促进人类健康的方法。