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.

项目摘要/摘要我们对衰老的分子和遗传机制的理解在过去的25中呈指数增长年。在无脊椎动物模型（例如线虫秀丽隐杆线虫）等无脊椎动物模型中的开创性研究具有一直处于许多突破的最前沿，包括发现控制寿命的第一个基因。尽管有这些重要的研究，但衰老的遗传和分子机制仍有许多方面仍然不太了解。这些机制之一是细胞对衰老的非自治控制细胞（通常是神经元）中的小细胞集中。多个备受推崇的出版物有在信号通路的起源中鉴定出的单个基因和神经元，最终改变了遗传和周围组织中的代谢反应。这些研究提供了大量证据，表明细胞非 - 对衰老的自主控制对于多种寿命途径是共同的，但它们缺乏特定的详细信息涉及的信号，受体，神经回路和下游效应子。我们的初步数据表明最研究的寿命干预，饮食限制（DR）部分通过单元非自治作用秀丽隐杆线虫中食物的气味抑制的信号通路。我们进一步发现博士和禁食导致诱导肠道蛋白，含黄素单加氧酶-2（FMO-2），这都是必要的足以改善健康范围，抗压力和寿命。我们还观察到FMO-2的诱导寿命的延伸都取决于血清素能信号传导，可以通过5-羟色胺概括拮抗剂药物，米亚梅林。该项目将绘制通过去除的细胞非自治途径最终导致肠道FMO-2诱导和寿命延长的食物。 AIM 1将识别并上学地关联了该神经电路中涉及的神经元，回答了重要的问题特定的细胞启动信号，该信号会传播信号，并最终将其整合到该信号。发出信号范围内的响应。结果将定义以食物感测和利用为导致的神经回路血清素可能与其他寿命途径重叠。第二个目标将集中于涉及的信号通过鉴定小肽，突触转运，神经元和组织与组织通信机理和涉及途径的受体。由此产生的数据将填充神经电路模型从AIM 1带有5-羟色胺以外的关键信号和受体，并可能导致未来的研究模仿/阻止这些信号。第三个目标将确定主要受体和转录因子在肠中诱导FMO-2。我们将使用前向遗传屏幕，靶向RNAi方法和现有 CHIP-SEQ数据定义了与DR介导的FMO-2诱导有关的主要肠基因。一起，这些目标将独立和协同行动以提供对主要信号网络的理解这会改变衰老。我们的最终目标是利用这种对衰老的控制机制的了解促进人类健康的方法。