Mechanisms of cell non-autonomous signaling through the hypoxic response

通过缺氧反应的细胞非自主信号传导机制

• 批准号: 10341075
• 负责人: SCOTT F LEISER
• 金额: $ 31.58万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341075
• 关键词: Adenylate Cyclase; Aging; Caenorhabditis elegans; Cell physiology; Cells; Cellular Structures; Data; Disease; Environment; Enzymes; FMO2; Future; Genes; Genetic; Gerontology; Goals; Growth; Health; Health Benefit; Human; Hypoxia; Hypoxia Inducible Factor; Individual; Intervention; Intestines; Invertebrates; Knowledge; Lead; Literature; Longevity; Longevity Pathway; Maps; Mediating; Medical; Modeling; Modification; Molecular; Nematoda; Nervous system structure; Neuronal Hypoxia; Neurons; Neuropeptides; Organism; Oxygen; Pathway interactions; Perception; Peripheral; Physiological; Physiology; Play; Process; Proteins; Publications; Publishing; Research Design; Resistance; Role; Sensory; Serotonergic System; Serotonin; Serotonin Production; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Stress; Techniques; Testing; Tissues; Work; base; deprivation; dietary restriction; healthspan; hypoxia inducible factor 1; improved; innovation; insight; neural circuit; neuromechanism; neuronal circuitry; neuronal metabolism; neurotransmission; novel; promoter; receptor; relating to nervous system; response; serotonin receptor; therapy development; tool; transcription factor

Project Summary/Abstract Led by groundbreaking studies in invertebrate models, our understanding of the mechanisms of aging has grown exponentially in the past 25 years. Despite this growth, there are many aspects of the genetic and molecular mechanisms of aging that are still not well understood. One of these mechanisms is the ability of small subsets of cells (frequently neurons) to modulate the aging process cell non-autonomously. Recently, multiple high-impact publications have identified individual genes and neurons that initiate signaling pathways and eventually modify the physiology of peripheral tissues to benefit health and longevity. 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, and neural circuits involved. Our preliminary data identify a new cell non-autonomous longevity pathway, led by the transcription factor necessary to respond to low oxygen environments, the hypoxia-inducible factor (hif-1). We further find that stabilization of HIF-1 in neurons, through either genetic or environmental approaches, leads 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 observe that induction of fmo-2 and extension of lifespan by HIF-1 stabilization each depend on the presence of the serotonin producing enzyme tph-1 and the serotonin receptor ser-7. This project will map core neural components of the cell non-autonomous pathway initiated by stabilization of neuronal HIF-1 that eventually leads to intestinal fmo-2 induction and extension of lifespan. Aim 1 will focus on the initiation of the response, including the identity of the neurons and the timing and mechanism of HIF-1's promotion of physiological changes cell non-autonomously. The results will establish where and how a small subset of neurons initiates a broad response to low oxygen. The second aim focuses on the neuron expressing ser-7, a highly conserved serotonin receptor that propagates the HIF-1-mediated signal. The third aim will focus on the neural circuit downstream of HIF-1, identifying key propagating and integrating cells and core signals both unique to this pathway and shared by other cell non-autonomous networks. The results will define a neural circuit led by HIF-1 and utilizing serotonin that may partially overlap with other longevity pathways. The resulting data are crucial to our understanding of defined networks that control physiology and the rate of aging, and will likely lead to future studies designed to mimic signals in these networks. 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.

项目概要/摘要 在无脊椎动物模型的突破性研究的引领下，我们对衰老机制的理解已经深入人心 过去25年呈指数级增长。尽管有这种增长，但遗传和基因的许多方面 衰老的分子机制仍不清楚。这些机制之一是能够 小细胞子集（通常是神经元）非自主地调节细胞的衰老过程。最近， 多个高影响力出版物已确定启动信号通路的单个基因和神经元 并最终改变周围组织的生理机能，以有益于健康和长寿。这些研究 提供大量证据表明细胞非自主控制衰老对于多种长寿者来说是常见的 途径，但它们缺乏有关具体信号、受体和所涉及神经回路的细节。我们的 初步数据确定了由转录因子主导的新细胞非自主长寿途径 缺氧诱导因子（hif-1）是应对低氧环境所必需的。我们进一步发现 通过遗传或环境方法，神经元中 HIF-1 的稳定性会导致诱导 肠道蛋白，即含黄素单加氧酶-2 (fmo-2)，这对于改善肠道菌群而言是必要且充分的 健康寿命、抗压能力和长寿。我们观察到 fmo-2 的诱导和寿命的延长 HIF-1 的稳定性分别取决于产生血清素的酶 tph-1 和血清素的存在 受体 Ser-7。该项目将绘制细胞非自主通路的核心神经组件的图谱 神经元 HIF-1 的稳定，最终导致肠道 fmo-2 诱导和寿命延长。目的 1 将重点关注响应的启动，包括神经元的身份以及时间和响应 HIF-1促进细胞非自主生理变化的机制。结果将确定 一小部分神经元在何处以及如何发起对低氧的广泛反应。第二个目标聚焦 表达 Ser-7 的神经元，这是一种高度保守的血清素受体，可传播 HIF-1 介导的 信号。第三个目标将重点关注 HIF-1 下游的神经回路，识别关键的传播和 整合该途径特有且由其他非自主细胞共享的细胞和核心信号 网络。结果将定义由 HIF-1 领导并利用可能部分重叠的血清素的神经回路 与其他长寿途径。由此产生的数据对于我们理解定义的网络至关重要 控制生理学和衰老速度，并可能导致未来旨在模拟这些信号的研究 网络。这些目标将共同独立和协同地发挥作用，以提供对 改变衰老的主要信号网络。我们的最终目标是利用这些控制知识 衰老机制，以开发促进人类健康的方法。