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: 10532756
• 负责人: SCOTT F LEISER
• 金额: $ 31.63万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532756
• 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; Literature; Longevity; Longevity Pathway; Maps; Mediating; Medical; Metabolism; Modeling; Modification; Molecular; Mutation; Nematoda; Nervous System; Neuronal Hypoxia; Neurons; Neuropeptides; Organism; Oxygen; Pathway interactions; Perception; Peripheral; Physiological; Physiology; 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; deprivation; dietary restriction; environmental change; health determinants; healthspan; hypoxia inducible factor 1; improved; innovation; insight; neural; neural circuit; neuromechanism; neuronal circuitry; neurotransmission; novel; promoter; receptor; response; serotonin receptor; therapy development; tool; transcription factor; transmission process

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.

项目摘要/摘要 在无脊椎动物模型的开创性研究的带领下，我们对衰老机制的理解 在过去的25年里呈指数级增长。尽管有这样的增长，但遗传和 衰老的分子机制仍不是很清楚。这些机制之一是能够 细胞的小亚群(通常是神经元)，以非自主的方式调节细胞的衰老过程。最近， 多项高影响力的出版物已经确定了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，从而有益于健康和长寿。这些研究 提供大量证据表明细胞对衰老的非自主控制是多重长寿的共同原因 途径，但缺乏具体的信号，受体，和涉及的神经回路的细节。我们的 初步数据证实了一种由转录因子领导的新的细胞非自主长寿途径 对低氧环境作出反应所必需的缺氧诱导因子(HIF-1)。我们进一步发现， 通过遗传或环境方法稳定神经元中的HIF-1，导致诱导 肠道蛋白，含有黄素的单加氧酶-2(FMO-2)，这是改善的必要和充分的 健康寿命、抗压性和长寿。我们观察到，FMO-2的诱导和寿命的延长 HIF-1的稳定性依赖于5-羟色胺产生酶TPH-1和5-羟色胺的存在 受体Ser-7。该项目将绘制由细胞启动的非自主通路的核心神经组件 稳定神经元HIF-1，最终导致肠道FMO-2的诱导和延长寿命。目标 1将重点放在反应的启动，包括神经元的身份和时间以及 缺氧诱导因子-1‘S促进细胞非自主生理性改变的机制。结果将确定 一小部分神经元在哪里以及如何启动对低氧的广泛反应。第二个目标聚焦于 在表达Ser-7的神经元上，Ser-7是一种高度保守的5-羟色胺受体，它传播HIF-1介导的 信号。第三个目标将集中在HIF-1下游的神经电路上，识别密钥传播和 整合细胞和核心信号，这两个信号是这条通路独有的，也是其他非自主细胞共享的 网络。结果将确定由HIF-1领导的神经回路，并利用可能部分重叠的5-羟色胺 与其他长寿途径相联系。产生的数据对于我们理解定义的网络是至关重要的 控制生理和衰老速度，并可能导致未来的研究，旨在模拟这些信号 网络。在一起，这些目标将独立和协同行动，以提供对 改变老化的主要信令网络。我们的最终目标是利用这种控制知识 研究衰老机制以开发促进人类健康的方法。