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领导下，我们对衰老机制的理解 在过去25年中成倍增长。尽管增长了这种增长，但遗传和 衰老的分子机制仍未得到充分理解。这些机制之一是 细胞的小子集（通常是神经元）非自主地调节衰老过程细胞。最近， 多个高影响力出版物已经确定了启动信号通路的单个基因和神经元 并最终改变外周组织的生理学，以使健康和寿命有益。这些研究 提供大量证据表明，细胞对衰老的非自主控制对于多种寿命是共同的 途径，但由于涉及的特定信号，受体和神经回路缺乏详细的详细信息。我们的 初步数据确定了一个由转录因子领导的新细胞非自治寿命途径 对低氧环境（低氧诱导因子（HIF-1））的反应所必需的。我们进一步发现 通过遗传或环境方法，神经元中HIF-1的稳定导致诱导 肠道蛋白，含黄素单加氧酶-2（FMO-2），既需要改进的必要又足够 健康范围，压力抵抗和寿命。我们观察到FMO-2的诱导和寿命的延长 HIF-1稳定都取决于血清素产生酶TPH-1和5-羟色胺的存在 受体Ser-7。该项目将绘制细胞非自治途径的核心神经成分。 神经元HIF-1的稳定，最终导致肠道FMO-2诱导和寿命的延伸。目的 1将侧重于响应的启动，包括神经元的身份和时间安排和 HIF-1非自主促进生理变化细胞的机制。结果将建立 一小部分神经元在哪里以及如何引发对低氧的广泛反应。第二个目标重点 在表达SER-7的神经元上，一种高度保守的5-羟色胺受体，可传播HIF-1介导的 信号。第三个目标将重点放在HIF-1下游的神经电路上，确定关键的传播和 整合细胞和核心信号既是该途径独有的，又由其他非自治的细胞共享 网络。结果将定义由HIF-1领导的神经回路，并利用5-羟色胺可能部分重叠 与其他寿命途径。最终的数据对于我们对定义网络的理解至关重要 控制生理学和衰老率，并可能导致未来的研究，以模仿这些信号 网络。这些目标共同采取独立和协同行动，以提供对一个人的理解 修改衰老的主要信号网络。我们的最终目标是利用这种控制知识 衰老的机制开发促进人类健康的方法。