Mechanisms of cell non-autonomous signaling through the hypoxic response

项目总结/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已经 在过去的25年里呈指数级增长。尽管这种增长，有许多方面的遗传和 衰老的分子机制仍然没有得到很好的理解。其中一种机制是 小的细胞亚群（通常是神经元）来非自主地调节细胞的衰老过程。最近， 多个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学以有益于健康和长寿。这些研究 提供了大量的证据表明，细胞非自主控制老化是常见的多种长寿 他们的研究涉及神经通路，但缺乏有关具体信号、受体和神经回路的详细信息。我们 初步数据确定了一个新的细胞非自主长寿途径，由转录因子 低氧诱导因子（HIF-1）是低氧环境下的一种重要因子。我们进一步发现， 通过遗传或环境途径，稳定神经元中的HIF-1，导致诱导神经元中的HIF-1表达。 肠蛋白，含黄素单加氧酶-2（fmo-2），这是必要的，足以改善 健康、抗压和长寿。我们观察到FMO-2的诱导和寿命的延长， HIF-1的稳定分别依赖于血清素产生酶tph-1和血清素 Ser-7受体。该项目将绘制细胞非自主通路的核心神经组件， 稳定神经元HIF-1，最终导致肠fmo-2诱导和寿命延长。目的 1将集中在反应的启动，包括神经元的身份和时间， HIF-1促进细胞非自主性生理变化的机制。结果将确立 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， 信号了第三个目标将集中在HIF-1下游的神经回路上，识别关键的传播， 整合细胞和核心信号，这两个独特的途径，并共享其他细胞非自主 网络.结果将定义一个由HIF-1和利用血清素领导的神经回路， 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， 控制生理和衰老的速度，并可能导致未来的研究旨在模拟这些信号， 网络.总之，这些目标将发挥独立和协同作用，以提供一个了解 主要的信号网络，修改老化。我们的最终目标是利用这种控制知识 衰老机制，以开发促进人类健康的方法。

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.