Gut stress-induced intercellular signaling networks promoting longevity and proteostasis

项目总结 细胞蛋白质平衡(蛋白质平衡)对于维持整个生物体的健康至关重要。 生活。衰老生物体中的蛋白平衡崩溃是一个巨大的临床问题，因为它是发展的基础 多个器官中与年龄相关的退行性蛋白质错误折叠疾病，如石棺减少，代谢 紊乱或痴呆症。由神经系统产生的中央调节信号，如激素和 神经肽因其在维持细胞非自主健康方面的作用而被最好地描述。然而， 肠内分泌细胞，即肠道，在产生分泌信号方面的作用，这些信号具有全系统的影响 延长动物的健康寿命的研究较少。识别由以下组织发起的细胞间信令网络 因此，如果我们要开始利用肠道，在整个衰老过程中延长健康组织功能是必不可少的 治疗策略的信号。我的实验室的长期目标是开发分子干预手段，使- AGE细胞间信号由肠道发起，以促进健康衰老和长期组织健康。我们使用C。 对于我们的工作来说，这是一个非常有用的系统，可以识别和可视化分子机制 活着的有机体中的细胞间信号网络。我的实验室发现轻微的肠道压力，由 在肠道中击倒分子伴侣Hsp90，启动保护蛋白的上调 在肌肉等其他组织中的质量控制反应。这会延长寿命并促进 在整个衰老过程中的压力恢复能力。我们鉴定了细胞膜相关的鸟苷环化酶TXT-1和 同源结构域转录因子CEH-58作为肠道到肌肉信号转导的重要中介。两家公司都- 神经营养因子在肌肉中发挥作用，传递从肠道接收的细胞外信号，激活保护性反应。 海绵。总体目标是确定TXT-1和CEH-58如何启动适应性调节反应 在促进健康的肌肉中。中心假说是Hsp90的肠道特异性降低-- 抑制激活一条新的细胞间信号通路，诱导保护性蛋白质质量控制反应。 肌肉细胞中的回旋(“肠道到肌肉的信号”)。我们的理论基础是，通过确定分子机制- 肠道到肌肉信号传递所需的核心成分的NISM我们将定义这一新的途径，并可以 治疗上以它为靶点，以延长生命周期。为了检验我们的中心假设，我们将使用遗传学方法 它允许可视化细胞间和组织特定的信号，以及组织特定的蛋白质组 和基因组方法学；目标1：确定核心的分子机制 参与促进蛋白质平衡的肠道到肌肉信号传递的组件；目标2：确定肠道应激- 在转录和分子水平上诱导HSF-1和CEH-58的拮抗调节；目标3：定义 结构性和暂时性TCS激活对蛋白平衡和长期健康的影响。在确定 肠道到肌肉信号转导的分子机制，我们希望揭示对肠道到肌肉信号转导的作用的新的基本见解。 肠道作为促进机体健康和对抗与年龄相关的疾病的中心器官。

PROJECT SUMMARY Cellular protein homeostasis (proteostasis) is essential to maintain the health of an entire organism throughout life. Proteostasis collapse in aging organisms is a massive clinical problem as it underlies the development of age-associated degenerative protein misfolding diseases in multiple organs, such as sarcopenia, metabolic disorders or dementia. Centrally regulated signals produced by the nervous system such as hormones and neuropeptides have been best characterized for their role in maintaining cell nonautonomous health. However, the role of enteroendocrine cells, i.e. the gut, in producing secreted signals that have system-wide effects to extend the health span of an animal is less well studied. Identifying intercellular signaling networks initiated by the gut to prolong healthy tissue function throughout aging is therefore essential if we are to begin utilize such signals for therapeutic strategies. The long-term goal of my lab is to develop molecular interventions that lever- age intercellular signals initiated by the gut to promote healthy aging and long-term tissue health. We use C. elegans for our work, as it is a tremendously useful system to identify and visualize the molecular mechanism of intercellular signaling networks in the living organism. My lab discovered that mild gut stress, triggered by knockdown of the molecular chaperone Hsp90 in the intestine, initiates the upregulation of protective protein quality control responses in other tissues such as muscle. This results in lifespan extension and promotes stress resilience throughout aging. We identified the cell membrane associated guanylate cyclase TXT-1 and the homeodomain transcription factor CEH-58 as crucial mediators of gut-to-muscle signaling. Both compo- nents function in the muscle to transduce extracellular signals received from the gut to activate protective re- sponses. The overall objective is to determine how TXT-1 and CEH-58 initiate adaptive regulatory responses in the muscle that promote health span. The central hypothesis is that intestine-specific reduction of Hsp90 ex- pression activates a new intercellular signaling pathway that induces protective protein quality control re- sponses in muscle cells (“gut-to-muscle signaling”). Our rationale is that by determining the molecular mecha- nism of core components required for gut-to-muscle signaling we will have defined this new pathway and can therapeutically target it to prolong health span. To test our central hypothesis, we will use genetic approaches that allow for the visualization of intercellular and tissue-specific signals, as well as tissue-specific proteomic and genomic methodologies in the following specific aims; Aim 1: Determine the molecular mechanism of core components involved in gut-to-muscle signaling that promote proteostasis; Aim 2: Determine the gut stress- induced antagonistic regulation of HSF-1 and CEH-58 at the transcriptional and molecular level; Aim 3: Define the effects of constitutive and transient TCS activation on proteostasis and long-term health. In determining the molecular mechanism of gut-to-muscle signaling, we expect to reveal fundamental new insights into the role of the gut as a central organ that promotes organismal health span and counteracts age-associated illnesses.