Gut stress-induced intercellular signaling networks promoting longevity and proteostasis

肠道应激诱导的细胞间信号网络促进长寿和蛋白质稳态

基本信息

批准号：
10717808
负责人：
Patricija van Oosten-Hawle
金额：
$ 37.05万
依托单位：
UNIVERSITY OF NORTH CAROLINA CHARLOTTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10717808
关键词：
Age Aging Alzheimer&apos s Disease Animals Auxins Binding Binding Sites Biological Models Caenorhabditis elegans Cell Nucleus Cell membrane Cells Chromatin Clinical Communication Data Degenerative Disorder Dementia Development Disease Distal Endocrine Enteroendocrine Cell Genes Genetic Transcription Genome Genomics Goals Guanylate Cyclase Health Heat Stress Disorders Heat-Shock Proteins 70 Heat-Shock Proteins 90 Hormones Human Impaired health Intervention Intestines Knowledge Life Longevity Mediating Mediator Membrane Metabolic Diseases Methodology Molecular Molecular Chaperones Muscle Muscle Cells Myopathy Names Nervous System Neurodegenerative Disorders Neurons Neuropeptides Organ Organism Outcome Pathway interactions Patients Peptides Process Proteins Proteomics Publications Quality Control Regulation Reporting Risk Role Set protein Signal Induction Signal Pathway Signal Transduction Stress Stress Response Signaling System Testing Therapeutic Time Tissues Up-Regulation Visualization Work age related combat design extracellular genetic approach healthspan healthy aging homeodomain improved insight knock-down muscle degeneration new therapeutic target paracrine pathogen pharmacologic preservation programs protein misfolding proteostasis public health relevance response sarcopenia small molecule stress resilience therapeutic target transcription factor transcriptome transmission process

项目摘要

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.

项目概要细胞蛋白质稳态（蛋白质稳态）对于维持整个有机体的健康至关重要衰老生物体中的蛋白质稳态崩溃是一个巨大的临床问题，因为它是细胞发育的基础。多个器官中与年龄相关的退行性蛋白质错误折叠疾病，例如肌肉减少症、代谢性疾病神经系统产生的中枢调节信号，例如激素和痴呆。神经肽因其在维持细胞非自主健康方面的作用而得到了最好的表征。肠内分泌细胞（即肠道）在产生具有全系统影响的分泌信号方面的作用延长动物健康寿命的研究较少。因此，如果我们要开始利用这种肠道功能，那么在整个衰老过程中延长健康组织功能的肠道就至关重要。我实验室的长期目标是开发能够杠杆化的分子干预措施。我们使用肠道启动的细胞间信号来促进健康衰老和长期组织健康。线虫对我们的工作的帮助，因为它是识别和可视化分子机制的非常有用的系统我的实验室发现，轻微的肠道压力是由生物体中的细胞间信号网络引发的。敲低肠道中的分子伴侣 Hsp90，启动保护蛋白的上调其他组织（例如肌肉）的质量控制反应会导致寿命延长并促进。我们确定了细胞膜相关的鸟苷酸环化酶 TXT-1 和同源结构域转录因子 CEH-58 是肠道到肌肉信号转导的关键介质。神经元在肌肉中发挥作用，转导从肠道接收到的细胞外信号，从而激活保护性反应。总体目标是确定 TXT-1 和 CEH-58 如何启动适应性调节反应。促进健康寿命的核心假设是肠道特异性 Hsp90 减少。压力激活新的细胞间信号传导途径，诱导保护性蛋白质质量控制重新我们的基本原理是通过确定分子机制。肠道到肌肉信号传导所需的核心成分，我们将定义这条新途径，并且可以为了测试我们的中心假设，我们将使用遗传方法。允许细胞间和组织特异性信号以及组织特异性蛋白质组的可视化目标 1：确定核心的分子机制；参与促进蛋白质稳态的肠道到肌肉信号转导的成分；目标 2：确定肠道压力 - 在转录和分子水平上诱导 HSF-1 和 CEH-58 的拮抗调节；目标 3：定义组成性和短暂的 TCS 激活对蛋白质稳态和长期健康的影响。肠道到肌肉信号传导的分子机制，我们期望揭示关于其作用的基本新见解肠道作为一个中心器官，可以促进生物健康寿命并对抗与年龄相关的疾病。