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.

项目摘要细胞蛋白稳态（蛋白抑制）对于维持整个生物的健康至关重要生活。衰老生物体中的蛋白结构崩溃是一个巨大的临床问题，因为它是发展的基础多种器官（例如肌肉减少症）中，与年龄相关的退化性蛋白质错误折叠性疾病疾病或痴呆症。神经系统产生的中心调节信号，例如激素和神经肽在维持细胞非自主健康中的作用最佳。然而，肠内分泌细胞的作用，即肠道，在产生具有全系统影响到的分泌信号中扩展动物的健康跨度的研究不善。识别由因此，如果我们要开始利用这种肠道，则必须延长整个衰老的健康组织功能治疗策略的信号。我实验室的长期目标是开发分子干预措施，以杠杆肠道发起的年龄间信号是为了促进健康的衰老和长期组织健康。我们使用C 秀丽隐杆线为我们的工作，因为这是一个非常有用的系统，可识别和可视化分子机制生物体中的细胞间信号网络。我的实验室发现，由肠分子伴侣Hsp90在肠中敲低，引发了保护蛋白的上调质量控制其他组织（例如肌肉）的反应。这导致寿命延长并促进整个衰老的压力弹性。我们鉴定了相关的细胞膜环化环化酶TXT-1和同源域转录因子CEH-58是肠道肌肉信号传导的关键介体。两者都组成肌肉中的NENTS功能翻译从肠道接收到的细胞外信号，以激活保护性重新赞助商。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跨度的肌肉中。中心假设是HSP90的肠道特异性还原陈述激活了一种新的细胞间信号通路，该途径诱导保护性蛋白质质量控制重新肌肉细胞中的赞助（“直至肌肉信号传导”）。我们的理由是，通过确定分子机械肠道到肌肉信号所需的核心组件的nism，我们将定义此新途径，并且可以以治疗为目标，以延长健康范围。为了检验我们的中心假设，我们将使用遗传方法这允许可视化细胞间和组织特异性信号以及组织特异性蛋白质组学以及以下特定目标中的基因组方法；目标1：确定核心的分子机制涉及肠道对肌肉信号的成分促进蛋白质的抑制；目标2：确定肠道应力 - 在转录和分子水平上诱导HSF-1和CEH-58的拮抗调节；目标3：定义构型和瞬态TCS激活对蛋白质和长期健康的影响。在确定肠道到肌肉信号传导的分子机制，我们希望揭示基本的新见解肠道是促进有机健康跨度并抵消与年龄相关的疾病的中心器官。