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

• 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
• 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' 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

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 细胞蛋白质稳态（蛋白质稳态）是维持整个生物体健康的关键 生活衰老生物体中的蛋白质稳态崩溃是一个巨大的临床问题，因为它是免疫调节的发展的基础。 多器官中与年龄相关的退行性蛋白质错误折叠疾病，如肌肉减少症、代谢性 疾病或痴呆。由神经系统产生的中枢调节信号，如激素和 神经肽的最佳特征在于它们在维持细胞非自主健康中的作用。然而，在这方面， 肠内分泌细胞（即肠道）在产生具有全系统效应的分泌信号中的作用， 延长动物的健康寿命的研究较少。识别细胞间信号传导网络， 因此，如果我们要开始利用这种消化道， 治疗策略的信号。我实验室的长期目标是开发分子干预手段- 老化细胞间的信号发起的肠道，以促进健康的老化和长期的组织健康。我们使用C。 我们的工作，因为它是一个非常有用的系统，以确定和可视化的分子机制 细胞间的信号网络。我的实验室发现轻微的肠道压力， 肠道中分子伴侣Hsp 90的敲低启动保护性蛋白的上调 其他组织如肌肉中的质量控制反应。这导致寿命延长， 在整个老化过程中的压力恢复能力。我们鉴定了细胞膜相关鸟苷酸环化酶TXT-1， 同源结构域转录因子CEH-58作为肠道到肌肉信号传导的关键介质。两种成分- 肌肉中的神经元功能是抑制从肠道接收到的细胞外信号，以激活保护性受体。 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 促进健康的肌肉。核心假设是，Hsp 90的精氨酸特异性减少， 表达激活一种新的细胞间信号通路，诱导保护性蛋白质质量控制再表达。 肌肉细胞中的自发信号（“肠道到肌肉的信号传导”）。我们的理论是通过确定分子机制- 如果我们不知道肠到肌肉信号传导所需的核心成分，我们将定义这一新途径， 治疗目标是延长健康寿命。为了检验我们的中心假设，我们将使用遗传学方法 允许细胞间和组织特异性信号的可视化，以及组织特异性蛋白质组学 目的1：确定核心的分子机制 参与促进蛋白质稳态的肠道-肌肉信号传导的组分;目的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;目的3： 组成性和瞬时TCS激活对蛋白质稳态和长期健康的影响。在确定 肠到肌肉信号的分子机制，我们希望揭示基本的新见解的作用， 肠道作为一个中心器官，促进有机体的健康寿命和抵消与年龄相关的疾病。