Cell non-autonomous function of the unfolded protein response

未折叠蛋白反应的细胞非自主功能

• 批准号: 8811078
• 负责人: Andrew G Dillin
• 金额: $ 29.9万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811078
• 关键词: Address; Affect; Age of Onset; Aging; Aging-Related Process; Animal Model; Animals; Atherosclerosis; Attenuated; Caenorhabditis elegans; Cell Survival; Cell physiology; Cells; Cellular Stress Response; Data; Defect; Diabetes Mellitus; Disease; Distal; Drosophila genus; Endocrine system; Endoplasmic Reticulum; Ensure; Environment; Functional disorder; Gene Expression; Generations; Genetic; Genetic Epistasis; Genetic Screening; Health; Individual; Intestines; Invertebrates; Labyrinth; Longevity; Maintenance; Malignant Neoplasms; Messenger RNA; Metabolic Diseases; Methodology; Methods; Molecular Chaperones; Mutagenesis; Nature; Nematoda; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Neurotransmitters; Obesity; Organ; Organism; Pathway interactions; Perception; Phenotype; Physiological; Proteins; Proteome; RNA Splicing; Reproduction; Research; Resistance; Role; Signal Transduction; Source; Stress; Structure; Techniques; Tissues; Translating; Translations; Up-Regulation; Vesicle Transport Pathway; Whole Organism; activating transcription factor; age related; aged; arm; biological adaptation to stress; cell type; endoplasmic reticulum stress; follow-up; insight; metabolomics; neurotransmission; new therapeutic target; novel; promoter; protective effect; protein degradation; protein folding; response; restoration; secretory protein; senescence; small molecule; stressor

DESCRIPTION (provided by applicant): Within invertebrate model organisms such as C. elegans and Drosophila, evidence strongly suggests that tissue-specific manipulations of stress response pathways can affect the aging process of the entire organism. While originating from a single tissue, these manipulations appear capable of propagating synchronous changes to age-related phenotypes across multiple tissues and organs. These compartment-specific stress responses share a role in ensuring maintenance of the proteome, a loss of which would otherwise be catastrophic to the viability of the cell. Because dysfunction in the endoplasmic reticulum (ER) has been associated with a wide-range of age-onset metabolic diseases, including diabetes, obesity, and atherosclerosis, we hypothesized that a restoration of the ER stress response might also have a protective effect on the viability of older animals. We did not know if such a manipulation would affect ER stress response and function cell-autonomously or whether the ER stress response too could be recognized and responded to by distal tissues. Surprisingly, we have discovered that activation of the UPRER in one cell type can also be communicated to a distal cell type that has not undergone ER stress. Using issue specific promoters in the nematode C. elegans that drive expression of spliced version of the UPRER -activating transcription factor XBP-1, we find that neuronal UPR activation can be communicated to distal cells, such as the intestine, resulting in the remote upregulation of ER chaperones. As a consequence, UPRER activation in the nervous system results in increased longevity and stress resistance of the entire animal. This cell non-autonomous response reinforces the idea that in a multi-cellular organism, the sensing of protein folding stress must b conveyed and responded to by the entire organism. The endocrine system is thus an integral and necessary part of multiple conserved cellular stress response pathways. Our data suggest that the UPRER is a cell non-autonomous regulator of age-dependent stress resistance and longevity. We do not yet know the source of this signal, and we do not yet understand the underlying mechanisms of its action. In this proposal, we employ a multi-pronged approach combining genetics, metabolomics, ribosomal profiling, and peptidomics to identify and characterize the signal and its origin. We then use similar techniques to examine the perception of the signal and its consequences in responding tissue. We undertake this research in the hope that novel mechanisms involved in cell non- autonomous UPRER signaling may provide new therapeutic targets for age-onset diseases. We further more hope that such explorations provide valuable insight towards understanding adaptations by which an environmental, extrinsic signal can be sensed and then amplified across the entire animal to coordinate the appropriate onset of reproduction, senescence and/or aging.

描述（由申请人提供）：在诸如秀丽隐杆线虫和果蝇等无脊椎动物模型的内部，有证据表明，应力反应途径的组织特异性操作会影响整个生物体的衰老过程。这些操作虽然起源于单个组织，但似乎能够传播多个组织和器官中与年龄相关的表型的同步变化。这些隔室特异性应力反应在确保蛋白质组维持方面具有作用，否则它将造成细胞生存能力灾难性。 由于内质网中（ER）的功能障碍与包括糖尿病，肥胖和动脉粥样硬化在内的大量年龄发作的代谢性疾病有关，因此我们假设对ER应激反应的恢复也可能对老年动物的可依赖性具有保护作用。我们不知道这样的操作是否会影响ER应力反应和功能细胞自治，或者是否也可以识别出ER应力反应并被远端组织响应。令人惊讶的是，我们发现一种细胞类型中的船长的激活也可以传达给尚未经历ER应力的远端细胞类型。使用线虫C.秀丽隐杆线虫中发行的特定启动子驱动升级版本的转录因子XBP -1的剪接版本的表达，我们发现可以将神经元UPR激活传达到诸如肠道远端细胞（例如肠），从而导致ER伴侣的远程上调。结果，神经系统中的贵族激活导致整个动物的寿命和抗应激性增加。这种细胞非自主反应加强了这样的观念，即在多细胞生物中，蛋白质折叠应激的感应必须由整个生物体传达和反应。因此，内分泌系统是多个保守细胞应力反应途径的组成部分和必要的一部分。 我们的数据表明，将升生是一种细胞的非自治调节剂，其依赖年龄的压力抗性和寿命。我们尚不知道该信号的来源，也不了解其作用的潜在机制。在此提案中，我们采用了一种多管齐下的方法，结合了遗传学，代谢组学，核糖体分析和肽组学来识别和表征信号及其起源。然后，我们使用类似的技术来检查信号的感知及其在反应组织中的后果。我们进行这项研究，希望参与细胞非自主申请信号传导的新型机制可以为年龄疾病提供新的治疗靶点。我们更有希望，这种探索为理解适应性提供了宝贵的见解，通过这些探索可以通过这种适应来感测环境，外部信号，然后在整个动物中放大，以协调繁殖，衰老和/或衰老的适当发作。