Cell non-autonomous function of the unfolded protein response

描述(申请人提供)：在无脊椎动物模式生物中，如线虫和果蝇，有证据强烈表明，对应激反应途径的组织特异性操作可以影响整个有机体的衰老过程。虽然这些操作起源于单个组织，但似乎能够在多个组织和器官中传播与年龄相关的表型的同步变化。这些隔室特有的应激反应在确保蛋白质组的维持方面具有共同的作用，否则蛋白质组的丧失将对细胞的生存能力造成灾难性的影响。由于内质网(ER)功能障碍与一系列年龄相关性代谢性疾病有关，包括糖尿病、肥胖和动脉粥样硬化，我们假设内质网应激反应的恢复也可能对老年动物的生存具有保护作用。我们不知道这样的操作是否会影响内质网应激反应和细胞自主功能，或者内质网应激反应是否也可以被远端组织识别和反应。令人惊讶的是，我们发现一种细胞类型的UPRER的激活也可以传递到没有经历内质网应激的远端细胞类型。利用线虫中的问题特异性启动子来驱动UPRER激活转录因子XBP-1的剪接版本的表达，我们发现神经元UPR的激活可以传递到远端细胞，如肠道，导致ER伴侣的远程上调。因此，神经系统中UPRER的激活会增加整个动物的寿命和抗应激能力。这种细胞的非自主反应强化了这样一种观点，即在多细胞有机体中，蛋白质折叠应力的感知必须由整个有机体来传达和响应。因此，内分泌系统是多种保守的细胞应激反应途径中不可或缺的一部分。我们的数据表明，UPRER是年龄相关的应激抗性和寿命的非自主细胞调节因子。我们还不知道这一信号的来源，也不了解其行动的基本机制。在这项建议中，我们采用多管齐下的方法，结合遗传学、代谢组学、核糖体图谱和多肽组学来识别和表征信号及其来源。然后，我们使用类似的技术来检查对信号的感知及其在反应组织中的后果。我们开展这项研究是希望参与细胞非自主UPRER信号转导的新机制可能为老年性疾病提供新的治疗靶点。我们更希望这样的探索能够为理解适应提供有价值的见解，通过这种适应，环境的外部信号可以被感知，然后在整个动物中被放大，以协调适当的生殖、衰老和/或衰老的开始。

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.