油酸调节机体基础免疫以提高其环境温度适应性的机制研究

Adaptive capacity to environmental temperature fluctuation is essential for animal survival. Microbial infectivity increases with temperature rise, therefore, representing higher infection risk to the host. However, whether host animals would adjust their immunity correspondingly to adapt to the temperature change is unclear. By using model organism C. elegans, the applicant found that animals could adjust their basal immunity in response to environmental temperature rise. Such adaptive response confers a survival benefit to the host upon subsequent pathogen infection via PMK-1. Moreover, prelimilary data have revealed that oleic acid, an important unsaturated fatty acid, is required for basal immune activation in response to temperature elevation. Based on these findings, this project aims to study the critical roles for oleic acid in temperature-induced basal immune activation as follows: (1) elucidate the critical roles of oleic acid and its metabolic enzymes in temperature-induced basal immune activation; (2) examine the interaction between oleic acid and PMK-1 pathway; (3) identify the upstream molecule(s) linking environmental temperature to oleic acid. This project would deepen our understanding of the physiological function of oleic acid, and provide mechanistic insights to how animals adapt to environmental temperature change.

生活在自然环境中的动物，需要适应多变的环境温度，其对环境温度的适应力直接影响其生存。环境温度升高时，多数病原菌感染宿主能力随之增强，意味着宿主遭受感染的风险上升。然而，宿主动物感受环境温度变化后，能否适应性地调节其免疫能力，以应对随温度变化的病原菌，目前还不清楚。申请者前期研究发现, 在模式动物秀丽隐杆线虫中, 当环境温度升高时，机体通过激活PMK-1通路上调其基础免疫力，以应对感染风险的提高。研究还发现，不饱和脂肪酸油酸是介导环境温度对基础免疫调控的关键。基于油酸参与调控环境温度适应力这一新发现，本项目拟从以下三方面深入研究油酸在其中的功能和机制: (1) 阐明油酸及其代谢基因在环境温度调节基础免疫中的功能; (2) 研究油酸与 PMK-1 通路的相互作用; (3) 鉴定油酸的上游调控基因。通过该项目的研究，使我们进一步了解油酸的生理功能，同时从机理上深入理解动物对环境温度的适应。

动物对环境温度的适应能力是其生存的基础。我们在本项目中研究了秀丽线虫适应环境高温的机制,阐明了以油酸为关键调控分子的高温适应通路，同时研究了油酸在动物应激反应中的新功能和新机制。主要研究成果包括：（1）发现秀丽线虫对环境高温存在记忆，短暂的环境高温持续性地激活了固有免疫基因的表达，进而促进寿命延长，而该记忆现象由组蛋白乙酰基转移酶CBP-1介导的组蛋白乙酰化所调控；（2）发现油酸调控组蛋白乙酰化介导的表观遗传记忆，油酸通过HSF-1和PMK-1来达到调控组蛋白乙酰化的目的；（3）发现长寿转录因子SKN-1具有抑制体细胞维持的功能，而该现象是由于SKN-1激活后油酸含量减少，进而抑制另一转录因子DAF-16所致；（4）发现DNA损伤可以提升线虫内质网应激反应，而该现象依赖于油酸的产生，并解析油酸通过生成不饱和磷脂酰胆碱发挥调控内质网应激的作用。综上，本项目的研究发现了动物适应环境高温的新机制，发现了油酸新的生理功能，加深了我们对油酸在衰老相关表型中重要作用的理解。