高原鼢鼠适应极端低氧环境的脂质代谢分子基础解析

To explore the mechanism of animal adaptation to extreme environmental conditions is a key issue in biological research. As a small subterranean rodent that inhabits the Tibetan plateau, the plateau zokor (Eospalax baileyi) not only faces the harsh plateau environment of coldness, hypoxia and high radiation, but also experiences even lower level of oxygen and higher level of carbon dioxide in the burrows. It therefore become a good model for adaptation studies under extreme environments. Previous studies showed that contrary to many animals which suppress total metabolism to reduce oxygen demand when experiencing hypoxia, small endotherms have an enhanced thermogenic capacity under hypoxia. In this project, we will study the molecular mechanism of plateau zokor adaptation to the enhanced level of hypoxic stress, from the special perspective of energy metabolism. Combining a variety of approaches such as comparative genomics, transcriptomics and molecular evolution theory, we attempt to predict genes that potentially involve in lipid metabolism in plateau zokor. With this gene pool, we will perform a series of assays, including cell expression system, transgenic mouse and artificial hypoxia control system, to identify their function and further illustrate the expression and regulatory networks of functional genes. The objective is to discover several new genes associated with lipid regulation and to demonstrate their functional mechanisms. Moreover, we aim to reveal the unique molecular adaptation mechanism of plateau zokor to its special habitats from the perspective of energy metabolism. With the implementation of this project, we will get new insights into the molecular mechanism of plateau adaptation. Also, our results can provide effective gene targets for rodent control in pastoral areas, which has positive significance to the development of agriculture and animal husbandry in plateau.

生物对极端环境的适应是生物学研究中的一个核心问题。高原鼢鼠作为一种在青藏高原营地下生活的鼠类，经受着高原低温、低氧、高辐射的严酷环境和洞穴更低氧含量的双重压力，成为研究极端环境适应的良好素材。研究发现，与大型动物在低氧条件下通过降低代谢水平来减少氧消耗相反，高原小型温血动物在低氧下的产热能力更高。因此，本项目将从能量代谢这一新的视角来研究高原鼢鼠对高原和洞穴双重低氧压力的适应。我们将结合比较基因组学、转录组学以及分子进化理论等多种方法，预测可能影响高原鼢鼠脂质代谢的基因，从多层次对这些基因的功能进行鉴定，并进一步解析功能基因的表达调控通路网络。目标是发现若干脂质调控相关的新基因及其作用机制，并从能量代谢的角度揭示高原鼢鼠对其特殊生境的独特分子适应机制。本项目的实施将为深入解析高原适应这一复杂性状奠定坚实基础；同时，也能为高原农牧区鼠害防治提供有效基因靶点，对高原农牧业的发展具有积极意义。

本项目主要从能量代谢这一角度对高原鼢鼠适应高原和洞穴双重低氧压力的分子基础和遗传学机制进行解析。通过对生活在不同海拔地区的高原鼢鼠进行大规模转录组学比较分析，鉴定出一系列与海拔高度密切相关的共表达模块，其中，糖代谢和脂代谢通路在所有组织中均有显著富集，且在大部分组织中，脂代谢相关基因显著富集于海拔正相关模块中，而糖代谢相关基因显著富集于海拔负相关模块中，提示着生活在低海拔地区的高原鼢鼠倾向于使用糖类作为其能量代谢基质，而在高海拔地区则倾向于使用脂类作为能量来源。在此基础上，为了进一步寻找可能的关键基因，我们综合应用分子进化理论，及细胞和动物实验技术，筛选出一批与能量代谢相关的潜在基因。通过RetSat转基因小鼠的低氧模拟培养，验证了在低氧条件下高原型突变个体可以保持相对较高的脂代谢水平。有趣的是，还发现高原突变型个体可能通过提高母鼠乳汁产量进而影响子代的体重发育，并进一步解析其可能的调控作用机制。额外地，我们还探究了假基因在地下洞穴生活物种中潜在的适应性作用。这些结果将为全面深入理解能量代谢在高原低氧适应中的作用提供科学依据，也能为高原代谢相关疾病的治疗，以及高原农牧区鼠害防治提供潜在基因靶点。