内质网内蛋白质错误折叠和聚集（“内质网应激”）可启动 “去折叠蛋白响应”（UPR）以维持蛋白质内稳态（“适应性UPR”），但长期、不可逆的内质网应激下UPR也可造成细胞功能丧失和细胞凋亡（“终结性UPR”）。IRE1a是最保守的UPR启动分子。作为RNase，IRE1a能特异剪切转录因子XBP1 的mRNA，启动有活性XBP1的翻译及下游适应性UPR，也能降解多种靠近内质网膜的mRNA及非编码RNA，造成终结性UPR。虽然IRE1a的这两种RNA酶活性对细胞造成截然不同的影响，但目前人们对IRE1a的RNA酶底物选择性、哪些RNA可能被IRE1a降解及其生理意义知之甚少。本项目将针对这一问题，综合运用高通量测序、生化、细胞生物学实验手段，鉴定IRE1a的RNA底物，考察IRE1a底物特异性的调控机制及其生理意义。该工作将帮助我们更好的认识UPR的调节机制，为治疗UPR相关疾病提供新思路。

The unfolded protein response (UPR) is an evolutionarily conserved intracellular signaling pathway triggered when unfolded proteins accumulate in the endoplasmic reticulum (ER) to cause “ER stress”. While the UPR initially serves to maintain ER homeostasis (“Adaptive UPR”), under irremediable ER stress it causes critical loss of cell function or even cell death (“Terminal UPR”). Irregular balance between Adaptive and Terminal UPR could lead to ER-stress-related diseases, such as neurodegenerative disease and diabetes. .The most ancient UPR component, Inositol-requiring enzyme-1alpha (IRE1alpha) plays a pivotal role in the UPR system. Upon sensing ER stress, active IRE1alpha as an RNase initiates splicing of XBP1 mRNA (which encodes a transcription factor). XBP1 up-regulates expression of chaperones and foldases, allowing the ER to adapt to ER stress. However, IRE1alpha could also degrade many RNAs that are spatially close to the ER, which largely contributes to the Terminal UPR. While these two IRE1alpha RNase activities have different influence on the cell fate, little is known about the regulatory mechanism of the RNase substrate specificity and the physiological significance of the RNA degradation by IRE1alpha. We propose to address these questions by performing deep sequencing, biochemical and cell biology assays. We anticipate to identify IRE1alpha’s RNase substrate genome-wide, and to understand how the RNase activity towards different substrates are regulated. The study will advance our understanding on the regulation of UPR balance, and may also facilitate development of new strategies against ER stress-related diseases.