汇报人：赵丽,Role of ERO1-α–mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress–induced apoptosis,Contents,研究背景,Endoplasmic reticulum(ER) stress–induced apoptosis is involved in many diseases, but the mechanisms linking ER stress to apopt-osis are incompletely understood. *CHOP:ＣＣＡＡＴ／增强子结合蛋白（ＣＨＯＰ）是ＥＲ应激特异的转录因子,研究背景,CHOP:正常情况下,ＣＨＯＰ表达十分低下，在ＥＲ应激反应时,ＩＲＥ-１、ＰＥＲＫ和ＡＴＦ６的活化均对ｃＨOＰ产生诱导，促使CＨOＰ激活，其表达显著增加，从而诱导细胞凋亡钙离子：从内质网内释放的钙离子可以通过激活钙联蛋白调节的钙调神经磷酸酶，使得前凋亡蛋白（Bad）去磷酸化，并使Ｂａｄ与其抑制蛋白解离，然后转移到线粒体进而激发细胞色素Ｃ的释放，从而导致细胞的凋亡,研究背景,Based on roles for C/EPB homologous protein (CHOP) and ER calcium release in apoptosis, we hypothesized that apoptos-is involves the activation of inositol 1,4,5-triphosphate (IP3) receptor (IP3R) via CHOP-induced ERO1- (ER oxidase 1 )IP3R:向胞浆内释放钙离子Hypothesis：CHOP ERO1 α IP3R 钙释放 凋亡*,,,,,研究背景,In ER-stressed cells,ERO1-α is induced by CHOP, and small interfering RNA(siRNA) knockdown of ERO1- α suppresses apoptosis.2. IP3-induced calcium release (IICR) is increased during ER stress , and this response is blocked by siRNA-mediated silencing of ERO1-α or IP3R1 and by loss-of-function mutations in ERO1 or CHOP.,研究背景,3.,,4.,,研究背景,5.,,,1 2 3 4 5,CHOP ERO1-α/IP3R calcium-dependent apoptosis,,,研究背景,半胱天冬酶（Caspase）是近年发现的一组存在于胞质溶胶中的酶，它能特异性的切割蛋白质中天冬氨酸残基后的肽键，使细胞内众多的功能蛋白分子活化或失活，诱导细胞凋亡。
IRE1:需肌醇酶,实验目标,ERS/CHOP通路诱导细胞凋亡模型，关键目标是阐明钙释放的分子机制验证假说：ERS CHOP ERO1α IP3R calcium release apoptosis,,,,,,实验结果,1. Role of ERO1-α in ER stress–induced apoptosis in macrophages.,,,CHOP对ERO1α具有诱导作用,1. Role of ERO1-α in ER stress–induced apoptosis in macrophages.,,,实验结果,,,1. Role of ERO1-α in ER stress–induced apoptosis in macrophages.,ERO1α促进细胞凋亡,实验结果,1. Role of ERO1-α in ER stress–induced apoptosis in macrophages.,,,实验结果,ERO1-α is critical for ER stress–induced apoptosis,实验结果,2.Role of ERO1-α in ER stress–induced activation of IICR.,ERO1-α激活IP3R诱导的钙释放,实验结果,2.Role of ERO1-α in ER stress–induced activation of IICR.,实验结果,2.Role of ERO1-α in ER stress–induced activation of IICR.,ERO1-α activates IP3-induced calcium release (IICR) during ER stress,实验结果,3.Relationships among IP3R1, NAC-inhibitable oxidation, CaMKII phosphorylation, and apoptosis.,实验结果,3.Relationships among IP3R1, NAC-inhibitable oxidation, CaMKII phosphorylation, and apoptosis.,,IP3R1 is necessary for ER stress–induced apoptosis,实验结果,3.Relationships among IP3R1, NAC-inhibitable oxidation, CaMKII phosphorylation, and apoptosis.,实验结果,4.Role of CHOP in ER stress–induced IICR.,4.Role of CHOP in ER stress–induced IICR.,CHOP is necessary for activation of IICR during ER stress in vitro and in vivo,实验结果,实验结果,5.ER stress–induced IICR in vivo.,实验结果,5.ER stress–induced IICR in vivo.,实验结论,ERO1- is critical for ER stress–induced apoptosis2. ERO1- activates IP3-induced calcium release (IICR) during ER stress3. IP3R1 is necessary for ER stress–induced apoptosis4. CHOP is necessary for activation of IICR during ER stress in vitro and in vivo,。