內(nèi)質(zhì)網(wǎng)應(yīng)激致細(xì)胞凋亡課件

匯報(bào)人：趙麗RoleofERO1-α–mediatedstimulationofinositol1,4,5-triphosphatereceptoractivityinendoplasmicreticulumstress–inducedapoptosis匯報(bào)人：趙麗RoleofERO1-α–mediated1Contents實(shí)驗(yàn)?zāi)康?/p>

2結(jié)果分析3研究背景31實(shí)驗(yàn)結(jié)論4Contents實(shí)驗(yàn)?zāi)康?結(jié)果分析3研究背景31實(shí)驗(yàn)結(jié)論42研究背景Endoplasmicreticulum(ER)stress–inducedapoptosisisinvolvedinmanydiseases,butthemechanismslinkingERstresstoapopt-osisareincompletelyunderstood.*CHOP:ＣＣＡＡＴ／增強(qiáng)子結(jié)合蛋白（ＣＨＯＰ）是ＥＲ應(yīng)激特異的轉(zhuǎn)錄因子研究背景Endoplasmicreticulum(ER)3研究背景CHOP:正常情況下,ＣＨＯＰ表達(dá)十分低下，在ＥＲ應(yīng)激反應(yīng)時(shí),ＩＲＥ-１、ＰＥＲＫ和ＡＴＦ６的活化均對(duì)ｃＨOＰ產(chǎn)生誘導(dǎo)，促使CＨOＰ激活，其表達(dá)顯著增加，從而誘導(dǎo)細(xì)胞凋亡。鈣離子：從內(nèi)質(zhì)網(wǎng)內(nèi)釋放的鈣離子可以通過激活鈣聯(lián)蛋白調(diào)節(jié)的鈣調(diào)神經(jīng)磷酸酶，使得前凋亡蛋白（Bad）去磷酸化，并使Ｂａｄ與其抑制蛋白解離，然后轉(zhuǎn)移到線粒體進(jìn)而激發(fā)細(xì)胞色素Ｃ的釋放，從而導(dǎo)致細(xì)胞的凋亡研究背景4研究背景BasedonrolesforC/EPBhomologousprotein(CHOP)andERcalciumreleaseinapoptosis,wehypothesizedthatapoptos-isinvolvestheactivationofinositol1,4,5-triphosphate(IP3)receptor(IP3R)viaCHOP-inducedERO1-(ERoxidase1)IP3R:向胞漿內(nèi)釋放鈣離子Hypothesis：CHOPERO1αIP3R鈣釋放凋亡*研究背景BasedonrolesforC/E5研究背景InER-stressedcells,ERO1-αisinducedbyCHOP,andsmallinterferingRNA(siRNA)knockdownofERO1-αsuppressesapoptosis.2.IP3-inducedcalciumrelease(IICR)isincreasedduringERstress,andthisresponseisblockedbysiRNA-mediatedsilencingofERO1-αorIP3R1andbyloss-of-functionmutationsinERO1orCHOP.研究背景InER-stressedcells,ERO1-6研究背景

3.

4.研究背景3.4.7研究背景

5.12345CHOPERO1-α/IP3Rcalcium-dependentapoptosis研究背景8研究背景半胱天冬酶（Caspase）是近年發(fā)現(xiàn)的一組存在于胞質(zhì)溶膠中的酶，它能特異性的切割蛋白質(zhì)中天冬氨酸殘基后的肽鍵，使細(xì)胞內(nèi)眾多的功能蛋白分子活化或失活，誘導(dǎo)細(xì)胞凋亡。IRE1:需肌醇酶研究背景半胱天冬酶（Caspase）是近年發(fā)現(xiàn)的一組存在于胞9實(shí)驗(yàn)?zāi)繕?biāo)ERS/CHOP通路誘導(dǎo)細(xì)胞凋亡模型，關(guān)鍵目標(biāo)是闡明鈣釋放的分子機(jī)制驗(yàn)證假說：ERSCHOPERO1αIP3Rcalciumrelease

apoptosis實(shí)驗(yàn)?zāi)繕?biāo)ERS/CHOP通路誘導(dǎo)細(xì)胞凋亡模型，關(guān)鍵目標(biāo)是闡明10實(shí)驗(yàn)結(jié)果1.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.

CHOP對(duì)ERO1α具有誘導(dǎo)作用實(shí)驗(yàn)結(jié)果1.RoleofERO1-αinERst111.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.

實(shí)驗(yàn)結(jié)果1.RoleofERO1-αinERstress121.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.ERO1α促進(jìn)細(xì)胞凋亡實(shí)驗(yàn)結(jié)果1.RoleofERO1-αinERstress131.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.實(shí)驗(yàn)結(jié)果ERO1-αiscriticalforERstress–inducedapoptosis1.RoleofERO1-αinERstress14實(shí)驗(yàn)結(jié)果2.RoleofERO1-αinERstress–inducedactivationofIICR.ERO1-α激活I(lǐng)P3R誘導(dǎo)的鈣釋放實(shí)驗(yàn)結(jié)果2.RoleofERO1-αinERstr15實(shí)驗(yàn)結(jié)果2.RoleofERO1-αinERstress–inducedactivationofIICR.實(shí)驗(yàn)結(jié)果2.RoleofERO1-αinERstr16實(shí)驗(yàn)結(jié)果2.RoleofERO1-αinERstress–inducedactivationofIICR.ERO1-αactivatesIP3-inducedcalciumrelease(IICR)duringERstress實(shí)驗(yàn)結(jié)果2.RoleofERO1-αinERstr17實(shí)驗(yàn)結(jié)果3.RelationshipsamongIP3R1,NAC-inhibitableoxidation,CaMKIIphosphorylation,andapoptosis.

實(shí)驗(yàn)結(jié)果3.RelationshipsamongIP3R18實(shí)驗(yàn)結(jié)果3.RelationshipsamongIP3R1,NAC-inhibitableoxidation,CaMKIIphosphorylation,andapoptosis.

實(shí)驗(yàn)結(jié)果3.RelationshipsamongIP3R19IP3R1isnecessaryforERstress–inducedapoptosis實(shí)驗(yàn)結(jié)果3.RelationshipsamongIP3R1,NAC-inhibitableoxidation,CaMKIIphosphorylation,andapoptosis.

IP3R1isnecessaryforERstre20實(shí)驗(yàn)結(jié)果4.RoleofCHOPinERstress–inducedIICR.

實(shí)驗(yàn)結(jié)果4.RoleofCHOPinERstres214.RoleofCHOPinERstress–inducedIICR.CHOPisnecessaryforactivationofIICRduringERstressinvitroandinvivo實(shí)驗(yàn)結(jié)果4.RoleofCHOPinERstress–in22實(shí)驗(yàn)結(jié)果5.ERstress–inducedIICRinvivo.實(shí)驗(yàn)結(jié)果5.ERstress–inducedIICRi23實(shí)驗(yàn)結(jié)果5.ERstress–inducedIICRinvivo.實(shí)驗(yàn)結(jié)果5.ERstress–inducedIICRi24實(shí)驗(yàn)結(jié)論ERO1-iscriticalforERstress–inducedapoptosis2.ERO1-activatesIP3-inducedcalciumrelease(IICR)duringERstress3.IP3R1isnecessaryforERstress–inducedapoptosis4.CHOPisnecessaryforactivationofIICRduringERstressinvitroandinvivo實(shí)驗(yàn)結(jié)論ERO1-iscriticalforER25內(nèi)質(zhì)網(wǎng)應(yīng)激致細(xì)胞凋亡課件26匯報(bào)人：趙麗RoleofERO1-α–mediatedstimulationofinositol1,4,5-triphosphatereceptoractivityinendoplasmicreticulumstress–inducedapoptosis匯報(bào)人：趙麗RoleofERO1-α–mediated27Contents實(shí)驗(yàn)?zāi)康?/p>

2結(jié)果分析3研究背景31實(shí)驗(yàn)結(jié)論4Contents實(shí)驗(yàn)?zāi)康?結(jié)果分析3研究背景31實(shí)驗(yàn)結(jié)論428研究背景Endoplasmicreticulum(ER)stress–inducedapoptosisisinvolvedinmanydiseases,butthemechanismslinkingERstresstoapopt-osisareincompletelyunderstood.*CHOP:ＣＣＡＡＴ／增強(qiáng)子結(jié)合蛋白（ＣＨＯＰ）是ＥＲ應(yīng)激特異的轉(zhuǎn)錄因子研究背景Endoplasmicreticulum(ER)29研究背景CHOP:正常情況下,ＣＨＯＰ表達(dá)十分低下，在ＥＲ應(yīng)激反應(yīng)時(shí),ＩＲＥ-１、ＰＥＲＫ和ＡＴＦ６的活化均對(duì)ｃＨOＰ產(chǎn)生誘導(dǎo)，促使CＨOＰ激活，其表達(dá)顯著增加，從而誘導(dǎo)細(xì)胞凋亡。鈣離子：從內(nèi)質(zhì)網(wǎng)內(nèi)釋放的鈣離子可以通過激活鈣聯(lián)蛋白調(diào)節(jié)的鈣調(diào)神經(jīng)磷酸酶，使得前凋亡蛋白（Bad）去磷酸化，并使Ｂａｄ與其抑制蛋白解離，然后轉(zhuǎn)移到線粒體進(jìn)而激發(fā)細(xì)胞色素Ｃ的釋放，從而導(dǎo)致細(xì)胞的凋亡研究背景30研究背景BasedonrolesforC/EPBhomologousprotein(CHOP)andERcalciumreleaseinapoptosis,wehypothesizedthatapoptos-isinvolvestheactivationofinositol1,4,5-triphosphate(IP3)receptor(IP3R)viaCHOP-inducedERO1-(ERoxidase1)IP3R:向胞漿內(nèi)釋放鈣離子Hypothesis：CHOPERO1αIP3R鈣釋放凋亡*研究背景BasedonrolesforC/E31研究背景InER-stressedcells,ERO1-αisinducedbyCHOP,andsmallinterferingRNA(siRNA)knockdownofERO1-αsuppressesapoptosis.2.IP3-inducedcalciumrelease(IICR)isincreasedduringERstress,andthisresponseisblockedbysiRNA-mediatedsilencingofERO1-αorIP3R1andbyloss-of-functionmutationsinERO1orCHOP.研究背景InER-stressedcells,ERO1-32研究背景

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4.研究背景3.4.33研究背景

5.12345CHOPERO1-α/IP3Rcalcium-dependentapoptosis研究背景34研究背景半胱天冬酶（Caspase）是近年發(fā)現(xiàn)的一組存在于胞質(zhì)溶膠中的酶，它能特異性的切割蛋白質(zhì)中天冬氨酸殘基后的肽鍵，使細(xì)胞內(nèi)眾多的功能蛋白分子活化或失活，誘導(dǎo)細(xì)胞凋亡。IRE1:需肌醇酶研究背景半胱天冬酶（Caspase）是近年發(fā)現(xiàn)的一組存在于胞35實(shí)驗(yàn)?zāi)繕?biāo)ERS/CHOP通路誘導(dǎo)細(xì)胞凋亡模型，關(guān)鍵目標(biāo)是闡明鈣釋放的分子機(jī)制驗(yàn)證假說：ERSCHOPERO1αIP3Rcalciumrelease

apoptosis實(shí)驗(yàn)?zāi)繕?biāo)ERS/CHOP通路誘導(dǎo)細(xì)胞凋亡模型，關(guān)鍵目標(biāo)是闡明36實(shí)驗(yàn)結(jié)果1.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.

CHOP對(duì)ERO1α具有誘導(dǎo)作用實(shí)驗(yàn)結(jié)果1.RoleofERO1-αinERst371.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.

實(shí)驗(yàn)結(jié)果1.RoleofERO1-αinERstress381.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.ERO1α促進(jìn)細(xì)胞凋亡實(shí)驗(yàn)結(jié)果1.RoleofERO1-αinERstress391.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.實(shí)驗(yàn)結(jié)果ERO1-αiscriticalforERstress–inducedapoptosis1.RoleofERO1-αinERstress40實(shí)驗(yàn)結(jié)果2.RoleofERO1-αinERstress–inducedactivationofIICR.ERO1-α激活I(lǐng)P3R誘導(dǎo)的鈣釋放實(shí)驗(yàn)結(jié)果2.RoleofERO1-αinERstr41實(shí)驗(yàn)結(jié)果2.RoleofERO1-αinERstress–inducedactivationofIICR.實(shí)驗(yàn)結(jié)果2.RoleofERO1-αinERstr42實(shí)驗(yàn)結(jié)果2.RoleofERO1-αinERstress–inducedactivationofIICR.ERO1-αactivatesIP3-inducedcalciumrelease(IICR)duringERstress實(shí)驗(yàn)結(jié)果2.RoleofERO1-αinERstr43實(shí)驗(yàn)結(jié)果3.RelationshipsamongIP3R1,NAC-inhibitableoxidation,CaMKIIphosphorylation,andapoptosis.

實(shí)驗(yàn)結(jié)果3.RelationshipsamongIP3R44實(shí)驗(yàn)結(jié)果3.RelationshipsamongIP3R1,NAC-inhibitableoxidation,CaMKIIphosphorylation,andapoptosis.

實(shí)驗(yàn)結(jié)果3.RelationshipsamongIP3R45IP3R1isnecessaryforERstress–inducedapoptosis實(shí)驗(yàn)結(jié)果3.RelationshipsamongI