內質網(wǎng)應激致細胞凋亡課件

匯報人：趙麗RoleofERO1-α–mediatedstimulationofinositol1,4,5-triphosphatereceptoractivityinendoplasmicreticulumstress–inducedapoptosis匯報人：趙麗RoleofERO1-α–mediated1Contents實驗目的

2結果分析3研究背景31實驗結論4Contents實驗目的2結果分析3研究背景31實驗結論42研究背景Endoplasmicreticulum(ER)stress–inducedapoptosisisinvolvedinmanydiseases,butthemechanismslinkingERstresstoapopt-osisareincompletelyunderstood.*CHOP:ＣＣＡＡＴ／增強子結合蛋白（ＣＨＯＰ）是ＥＲ應激特異的轉錄因子研究背景Endoplasmicreticulum(ER)3研究背景CHOP:正常情況下,ＣＨＯＰ表達十分低下，在ＥＲ應激反應時,ＩＲＥ-１、ＰＥＲＫ和ＡＴＦ６的活化均對ｃＨOＰ產(chǎn)生誘導，促使CＨOＰ激活，其表達顯著增加，從而誘導細胞凋亡。鈣離子：從內質網(wǎng)內釋放的鈣離子可以通過激活鈣聯(lián)蛋白調節(jié)的鈣調神經(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，然后轉移到線粒體進而激發(fā)細胞色素Ｃ的釋放，從而導致細胞的凋亡研究背景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

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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)的一組存在于胞質溶膠中的酶，它能特異性的切割蛋白質中天冬氨酸殘基后的肽鍵，使細胞內眾多的功能蛋白分子活化或失活，誘導細胞凋亡。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實驗目標ERS/CHOP通路誘導細胞凋亡模型，關鍵目標是闡明鈣釋放的分子機制驗證假說：ERSCHOPERO1αIP3Rcalciumrelease

apoptosis實驗目標ERS/CHOP通路誘導細胞凋亡模型，關鍵目標是闡明10實驗結果1.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.

CHOP對ERO1α具有誘導作用實驗結果1.RoleofERO1-αinERst111.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.

實驗結果1.RoleofERO1-αinERstress121.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.ERO1α促進細胞凋亡實驗結果1.RoleofERO1-αinERstress131.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.實驗結果ERO1-αiscriticalforERstress–inducedapoptosis1.RoleofERO1-αinERstress14實驗結果2.RoleofERO1-αinERstress–inducedactivationofIICR.ERO1-α激活IP3R誘導的鈣釋放實驗結果2.RoleofERO1-αinERstr15實驗結果2.RoleofERO1-αinERstress–inducedactivationofIICR.實驗結果2.RoleofERO1-αinERstr16實驗結果2.RoleofERO1-αinERstress–inducedactivationofIICR.ERO1-αactivatesIP3-inducedcalciumrelease(IICR)duringERstress實驗結果2.RoleofERO1-αinERstr17實驗結果3.RelationshipsamongIP3R1,NAC-inhibitableoxidation,CaMKIIphosphorylation,andapoptosis.

實驗結果3.RelationshipsamongIP3R18實驗結果3.RelationshipsamongIP3R1,NAC-inhibitableoxidation,CaMKIIphosphorylation,andapoptosis.

實驗結果3.RelationshipsamongIP3R19IP3R1isnecessaryforERstress–inducedapoptosis實驗結果3.RelationshipsamongIP3R1,NAC-inhibitableoxidation,CaMKIIphosphorylation,andapoptosis.

IP3R1isnecessaryforERstre20實驗結果4.RoleofCHOPinERstress–inducedIICR.

實驗結果4.RoleofCHOPinERstres214.RoleofCHOPinERstress–inducedIICR.CHOPisnecessaryforactivationofIICRduringERstressinvitroandinvivo實驗結果4.RoleofCHOPinERstress–in22實驗結果5.ERstress–inducedIICRinvivo.實驗結果5.ERstress–inducedIICRi23實驗結果5.ERstress–inducedIICRinvivo.實驗結果5.ERstress–inducedIICRi24實驗結論ERO1-iscriticalforERstress–inducedapoptosis2.ERO1-activatesIP3-inducedcalciumrelease(IICR)duringERstress3.IP3R1isnecessaryforERstress–inducedapoptosis4.CHOPisnecessaryforactivationofIICRduringERstressinvitroandinvivo實驗結論ERO1-iscriticalforER25內質網(wǎng)應激致細胞凋亡課件26匯報人：趙麗RoleofERO1-α–mediatedstimulationofinositol1,4,5-triphosphatereceptoractivityinendoplasmicreticulumstress–inducedapoptosis匯報人：趙麗RoleofERO1-α–mediated27Contents實驗目的

2結果分析3研究背景31實驗結論4Contents實驗目的2結果分析3研究背景31實驗結論428研究背景Endoplasmicreticulum(ER)stress–inducedapoptosisisinvolvedinmanydiseases,butthemechanismslinkingERstresstoapopt-osisareincompletelyunderstood.*CHOP:ＣＣＡＡＴ／增強子結合蛋白（ＣＨＯＰ）是ＥＲ應激特異的轉錄因子研究背景Endoplasmicreticulum(ER)29研究背景CHOP:正常情況下,ＣＨＯＰ表達十分低下，在ＥＲ應激反應時,ＩＲＥ-１、ＰＥＲＫ和ＡＴＦ６的活化均對ｃＨOＰ產(chǎn)生誘導，促使CＨOＰ激活，其表達顯著增加，從而誘導細胞凋亡。鈣離子：從內質網(wǎng)內釋放的鈣離子可以通過激活鈣聯(lián)蛋白調節(jié)的鈣調神經(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，然后轉移到線粒體進而激發(fā)細胞色素Ｃ的釋放，從而導致細胞的凋亡研究背景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)的一組存在于胞質溶膠中的酶，它能特異性的切割蛋白質中天冬氨酸殘基后的肽鍵，使細胞內眾多的功能蛋白分子活化或失活，誘導細胞凋亡。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實驗目標ERS/CHOP通路誘導細胞凋亡模型，關鍵目標是闡明鈣釋放的分子機制驗證假說：ERSCHOPERO1αIP3Rcalciumrelease

apoptosis實驗目標ERS/CHOP通路誘導細胞凋亡模型，關鍵目標是闡明36實驗結果1.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.

CHOP對ERO1α具有誘導作用實驗結果1.RoleofERO1-αinERst371.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.

實驗結果1.RoleofERO1-αinERstress381.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.ERO1α促進細胞凋亡實驗結果1.RoleofERO1-αinERstress391.RoleofERO1-αinERstress–inducedapoptosisinmacrophages.實驗結果ERO1-αiscriticalforERstress–inducedapoptosis1.RoleofERO1-αinERstress40實驗結果2.RoleofERO1-αinERstress–inducedactivationofIICR.ERO1-α激活IP3R誘導的鈣釋放實驗結果2.RoleofERO1-αinERstr41實驗結果2.RoleofERO1-αinERstress–inducedactivationofIICR.實驗結果2.RoleofERO1-αinERstr42實驗結果2.RoleofERO1-αinERstress–inducedactivationofIICR.ERO1-αactivatesIP3-inducedcalciumrelease(IICR)duringERstress實驗結果2.RoleofERO1-αinERstr43實驗結果3.RelationshipsamongIP3R1,NAC-inhibitableoxidation,CaMKIIphosphorylation,andapoptosis.

實驗結果3.RelationshipsamongIP3R44實驗結果3.RelationshipsamongIP3R1,NAC-inhibitableoxidation,CaMKIIphosphorylation,andapoptosis.

實驗結果3.RelationshipsamongIP3R45IP3R1isnecessaryforERstress–inducedapoptosis實驗結果3.RelationshipsamongI