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細(xì)胞器與疾病

(分子醫(yī)學(xué))AmammaliancellNucleusThenucleusisamembraneboundstructurethatcontainsthecell'shereditaryinformationandcontrolsthecell'sgrowthandreproduction.Itiscommonlythemostprominentorganelleinthecell

TheNuclearPoreComplexes

formacontinuousaqueouschannelbetweencytoplasm&nucleoplasm

-nuclearporecomplexislarge–about120millionDaltons-30differentproteinsfoundinpore;basicsubunitrepeated16times.“Centralgranule"nowcalled"transporter"functionstomovemoleculesthroughpore.ThereisaringofproteinsthatanchorsporetoN.E.andthe"basket"offiberswithunknownfunctionnoobviousmotorproteinswerefoundTheNucleolusTheregionofthenucleuswhereportionsofchromosomesthatcontaingenescodingforribosomalRNAaretranscribedandribosomalsubunitsareassembledStretchofDNAwithrRNAgenesnucleolarorganizingregion=(NOR)RibosomalproteinsaresynthesizedincytoplasmandtransportedintothenucleusTheseproteinsselfassociatewithappropriaterRNAduringrRNAsynthesisformingimmatureribosomalsubunitsRibosomesfinishselfassemblyincytoplasmEndoplasmicReticulumTheEndoplasminReticulum(ER)isanextensive,extra-nuclearmembranesystemwiththefollowingfunctions:ERisahomeforvariousenzymesinvolvedinproteinfolding,drugdetoxification,membranelipidbiosynthesis,cholesterolandfattyacidmetabolismERisanentrypointforproteinsorting.Targetingoftheseproteinsismediatedbysignalsequence.ThemembraneproteinsareinsertedintotheERmembraneintheirproperorientation.SecretedproteinsaretranslocatedintoERlumenandthentransportedtothedestinationplaceRoughandSmoothERTworegionsoftheERdifferinbothstructureandfunction.RoughERhasribosomesattachedtothecytoplasmicsideofthemembrane.SmoothERlacksattachedribosomes.Typically,thesmoothERisatubulenetworkandtheroughERisaseriesofflattenedsacs.ThesmoothERhasawiderangeoffunctionsincludingcarbohydrateandlipidsynthesis.ItservesasatransitionalareaforvesiclesthattransportERproductstovariousdestinations.InlivercellsthesmoothERproducesenzymesthathelptodetoxifycertaincompounds.InmusclesthesmoothERassistsinthecontractionofmusclecellsandinbraincellsitsynthesizesmaleandfemalehormones.TheroughERmanufacturesmembranesandsecretoryproteins

TheroughandsmoothERareUsuallyinterconnectedandtheproteinsandmembranesmadebytheroughERmoveintothesmoothERtobetransferredtootherlocations.Thecytoplasmhasareducingenvironment,whileERlumenisoxidizing.ThisdifferenceisgeneratedbyunequaldistributionoftrypeptideglutathioneandisessentialforformationofdisulfidebondsinproteinsandforproperfoldingMitochondriaMitochondria(singular:mitochondrion)arethesitesofaerobicrespiration,andgenerallyarethemajorenergyproductioncenterineukaryotesThenumberofmitochondriarangefromonetothousandspercells.TheyareoftenpositionedincellsnearesttositesofenergyutilizationOneoftherichestsourcesofmitochondriaisahummingbirdflightmuscleMitochondriaareadoublemembraneorganelleinwhichtheinnermembraneisin-foldedtoform“cristae”.Theoutermembraneisafairlysimplephospholipidbilayer,containingporins,proteinsthatrenderitpermeabletomoleculesofabout10kilodaltonsorless.Ions,nutrientmolecules,ATP,ADP,etc.easilypassthroughtheoutermembraneandentertheintermembranespaceTheinnermembraneismorecomplexandcontainsrespiratorychainsandtransportersThematrixlieswithintheinnermembrane.TheaccesstothiscompartmentoftenrequiresspecifictransportersTheGolgiComplexLocatednearcellnucleus,consistsofflattened,membrane-boundedsacs(cisternae)formingastackEachstackhas:cis-faceisanentryface-adjacenttoERtoacceptincomingvesiclestrans-faceisanexitface–pointstowardsplasmamembrane,producesvesiclesforforwardflowThefunctionoftheGolgi

istotransportandprocesssecretedandmembraneproteinsfromERtothecellsurfaceCis–removalofmannose, phosphorylationMedial

–removalofmannose,additionofN-acetylglucosamineTrans–Removalofgalactose,additionofsialicacidTGN–additionofsialicacid,SortingCisternaesegregatedintoconvex("cis"),medial(middle),andconcave("trans")compartments.ERcysmedialtransTGNGolgistructure/function/-relateddiseasesGolgiandMitosisGolgiandApoptosisGolgiandLiverCancerHNEinducesGolgiFragmentsControl30min1h2h4hTheEndocyticPathwayEndosomesandLysosomesLysosomes1、初級溶酶體直徑約0.2~0.5um膜厚7.5nm,內(nèi)含物均一,無明顯顆粒,是高爾基體分泌形成的(如右圖)。含有多種水解酶,但沒有活性,只有當(dāng)溶酶體破裂,或其它物質(zhì)進(jìn)入,才有酶活性。其水解酶包括蛋白酶,核酸酶、脂酶、磷酸酶、硫酸酯酶、磷脂酶類,已知60余種,這些酶均屬于酸性水解酶,反應(yīng)的最適PH值為5左右,溶酶體膜雖然與質(zhì)膜厚度相近,但成分不同,LysosomesLysosomesareactiveinrecyclingthecell'sorganicmaterialandintheintracellulardigestionofmacromolecules.Lysosomescontainvarioushydrolyticenzymesthatarecapableofdigestingnucleicacids,polysaccharides,fatsandproteins.Theinsideofalysosomeisacidic.Inhumans,avarietyofinheritedconditionscanaffectlysosomes.Thesedefectsarecalledstoragediseases.Peoplewiththesedisordersaremissingoneormoreofthelysosomalhydrolyticenzymes.動物細(xì)胞溶酶體系統(tǒng)示意圖Lysosome-relateddiseases

溶酶體酶缺失或溶酶體酶的代謝環(huán)節(jié)故障,影響細(xì)胞代謝,引起疾病。如臺-薩氏(Tay-Sachs)等各種儲積癥(隱性的遺傳?。?。某些病原體(麻瘋桿菌、利什曼原蟲或病毒)被細(xì)胞攝入,進(jìn)入吞噬泡但并未被殺死而繁殖(抑制吞噬泡的酸化或利用胞內(nèi)體中的酸性環(huán)境)。類風(fēng)濕性關(guān)節(jié)炎溶酶體膜很易脆裂,其釋放的酶導(dǎo)致關(guān)節(jié)組織損傷和發(fā)炎。

矽肺二氧化硅塵粒(矽塵)吸入肺泡后被巨噬細(xì)內(nèi)吞噬,含有矽塵的吞噬小體與溶酶體合并成為次級溶酶體。二氧化硅的羥基與溶酶體膜的磷脂或蛋白形成氫鍵,導(dǎo)致吞噬細(xì)胞溶酶體崩解,細(xì)胞本身也被破壞,矽塵釋出,后又被其他巨噬細(xì)內(nèi)吞噬,如此反復(fù)進(jìn)行。受損或已破壞的巨噬細(xì)胞釋放“致纖維化因子”,并激活成纖維細(xì)胞,導(dǎo)致膠原纖維沉積,肺組織纖維化。TheCytoskeletonCytoskeletonisanetworkofproteinfilamentsinthecytoplasmMainfunctions:Supportslargevolumeofthecytoplasm.Participatesinlarge-scalemovementsassociatedwiththechangesincellshapeandcellmotility.Providesmachineryfororganelletransport,chromasomesegregationduringmitosis,andcelldivision.ActinfilamentsMicrotubulesIntermediatefilamentsMajorcomponentsofcytoskeletonThecytoskeletalfilamentsCommonFeatures:LinearpolymersofproteinsubunitsActin(~8nmindiameter)IntermediateFilaments(~10nmindiameter)Microtubules(~24nmindiameter)Filamentsaredynamic,i.e.theycanassembleanddisassembleHighlyconserved

IntermediateFilamentsIntermediatefilamentsenablecellstowithstandmechanicalstresswhencellsarestretched.Theycanspantheentirecytoplasmandareanchoredtotheplasmamembrane.TheMicrotubuleCytoskeletonAlsopenetratestheentirevolumeofthecellWhereasactinfibersareconcentratedattheperiphery,mostmicrotubulesradiatefromacentrallocationinthecellMainfunctions:intracellulartransportandmitosisMicrotubulesprovideanorganizationalstructureinaninterphasecellandseparatechromosomesinadividingcellMicrotubulesMicrotubulesProvideTracksforTransportMicrotubulesarelonghollowcylindersmadeoftubulinProtofilamentsarelinearchainsoftubulindimers,aparallelbundleof13protofilamentsformsamicrotubuleTherearethreekindsoftubulins,eachwithmanysubtypes:a-tubulinandb-tubulinforma/btubulindimersandrepresentthebasicbuildingblockofmicrotubulesg-tubulinisinvolvedinmorespecializedprocesses,suchasnucleationMicrotubuleshaveaGTP“cap”stabilizingtheends.MotorProteinsMotorproteinsbindtomicrotubulesandmovebycyclesofconformationalchangesusingenergyfromATP.Oneendoftheproteincanbindtospecificcellularcomponents.ActinisthemostcommonproteininthecytoplasmActinfilamentsareconcentratedbeneaththeplasmamembraneandgivethecellmechanicalstrengthAssemblyofactinfilamentscandeterminecellshapeandcausecellmovementAssociationofactinfilamentswithmyosincanformcontractilestructuresActinfilaments=microfilaments核蛋白體

在粗面內(nèi)質(zhì)網(wǎng)表面的稱固著核蛋白體,在細(xì)胞質(zhì)內(nèi)分散存在的稱游離核蛋白體。數(shù)個(gè)或致十個(gè)核蛋白體聚集在一起稱多聚核蛋白體,系由信息核糖核酸(mRNA)將核蛋白體串連在一起形成。

核蛋白體在一定濃度的鎂離子溶液內(nèi),可分成一大一小兩個(gè)亞單位。分別稱為大亞基與小亞基,可用超速離心法將兩者分開。兩個(gè)亞基合在一起時(shí),由于一大一小,形成葫蘆狀。核蛋白體與蛋白質(zhì)合成有密切關(guān)系,是氨基酸根據(jù)mBNA中的遺傳密碼順序形成多肽的場所。合成內(nèi)用蛋白質(zhì)多的細(xì)胞,游離的核蛋白體豐富,如幼稚細(xì)胞或胚胎細(xì)胞。合成外用蛋白質(zhì)多的細(xì)胞,則粗面內(nèi)質(zhì)網(wǎng)豐富,例如肝細(xì)胞、胰腺泡細(xì)胞及漿細(xì)胞等。中心粒

(centrio1es)中心粒與細(xì)胞分裂有關(guān),在間期,中心粒常在細(xì)胞核一側(cè)。中心粒呈短簡狀,成雙存在,彼此垂直分布,又稱雙體(diplosome)。每個(gè)中心粒由9組三聯(lián)體構(gòu)成,彼此成45o,使9組三聯(lián)體排列成風(fēng)車狀。每個(gè)三聯(lián)體由3根微管組成。在核分裂時(shí),雙體復(fù)制,并移向細(xì)胞的兩極。以后各端中心粒的紡錘絲與染色體相連,并將染色體引向兩極,形成二個(gè)核。線粒體遺傳病1894年,首次發(fā)現(xiàn)1897年,正式命名為mitochondrion(線粒體)1963年,Nass在雞胚中發(fā)現(xiàn)線粒體中存在DNA

Schatz分離到完整的線粒體DNA1981年,測定人mtDNA的DNA序列1987年,Wallac提出mtDNA突變可引起疾病1988年,首次報(bào)道m(xù)tDNA突變mtDNA的結(jié)構(gòu)和遺傳特征mtDNA的結(jié)構(gòu)特點(diǎn)線粒體是細(xì)胞質(zhì)中獨(dú)立的細(xì)胞器,也是動物細(xì)胞核外唯一的含有DNA(mitochondrialDNA,mtDNA)的細(xì)胞器。1981年,劍橋大學(xué)的Anderson小組測定了人mtDNA的完整DNA序列,稱為“劍橋序列”。由于缺乏組蛋白的保護(hù),線粒體亦缺乏DNA損傷修復(fù)系統(tǒng),mtDNA的突變率較高。人mtDNA是一個(gè)長為16,569bp的雙鏈閉合環(huán)狀分子,外環(huán)含G較多,稱重鏈(H鏈),內(nèi)環(huán)含C較多,稱輕鏈(L鏈)。mtDNA的結(jié)構(gòu)和遺傳特征mtDNA結(jié)構(gòu)緊湊,沒有內(nèi)含子,唯一的非編碼區(qū)是D環(huán)區(qū),長約1,000bp左右。D環(huán)區(qū)包括mtDNA重鏈復(fù)制起始點(diǎn),重輕鏈轉(zhuǎn)錄的啟動子。線粒體的H鏈?zhǔn)?2種多肽鏈、12SrRNA、16SrRNA和14種tRNA的轉(zhuǎn)錄模板,L鏈?zhǔn)?種多肽鏈和8種tRNA轉(zhuǎn)錄的模板。人類的mtDNA編碼13條多肽鏈、22種tRNA和2種rRNA。13種蛋白質(zhì)均是呼吸鏈酶復(fù)合物的亞單位。由于缺乏組蛋白的保護(hù),線粒體亦缺乏DNA損傷修復(fù)系統(tǒng),mtDNA的突變率較高。一、mtDNA的結(jié)構(gòu)特征線粒體是細(xì)胞質(zhì)中獨(dú)立的細(xì)胞器,也是動物細(xì)胞核外唯一的含有DNA的細(xì)胞器。1981年,劍橋大學(xué)的Anderson小組測定了人mtDNA的完整DNA序列,稱為“劍橋序列”。第一節(jié)mtDNA的結(jié)構(gòu)和遺傳特征1.mtDNA具有半自主性mtDNA的遺傳學(xué)特性ComplexSubunitsNuclearmtDNAⅠ41347Ⅱ440Ⅲ11101Ⅳ13103tDNA的UGA編碼色氨酸,而非終止信號。其tRNA的通用性較強(qiáng),22個(gè)tRNA可識別48個(gè)密碼子。3.mtDNA為母系遺傳2.mtDNA的遺傳密碼與通用密碼不同1.mtDNA具有半自主性mtDNA的遺傳學(xué)特征mtDNA的母系遺傳1、母親將她的mtDNA傳遞給兒子和女兒,但只有女兒能將其mtDNA傳遞給下一代;

2、人的細(xì)胞里通常有上千個(gè)mtDNA拷貝,在突變體和正常mtDNA共存的細(xì)胞中,子細(xì)胞出現(xiàn)三種基因型:純合的突變體、純合的正常、突變體和正常的的雜合;3、線粒體病發(fā)病有一閾值,只有當(dāng)異常的mtDNA超過閾值才發(fā)病。女性攜帶者未發(fā)病,但仍可以通過mtDNA

突變體向下代傳遞。母系遺傳的特點(diǎn):mtDNA的遺傳學(xué)特征1.mtDNA具有半自主性2.mtDNA的遺傳密碼與通用密碼不同3.mtDNA為母系遺傳4.mtDNA在有絲分裂和減數(shù)分裂間都要經(jīng)過復(fù)制分離5.mtDNA的雜質(zhì)性與閾值效應(yīng)6.mt

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