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Dystrofine ni poroteyine nyamukuru ya dystrofine-glycoprotein (DGC) mu mitsi ya skeletale na cardiomyocytes.Dystrofine ihuza actin cytoskeleton na matrise idasanzwe (ECM).Gucika kw'isano iri hagati ya matrice idasanzwe na cytoskeleton yo mu nda irashobora kugira ingaruka mbi kuri homeostasis ya selile yimitsi ya skeletale, biganisha kuri dystrofi nyinshi.Byongeye kandi, gutakaza imikorere ya DGCs biganisha ku kwaguka kwimitsi yumutima no gupfa imburagihe.Dystrophine ikora nk'isoko ya molekile kandi DHA igira uruhare runini mukubungabunga ubusugire bwa sarcolemma.Byongeye kandi, ibimenyetso birimo gukusanya DGC n'ibimenyetso byerekana imashini, nubwo uru ruhare rutarasobanuka neza.Iyi ngingo yo gusubiramo igamije gutanga ibitekerezo bigezweho bya DGCs nuruhare rwabo muri mashini.Turabanza tuganire ku isano itoroshye hagati yimikorere yimikorere yimikorere yimikorere yimikorere yimikorere yimikorere, hanyuma dusuzume ubushakashatsi buherutse gukorwa kubyerekeye uruhare rwa dystrofine glycoprotein murwego rwo gukanika imashini no kubungabunga ubusugire bwimitsi yimitsi.Hanyuma, turasubiramo ibitabo byubu kugirango dusobanukirwe nuburyo ibimenyetso bya DGC bihuza n'inzira zo gukanika kugirango twerekane ingingo zishobora guterwa ejo hazaza, twibanze cyane kumutima.
Ingirabuzimafatizo zihora zitumanaho hamwe na microen ibidukikije, kandi ibiganiro byuburyo bubiri hagati yabyo birakenewe mugusobanura no guhuza amakuru yibinyabuzima.Ibinyabuzima bigenzura ibyingenzi byakurikiyeho (urugero, cytoskeletal rearrangements) mugucunga fenotipike rusange mumwanya nigihe.Hagati yiki gikorwa muri cardiomyocytes nakarere kahenze, akarere aho sarcolemma ihuza sarcomere igizwe na integrin-talin-vinculin na dystrophine-glycoproteine ​​(DGC).Bifatanije na cytoskeleton yo mu nda, ibyo bintu bifatika (FAs) bikwirakwiza casake yimpinduka ziterwa na selile na biochemical selile zigenzura itandukaniro, ikwirakwizwa, organogenezi, kwimuka, gutera indwara, nibindi byinshi.Guhindura imbaraga za biomehanike muri biochemiki na / cyangwa (epi) impinduka zikomoka ku bwoko bizwi nka mechanotransduction1.
Integrin transmembrane reseptor 2 imaze igihe kinini izwiho guhuza matrice idasanzwe mungirabuzimafatizo no guhuza ibimenyetso byimbere ninyuma.Mugihe kimwe na integin, DGCs ihuza ECM na cytoskeleton, igashyiraho isano ikomeye hagati yinyuma ninyuma ya selire3.Dystrophine yuzuye (Dp427) igaragarira cyane cyane mumitsi yumutima na skeletale, ariko ikanagaragara no mubice byumubiri wo hagati, harimo retina na Purkinje tissue4.Guhinduka kwa integin hamwe na DGC bibwira ko aribyo bitera imitsi ya dystrofiya yimitsi hamwe niterambere ryagutse ryumutima (DCM) (Imbonerahamwe 1) 5,6.By'umwihariko, ihinduka rya DMD rikubiyemo poroteyine yo hagati ya Dystrofine DGCs itera Duchenne imitsi ya Dystrofiya (DMD) 7.DGC igizwe nibice byinshi birimo α- na β-dystroglycan (α / β-DG), sarcoglycan-sarcospan, syntrophine, na dystrofine8.
Dystrophine ni poroteyine ya cytoskeletal yashizweho na DMD (Xp21.1-Xp22) igira uruhare runini mu kubungabunga DGC.DGC ikomeza ubusugire bwa sarcolemma, plasma membrane yimitsi yimitsi.Dystrofine irushaho kwangiza ibyangiritse biterwa no kugabanuka ukora nk'isoko ya molekile na scafold 9,10.Dystrofine yuzuye ifite uburemere bwa 427 kDa, ariko, kubera porotokoro nyinshi zimbere muri DMD, hariho isoforms nyinshi zisanzwe zaciwe, harimo na Dp7111.
Intungamubiri za poroteyine zerekanwe ko ziherereye kuri dystrofine, harimo imashini ikora nka moteri ya neuronal nitric oxyde synthase (nNOS), Yego ifitanye isano na poroteyine (YAP), na caveolin-3, bityo igereranya ibice byingenzi byerekana ibimenyetso bya selile.Ibicuruzwa 12, 13, 14. Usibye gufatira hamwe, uburyo bwa selile bujyanye nimikoranire hagati ya selile na matrix, byakozwe na integin hamwe nintego zabo zo hepfo, ibyo bigo byombi byerekana intera iri hagati y "imbere" na "hanze" ya selire .Kurinda ibyo bintu byibanze kurimbuka bidasanzwe ningirakamaro kumyitwarire ya selile no kubaho.Mubyongeyeho, amakuru ashyigikira ko dystrofine ari modulator yimiyoboro ya ion ya mehanosensitif, harimo imiyoboro ikora cyane, cyane cyane L yo mu bwoko bwa Ca2 + na TRPC 15.
Nubwo dystrofine ari ingenzi kumikorere ya homeostatike yingirangingo zimitsi, uburyo bushyigikiwe neza ntibusobanutse neza, cyane cyane uruhare rwa dystrofine nubushobozi bwayo bwo gukora nka mehanosensor no kurinda imashini.Bitewe no gutakaza dystrofine, havutse ibibazo byinshi bidashubijwe, harimo: ni poroteyine zikoresha imashini nka YAP na AMPK zimuriwe muri sarcolemma;Hariho inzira nyabagendwa hamwe na integin, ibihe bishobora kuganisha kuri moteri idasanzwe?Ibi byose biranga bishobora kugira uruhare muri fenotipike ikomeye ya DCM igaragara kubarwayi barwaye DMD.
Mubyongeyeho, ishyirahamwe ryimpinduka muri selile yimikorere ya selile hamwe na fenotype ya DMD muri rusange ifite akamaro gakomeye mubuvuzi.DMD ni X ihuza imitsi ya dystrofiya yibasira abagabo 1: 3500-5000, irangwa no gutakaza hakiri kare (<5 ans) hamwe na DCM igenda itera imbere hamwe na prognoz mbi cyane kurusha DCM yizindi etiologiya16,17,18.
Ibinyabuzima byo gutakaza dystrofine ntabwo byasobanuwe neza, kandi hano turasuzuma ibimenyetso bishyigikira igitekerezo kivuga ko dystrofine igira uruhare rukomeye rwa mikorobe, ni ukuvuga gukomeza ubusugire bwa sarcolemma, kandi ni ingenzi mu gukoresha imashini.Twongeyeho, twasuzumye ibimenyetso byerekana inzira nyabagendwa hamwe na integin, cyane cyane ihuza laminine α7β1D mu ngirabuzimafatizo zikomeye.
Kwinjiza no gusiba bifite inshingano nyinshi zo guhinduka muri DMD, hamwe na 72% bya mutation biterwa niyi ihinduka19.Mubuvuzi, DMD yerekana akiri muto (years5 ans) hamwe na hypotension, ikimenyetso cyiza cya Gower, gutinda gutera imbere kwimpinduka zijyanye nimyaka, kudindira mumutwe, hamwe na atrophy yimitsi ya skeletale.Guhangayikishwa n'ubuhumekero mu mateka byabaye intandaro yo guhitana abarwayi ba DMD, ariko ubuvuzi bunoze (corticosteroide, umuvuduko ukabije w'umuyaga uhumeka) bwongereye igihe cyo kubaho muri aba barwayi, kandi imyaka yo hagati y'abarwayi ba DMD yavutse nyuma ya 1990 ni 28.1 ans 20, 21 ..Nyamara, uko abarwayi barokoka biyongera, guhanura DCM igenda itera imbere cyane ugereranije nizindi ndwara z'umutima16, biganisha ku kunanirwa k'umutima kurangiza, kuri ubu akaba ari yo mpamvu nyamukuru itera urupfu, bingana na 50% by'impfu za DMD 17,18.
Iterambere rya DCM rirangwa no kwiyongera kwi bumoso kwaguka no kubahiriza, kunanura umuyaga, kwiyongera kwa fibrofatty, kugabanuka kwimikorere ya systolike, no kongera inshuro nyinshi.Impamyabumenyi ya DCM ku barwayi barwaye DMD ni rusange ku isi hose mu gihe cy'ubugimbi (90% kugeza ku myaka 18), ariko igaragara ku barwayi bagera kuri 59% ku myaka 10 y'amavuko 8.22.Gukemura iki kibazo ni ingenzi kuko igice cyo gusohora amashanyarazi cyagiye kigabanuka gahoro gahoro ku kigero cya 1.6% kumwaka23.
Indwara y'umutima ikunze kugaragara ku barwayi barwaye DMD, cyane cyane sinus tachycardia na tachycardia ya ventricular tachycardia, kandi ni yo nyirabayazana w'urupfu rutunguranye rw'umutima22.Arhythmias ni ibisubizo byinjira muri fibrofatty, cyane cyane muri subbasal ibumoso ya ventricle, ibangamira kugaruka kwizunguruka kimwe na [Ca2 +] i gutunganya imikorere mibi hamwe numuyoboro wa ion udakora neza 24,25.Kumenyekanisha kwerekana umutima wumutima birakomeye, kuko ingamba zo kuvura hakiri kare zishobora gutinda gutangira DCM ikabije.
Akamaro ko kuvura imikorere mibi yumutima hamwe nuburwayi bwimitsi ya skeletale byerekanwe mubushakashatsi bushimishije bwakoresheje imbeba yimbeba ya DMD yitwa mdx26 yiga ku ngaruka zo kunoza imitsi ya skeletale idakemuye ibibazo byumutima byihishe muri DMD.Hano, abanditsi berekanye paradoxique inshuro 5 kwiyongera kwimikorere yumutima nyuma yo kunoza imitsi ya skeletale, kandi imbeba zaragabanutse cyane mubice byo gusohora26.Kunoza imikorere yimitsi ya skeletale ituma imyitozo ngororamubiri ihanitse yo gushyira imbaraga nyinshi kuri myocardium, bigatuma ishobora kwandura imikorere mibi rusange.Ibi birerekana akamaro ko kuvura abarwayi ba DMD muri rusange no kwitondera kwirinda imitsi ya skeletale yonyine.
DGCs ikora imirimo myinshi yinyongera, aribyo, gutanga imiterere ihamye kuri sarcolemma, ihinduka umusemburo wa molekile ukora nkumuhuza wibimenyetso, ugenga imiyoboro ya ion ya sensibilité, intandaro yimashini ihenze, kandi ikagira uruhare mugukwirakwiza ingufu zuruhande mukarere ka karere. imbavu (Ishusho 1b)..Dystrophine igira uruhare runini muri ubu bushobozi, kandi bitewe nuko hari benshi bateza imbere imbere, hariho isoforms zitandukanye, buriwese afite uruhare rutandukanye mubice bitandukanye.Imvugo itandukanye yerekana imiterere ya dystrofine isoforms ishyigikira igitekerezo cyuko buri isoform igira uruhare rutandukanye.Kurugero, umutima wumutima ugaragaza uburebure bwuzuye (Dp427m) kimwe na isoform ngufi ya Dp71m ya dystrofine, mugihe tissue skeletale yerekana gusa iyambere muri ebyiri.Kwitegereza uruhare rwa buri bwoko bwubwoko ntibishobora kwerekana imikorere yumubiri gusa, ahubwo binatera indwara ya dystrofi yimitsi.
Igishushanyo cyerekana dystrofine yuzuye (Dp427m) hamwe na Dof71 isoform ntoya.Dystrophine ifite inshuro 24 zisubiramo zitandukanijwe nizunguruka enye, hamwe nubutegetsi bwa actin-binding (ABD), domaine ikungahaye kuri sisitemu (CR), na C-terminus (CT).Abafatanyabikorwa b'ingenzi bahuza bamenyekanye, harimo microtubules (MTs) na sarcolemma.Hariho isoforms nyinshi za Dp71, Dp71m bivuga ingirangingo z'imitsi naho Dp71b bivuga imitsi ya isoform.By'umwihariko, Dp71f bivuga cytoplasme isoform ya neuron.b Urusobe rwa dystrofine-glycoprotein (DHA) ruherereye muri sarcolemma muri rusange.Imbaraga za biomehanike zihindura hagati ya ECM na F-actin.Reba inzira ishobora kwambukiranya hagati ya DGCs na integrin adhesion, Dp71 irashobora kugira uruhare muguhuza ibitekerezo.Byakozwe na Biorender.com.
DMD ni dystrofiya ikunze kugaragara kandi iterwa na mutation muri DMD.Ariko, kugirango dushimire byimazeyo gusobanukirwa nubu uruhare rwa anti-dystrofine, ni ngombwa kubishyira mu rwego rwa DGC muri rusange.Rero, izindi poroteyine zigize izasobanurwa muri make.Intungamubiri za poroteyine za DGC zatangiye kwigwa mu mpera za 1980, hitawe cyane cyane kuri dystrofine.Koenig27,28, Hoffman29 na Ervasti30 bakoze ikintu gikomeye bavumbuye dystrofine, proteine ​​427 kDa mumitsi ikomeye31.
Ibikurikiraho, izindi subcomplexes zerekanwe ko zifitanye isano na dystrofine, harimo sarcoglycan, transsyn, dystrophine subcomplex, dysbrevin, na syntrophine8, hamwe hamwe bigizwe nicyitegererezo cya DGC.Iki gice kizabanza gukwirakwiza ibimenyetso byerekana uruhare rwa DGC mumyumvire ya mehanosensory mugihe cyo gusuzuma ibice byihariye.
Isoform yuzuye ya dystrofine iboneka mumyanya myakura ni Dp427m (urugero: “m” kugirango imitsi itandukane n'ubwonko) kandi ni poroteyine nini imeze nk'inkoni ifite domaine enye zikora ziri munsi ya sarcolemma ya cardiomyocyte, cyane cyane mukarere kahenze 29, 32.
Benshi mubateza imbere imbere muri DMD batanga isoforms nyinshi ya dystrofine yaciwe, bimwe muribi byihariye.Ugereranije na Dp427m, Dp71m yaciwe ku buryo bugaragara kandi ibuze indangarugero isubiramo cyangwa N-terminal ABD.Ariko, Dp71m igumana C-terminal ihuza imiterere.Muri cardiomyocytes, uruhare rwa Dp71m ntirusobanutse, ariko byagaragaye ko ruherereye muri T tubules, byerekana ko rushobora gufasha kugenzura guhuza kwishishanya-kugabanya 33,34,35.Nkuko tubizi, ubushakashatsi buherutse kuvumburwa Dp71m mumyanya yumutima ntabwo bwitabiriwe cyane, ariko ubushakashatsi bumwe bwerekana ko bufitanye isano numuyoboro wa ion ukora, kandi Masubuchi yavuze ko bishobora kugira uruhare mugutunganya nNOS33..
Mu myanya ndangagitsina, isoform ya Dp71b yigaragaza cyane, hamwe na 14 isoforms yavuzwe38.Gusiba kwa Dp71b, umugenzuzi wingenzi wumuyoboro wa potasiyumu ya aquaporine 4 na Kir4.1 muri sisitemu yo hagati, byagaragaye ko uhindura inzitizi yubwonko bwamaraso40.Urebye uruhare rwa Dp71b mugutunganya imiyoboro ya ion, Dp71m irashobora kugira uruhare nkurwo muri cardiomyocytes.
Kuba DGC ihari muri ganglia ihenze ihita yerekana uruhare muri mashini ya moteri, kandi rwose byagaragaye ko ifatanya na integin-talin-vinculine 41.Byongeye kandi, urebye ko igice gihenze aricyo cyibanze kuri transoteri ya transotransduction, aho Dp427m iherereye hano irerekana uruhare rwayo mukurinda selile kwangirika kwatewe no kwikuramo.Byongeye, Dp427m ikorana na actin na microtubule cytoskeleton, bityo ikuzuza isano iri hagati yimiterere yimitsi idasanzwe na matrix idasanzwe.
N-terminus ikubiyemo indangarubuga ya 1 (ABD1) igizwe na domodine ebyiri za homoduline homology (CH) zisabwa kugirango zikorane na F-actin no guhambira γ-actin isoform kuri sarcolemma 42,43.Dystrophine irashobora kugira uruhare muri viscoelasticité yumutima wa kardiomyocytes yomeka kuri cytoskeleton ya subarcolemmal, kandi kuba muri ganglia ihenze ishyigikira uruhare rwayo mumashanyarazi ndetse no gukanika imashini 44,45.
Intangiriro yibanze igizwe na 24 spekrine isa na proteine ​​zisubiramo, buri kimwe muri byo kikaba gisigara hafi ya aminide acide 100.Gusubiramo ibintu bisubirwamo hamwe na bine hinge, bigatanga poroteyine ihinduka kandi ikanaguka cyane.Dystrophine spectrin isubiramo irashobora kugaragara muburyo bwa physiologique yingufu (15-30 pN) kuva kuri 21 nm kugeza kuri 84 nm, imbaraga zishobora kugerwaho na myosine 46.Ibi bintu biranga spekrine isubiramo indangarugero yemerera dystrofine gukora nka molekulari ya shokora.
Inkoni yo hagati ya Dp427m ituma ibaho muri sarcolemma, cyane cyane binyuze mumikoreshereze ya hydrophobique na electrostatike hamwe na fosifatiqueylserine 47,48.Igishimishije, intandaro yo hagati ya dystrofine ikorana bitandukanye na sarcolemma fosifolipide mumyanya ya skeletale na cardiac, bishoboka ko igaragaza imiterere itandukanye.bikomeye, mugihe imitsi ya skeletale nayo ifitanye isano na R10-R1249.
Guhambira kuri act-actin cytoskeleton bisaba ABD2 spectrin gusubiramo akarere ka 11-17, bigizwe nibisigisigi byibanze bya aside amine kandi bitandukanye na F-actin-ihuza CH.Microtubules ikorana na domaine yibanze ya dystrofine, iyi mikoranire isaba ibisigisigi bya spekrine isubiramo 4-15 na 20-23, kandi kuba ankyrin B irasabwa kugirango hirindwe microtubules kururu rubuga.Imiyoboro idahari 50,51,52.Ikinyuranyo hagati ya microtubules na dystrofine cyerekanwe ko cyongera indwara ya DMD mu kongera ubwoko bwa ogisijeni ikora (X-ROS).
Indangarugero ya CR ikoresheje ankyrin B niyindi inanga ya sarcolemmal fosifolipide 52.Ankyrin-B na ankyrin-G birasabwa kugirango urubavu rwa dystrofine / DGC, kandi kubura kwabo bivamo gukwirakwiza sarcolemmal ya DGC52.
Indangarugero ya CR ikubiyemo indangarugero ya WW ihuza byimazeyo na PPxY ihuza motif ya β-DG.Muguhuza na dystrofine-glycan, dystrofine yuzuza isano iri hagati yimbere ninyuma ya selire 54.Iri sano ni ingenzi kumitsi ikomye, nkuko bigaragazwa nuko guhagarika isano iri hagati ya ECM nimbere yimbere ya selile biganisha kumitsi igabanya ubuzima.
Hanyuma, indangarugero ya CT ni agace kabitswe cyane kagizwe na helix ihuriweho kandi ni ingenzi cyane guhuza α-dystrobrevin na α1-, β1-syntrophine 55,56.α-dystrobrevin ihuza na CT domaine ya dystrofine kandi itanga ubundi buryo bwo kurwanya dystrofine muri sarcolemma57.
Mugihe cyo gukura no gusama, Utrophine igaragara cyane mubice bitandukanye, harimo selile endothelia selile, tissue nervice, hamwe nuduce twimitsi 58.Utrophine igaragazwa na UTRN iherereye kuri chromosome 6q kandi ni autologique ya dystrofine hamwe na 80% bya poroteyine homology.Mugihe cyiterambere, utrophine iba muri sarcolemma ariko igahagarikwa cyane mubice byimitsi nyuma yo kubyara, aho isimburwa na dystrofine.Nyuma yo kuvuka, kwifashisha utrophine bigarukira gusa kumitsi no guhuza imitsi ya neuromuscular imitsi ya skeletale 58,59.
Abafatanyabikorwa ba Utrophin basa cyane cyane na dystrofine, nubwo hari itandukaniro ryingenzi ryasobanuwe.Kurugero, dystrofine ikorana na β-DG ikoresheje domaine yayo ya WW, igahagarikwa na domaine ya ZZ (yitiriwe ubushobozi bwayo bwo guhuza ion zinc ebyiri) mukarere kayo ka CT, aho ibisigisigi bya acide ya sisitemu 3307-3354 bifite akamaro kanini kuriyi mikoranire60 ., 61.Icy'ingenzi, guhuza utrophine na β-DG byari munsi yikubye inshuro 2 ugereranije na dystrofine 61. Bivugwa ko Dystrophine ihuza F-actin ikoresheje spekrine isubiramo 11-17, mu gihe ibibanza bisa muri utrophine bidashobora guhuza F-actin, ndetse no kuri kwibanda cyane, ariko birashobora gukorana binyuze muri CH-domaine zabo.Igikorwa 62,63,64.Hanyuma, bitandukanye na dystrofine, utrophine ntishobora guhuza na microtubules51.
Muburyo bwa biomehanike, utrophin spectrin isubiramo ifite uburyo butandukanye bugaragara ugereranije na dystrofine65.Utrophin-spectrin isubiramo kohereza imbaraga murwego rwo hejuru, bisa na titin ariko ntabwo dystrophine65.Ibi bihuye n’aho biherereye n’uruhare rwabyo mu gukwirakwiza imbaraga zikomeye za elastike ku masangano ya tendon, ariko birashobora gutuma utrophine idakwiriye gukora nkisoko ya molekile mu mbaraga ziterwa no kwikuramo 65.Ufatiye hamwe, aya makuru yerekana ko ubushobozi bwa mikorotransduction hamwe nubushobozi bwa mikorobe bishobora guhinduka imbere ya utrophine ikabije, cyane cyane bitewe nabafatanyabikorwa / uburyo butandukanye, ariko ibi bisaba ubushakashatsi bwimbitse.
Duhereye ku mikorere, kuba utrophine ikekwa ko igira ingaruka zisa na dystrofine bituma iba intego yo kuvura DMD66,67.Mubyukuri, abarwayi bamwe ba DMD bagaragaye ko bakabije kurenza utrophine, bishoboka ko ari uburyo bwo kwishyura indishyi, kandi phenotype yagaruwe neza muburyo bwimbeba hamwe na utrophine ikabije 68.Nubwo kugenzura utrophine ari ingamba zishobora kuvura, harebwa itandukaniro ryemewe n’imikorere hagati ya utrophine na dystrofine hamwe n’akamaro ko gutera iyi mitekerereze ikabije hamwe na hamwe na sarcolemma bituma ingamba ndende za utrophine zitarasobanuka neza.Ikigaragara ni uko abatwara igitsina gore berekana imiterere ya mozayike yerekana imvugo ya utrophine, kandi ikigereranyo kiri hagati ya dystrofine na utrophine gishobora kugira ingaruka ku ntera y’umutima wagutse muri aba barwayi, 69 nubwo modine ya murine yabatwara yerekanye..
Dystroglycan subcomplex igizwe na poroteyine ebyiri, α- na β-dystroglycan (α-, β-DG), byombi byandukuwe bivuye muri gene DAG1 hanyuma bigasobanurwa nyuma bikabikwa muri poroteyine ebyiri zigizwe na 71.α-DG ni glycosylated cyane mubice bidasanzwe bya DGCs kandi ikorana neza nibisigara bya protine muri laminine α2 kimwe na agrin72 na picaculin73 hamwe na CT / CR mukarere ka dystrofine 73,74,75,76.O-ihuza glycosylation, cyane cyane ibisigisigi bya serine, irakenewe kugirango imikoranire yayo na ECM.Inzira ya glycosylation ikubiyemo imisemburo myinshi ihinduka ryayo ritera imitsi (reba na Imbonerahamwe 1).Muri byo harimo O-mannosyltransferase POMT2, fucutine na proteine ​​bifitanye isano na fucutine (FKRP), fosifotransferase ebyiri ya ribitol yongeramo fosifate ya tandem ribitol yibanze ya glycan, hamwe na poroteyine LARGE1 yongeramo xylose na glucose.Umurongo wa uronic aside polysaccharide, uzwi kandi nka matrix glycan kumpera ya glycan77.FKRP igira kandi uruhare mu iterambere no kubungabunga ECM, kandi ihinduka ryarwo rituma imvugo igabanuka ya laminine α2 na α-DG77,78,79.Byongeye kandi, FKRP irashobora kandi kuyobora ishingwa rya lamina basal na matrix yumutima udasanzwe binyuze muri glycosylated fibronectin 80.
β-DG ikubiyemo PPxY ihuza motif ihuza neza kandi ikurikirana YAP12.Ubu ni ubushakashatsi bushimishije kuko bivuze ko DGC igenga selile yumutima.α-DH muri neonatal cardiomyocytes ikorana na agrin, itera kuvugurura umutima hamwe na lysis ya DGC76 kubera gukura kwa selile.Mugihe umutima wa kardiomyocytes ukuze, imvugo ya aggrin igabanuka kuruhande rwa laminine, ikekwa ko igira uruhare mu guta muri yombi selile76.Morikawa12 yerekanye ko gukubitwa kabiri kwa dystrofine na salvador, igenzura nabi YAP, biganisha kuri hyperproliferation ya cardiomyocytes muri rumen itera infarct.Ibi byatumye habaho igitekerezo gishimishije kivuga ko manipulation YAP ishobora kuba iy'ubuvuzi mu gukumira igihombo nyuma yo kwandura myocardial.Rero, agrin-iterwa na DGC lysis irashobora kugereranya umurongo wemerera gukora YAP kandi ni inzira ishobora kuvura umutima.
Muburyo bwa tekinike, α- na β-DG basabwa gukomeza imikoranire hagati ya sarcolemma nigice cyibanze 81.Byombi α-DG na α7 integin bigira uruhare mukubyara ingufu muri ganglion ihenze, kandi gutakaza α-DG bitera gutandukanya sarcolemma na lamina basal, bigatuma imitsi yimitsi ya skeletale ishobora kwangirika kwangirika.Nkuko byasobanuwe mbere, uruganda rwa dystroglycan rugenga igicuruzwa rusange cya DGCs, aho guhuza ligand laminine bivamo fosifori ya tirozine ya fosifori ya PPPY ihuza motif ya β-DG892.Tososine fosifora hano iteza imbere gusenya dystrofine, ihindura ikigo cya DGC.Mu buryo bwa physiologique, iki gikorwa kiragenzurwa cyane, kikaba kidahari muri dystrofi yimitsi82, nubwo uburyo bwibanze bugenzura iki gikorwa butumvikana neza.
Kurambura cycle byerekanwe gukora inzira ya ERK1 / 2 na AMPK unyuze muri dystrofine hamwe na protein plectin83.Hamwe na hamwe, plectine na dystroglycan ntibisabwa gusa gukora nka scafold, ahubwo no kugira uruhare muri moteri ya moteri, kandi gukubita plectine bituma igabanuka ryibikorwa bya ERK1 / 2 na AMPK83.Plectin ihuza kandi na cytoskeletal intermediate filament desmin, kandi desmin overexpression yerekanwe kunoza phenotype yindwara muri mdx: imbeba za desmin na mdx, icyitegererezo cyimbeba ya DMD84.Mugukorana na β-DG, plectin ihuza mu buryo butaziguye DGC niki gice cya cytoskeleton.Byongeye kandi, dystroglycan ikorana ningingo yo gukura reseptor-binding protein 2 (Grb2), izwiho kugira uruhare muri gahunda ya cytoskeletal85.Gukora kwa Ras by integrin byagaragaye ko byahujwe binyuze muri Grb2, bishobora gutanga inzira ishobora kunyura hagati yinzira na DGC86.
Guhinduka muri genes zigira uruhare muri α-DH glycosylation biganisha kubyo bita dystrofi yimitsi.Dystroglycanopathies yerekana ivanguramoko ariko biterwa ahanini nihungabana ryimikoranire hagati ya α-DG na laminine α277.Dystrophiglicanose iterwa nihinduka ryibanze muri DAG1 muri rusange ni gake cyane, birashoboka ko ari urusoro rwica87, bityo bikemeza ko hakenewe kwishyiriraho selile na ECM.Ibi bivuze ko indwara nyinshi za dystrofique glycan ziterwa na mutation ya kabiri ya poroteyine ijyanye na glycosylation.Kurugero, ihinduka ryimiterere muri POMT1 ritera syndrome ikabije ya Walker-Warburg, irangwa no kubura ubuzima no kugabanya igihe cyo kubaho (munsi yimyaka 3) 88.Nyamara, ihinduka rya FKRP ryigaragaza cyane nka dystrofi yimitsi-umukandara (LGMD), ubusanzwe (ariko ntabwo buri gihe) yoroheje.Ariko, ihinduka muri FKRP ryerekanwe ko ari impamvu idasanzwe ya WWS89.Guhinduka kwinshi byagaragaye muri FKRP, aho mutation yabashinze (c.826> A) ikunze gutera LGMD2I90.
LGMD2I ni dystrofiya yoroheje yoroheje imitsi itera indwara ishingiye ku guhagarika isano iri hagati ya matrice idasanzwe na cytoskeleton.Ntibisobanutse neza ni isano iri hagati ya genotype na phenotype kubarwayi bafite ihinduka ryimiterere yiyi genes, kandi mubyukuri iki gitekerezo kireba izindi poroteyine za DSC.Kuki abarwayi bamwe bafite ihindagurika rya FKRP berekana phenotype yindwara ihuye na WWS mugihe abandi bafite LGMD2I?Igisubizo cyiki kibazo gishobora kuba muri i) niyihe ntambwe yinzira ya glycosylation iterwa na mutation, cyangwa ii) urwego rwa hypoglycosylation kurwego runaka.Hypoglycosylation ya α-DG irashobora kwemerera urwego runaka rwo gukorana na ECM bikavamo fenotipike yoroheje muri rusange, mugihe gutandukana na membrane yo munsi byongera ubukana bwa fenotype yindwara.Abarwayi bafite LGMD2I nabo batezimbere DCM, nubwo ibi bitanditse neza ugereranije na DMD, bigatuma byihutirwa gusobanukirwa niyi miterere murwego rwa cardiomyocytes.
Sarcospan-sarcoglycan subcomplex iteza imbere gushiraho DHA kandi ikorana na β-DH.Hano hari sarcoglycans enye zidafite icyerekezo mu ngingo z'umutima: α, β, γ, na δ91.Vuba aha byasobanuwe ko ihinduka rya c.218C> T missense muri exon 3 ya gene ya SGCA no gusiba igice cya heterozygous muri exons 7-8 bitera LGMD2D92.Ariko, muriki gihe, abanditsi ntibasuzumye umutima wumutima.
Andi matsinda yasanze SGCD muri moderi ya porcine93 na mouse94 bituma igabanuka rya poroteyine muri sarcoglycan subcomplex, bigahungabanya imiterere rusange ya DGCs kandi biganisha kuri DCM.Byongeye kandi, 19% by'abarwayi bose bafite ihinduka rya SGCA, SGCB, cyangwa SGCG bavuzwe ko baguye umutima, kandi 25% by'abarwayi bose na bo bakeneye ubufasha bw'ubuhumekero95.
Guhinduka kwinshi muri sarcoglycan (SG) δ bituma kugabanuka cyangwa kubura burundu ibigo bya sarcoglycan bityo rero DGC mubice byumutima kandi ishinzwe LGMD hamwe na DCM96 ifitanye isano.Igishimishije, ihinduka-ryiganje muri SG-δ ryihariye kuri sisitemu yumutima nimiyoboro yimitsi kandi niyo ntandaro yumuryango wagutse yumutima.SG-δ R97Q na R71T ihindagurika-mbi ihinduka ryagaragaye ko ryerekanwe neza muri kardiomyocytes yimbeba nta kwangirika gukabije kwa DGC98.Nyamara, ingirangingo z'umutima zitwara izo mutation zirashobora kwibasirwa cyane no kwangirika kwa sarcolemma, kwinjirira, hamwe no kudakora neza kwa mashini munsi ya stress ya mashini, bihuye na fenotipike ya DCM98.
Sarcospan (SSPN) ni tetraspanine ya 25 kDa iherereye muri subcomplex ya sarcoglycan kandi ikekwa ko ikora nka poroteyine 99.100.Nka poroteyine, SSPN ihindura aho ikorera hamwe na glycosylation ya α-DG99,101.Gukabya gukabije kwa SSPN mubyitegererezo byimbeba byagaragaye ko byongera guhuza imitsi na laminine 102.Byongeye kandi, SSPN yerekanwe gukorana na integin, byerekana urugero rwambukiranya imipaka hagati ya komisiyo zombi zimbavu, DGC, hamwe na integrin-talin-vinculin glycoprotein 100,101,102.Knockdown ya SSPN nayo yatumye kwiyongera kwa α7β1 mumitsi ya skeletale yimbeba.
Ubushakashatsi buherutse gukorwa bwerekanye ko gukabya gukabije kwa sarcospan byongera gukura na glycosylation ya α-DG mu ngingo z'umutima zidashingiye kuri galactosylaminotransferase 2 (Galgt2) gukomanga ku mbeba ya mdx ya DMD, bityo bikagabanya fenotipi y’indwara 101. Kwiyongera kwa glycosylation y’uruganda rwa dystroglycan. ECM, bityo benshi bagabanya indwara.Byongeye kandi, berekanye ko gukabya gukabije kwa sarcospan bigabanya imikoranire ya β1D integrin na DGCs, bikagaragaza uruhare rushoboka kuri sarcospan mugutunganya ibigo byuzuye101.
Syntrophine ni umuryango wa poroteyine nto (58 kDa) ziherereye kuri DGC, ubwazo ntizifite ibikorwa byimikorere yimisemburo, kandi zikora nka adaptate103,104.Isoform eshanu (α-1, β-1, β-2, γ-1 na γ-2) zagaragaye zerekana imvugo yihariye, hamwe na α-1 isoform yiganjemo cyane cyane mu mitsi ikabije 105.Syntrophine ni poroteyine zingenzi zorohereza itumanaho ryorohereza itumanaho hagati ya dystrofine na molekile zerekana ibimenyetso, harimo na synthase ya nitric oxyde nitric (nNOS) mu mitsi ya skeletale106.α-syntrophine ikorana na dystrofine 16-17 spectrin isubiramo indangarugero, nayo ihuza na nNOS106,107 PDZ-ihuza motif.
Syntrophine kandi ikorana na dystrobrevin ikoresheje domaine ya PH2 na SU ihuza, kandi ikorana na actin cytoskeleton 108.Mubyukuri, syntrophine isa nkaho igira uruhare runini mugutunganya imbaraga za cytoskeletal, kandi α na β isoforms zirashobora gukorana neza na F-actin 108 bityo bikaba bishoboka ko bigira uruhare mukugenzura uburakari hamwe na biomehanike ya selire Ingaruka.Mubyongeyeho, syntrophine yerekanwe kugenzura cytoskeleton binyuze muri Rac1109.
Guhindura urwego rwa syntrophine irashobora kugarura imikorere, kandi ubushakashatsi buherutse gukoresha mini-dystrofine bwerekanye ko kubaka ΔR4-R23 / ΔCT byashoboye kugarura α-syntrophine kimwe nizindi poroteyine za DGC kurwego ugereranije na WT mdx cardiomyocytes.
Usibye uruhare rwabo mugutunganya cytoskeleton, syntrophine nayo yanditse neza mugutunganya imiyoboro ya ion 111,112,113.PDZ ihuza motif ya syntrophine igenga umuyoboro wa voltage yumutima uterwa na Nav1.5111, igira uruhare runini mugushiraho umutima ushimishije.Igishimishije, muburyo bwimbeba ya mdx, imiyoboro ya Nav1.5 wasangaga itagengwa kandi umutima utera umutima wabonetse mubikoko 111.Byongeye kandi, umuryango wimiyoboro ya ion ya mehanosensitif, umuyoboro wigihe gito ushobora kwakirwa (TRPC), wagaragaye ko ugengwa na α1-syntrophine mumyanya yumutima 113 kandi kubuza TRPC6 byagaragaye ko bizamura imitekerereze idasanzwe muburyo bwa DMD112.Kongera ibikorwa bya TRPC6 muri DMD byavuzwe ko bivamo umutima utera umutima, woroherwa iyo uhujwe na PKG 112.Muburyo bwa tekinike, dystrophine depletion itera kwaguka guterwa no kwaguka kwa [Ca2 +] i ikora hejuru ya TRPC6 kugirango ikore, nkuko bigaragara muri cardiomyocytes na selile yimitsi itwara imitsi112,114.Hyperactivation ya TRPC6 kurambura bituma iba mikorosensor nini nintego yo kuvura muri DMD112,114.
Gutakaza dystrofine biganisha kuri lysis cyangwa guhagarika ibimenyetso byurwego rwa DGC rwose, hamwe no gutakaza ibikorwa byinshi bya mikoroprotective na mehanotransduction, bikavamo fenotipiki yibiza igaragara mumitsi yimitsi ikabije muri DMD.Kubwibyo, birashobora kuba byiza gutekereza ko RSKs ikorera hamwe kandi ko ibice bitandukanye biterwa no kubaho no gukora ibindi bice.Ibi ni ukuri cyane cyane kuri dystrofine, bigaragara ko isabwa guterana no kwihererana na sarcolemma complex muri cardiomyocytes.Buri kintu cyose kigira uruhare rwihariye mugutanga umusanzu muri sarcolemma muri rusange, kwimakaza poroteyine zingenzi zikoreshwa, kugenzura imiyoboro ya ion no kwerekana imiterere ya gene, no gutakaza poroteyine imwe muri DGC biganisha ku kugabanuka kwa myocardium yose.
Nkuko byerekanwe haruguru, poroteyine nyinshi za DGC zigira uruhare mu gukanika no gutangaza ibimenyetso, kandi dystrofine ikwiranye n’uru ruhare.Niba DGC iherereye mu rubavu, ibi biremeza igitekerezo cyuko igira uruhare muri moteri ya moteri hamwe na integin.Niyo mpamvu, abayobozi ba DGC bahinduranya imbaraga za anisotropique kandi bakagira uruhare muburyo bwo guhindura imikorere ya mikorosensorie na cytoskeletal ya mikorobe yo mu bwoko bwa mikorobe idasanzwe, ijyanye nicyitegererezo cya tensegrity.Byongeye kandi, Dp427m yerekana imbaraga za biomehanike zinjira mugukwirakwiza spekrine isubiramo murwego rwibanze rwagati, bityo ikora nka mikorobe ikomeza imbaraga za 25 pN zitabishaka hejuru ya 800 nm.Mugutandukanya, dystrofine irashobora "guhuza" imbaraga zo kwikuramo-kuruhuka byakozwe na cardiomyocytes10.Urebye ubudasa bwa poroteyine na fosifolipide zikorana na spekrine isubiramo domaine, birashimishije kumenya niba spekrine isubiramo itabishaka ihindura kinetics ihuza poroteyine zikoreshwa mu buryo busa na talin116,117,118.Icyakora, ibi ntibiramenyekana kandi birakenewe ko hakorwa iperereza rindi.