Ukuqinisekiswa kwemodeli yomsebenzi wemoto wezingane ezine-cerebral palsy.
Ukuthuthukiswa kwemodeli yokusebenza kwezimoto ezinganeni ezine-cerebral palsy (CP) akukabhalwa phansi. Izinjongo zalolu cwaningo bekuwukuhlola imodeli yemodeli yokusebenza kwemoto ezinganeni ezine-CP nokusebenzisa imodeli ukuze kwakhiwe amajika okusebenza kwe-gross motor ezingeni ngalinye kwangu-5 we-Gross Motor Function Classification System (GMFCS). Isampula ehleliwe yezingane ezingu-586 ezine-CP, ezineminyaka engu-1 kuye kwengu-12 ubudala, ezihlala e-Ontario, e-Canada, futhi ezaziwa ngezikhungo zokuhlunyeleliswa zabamba iqhaza. Izifundo zahlukaniswa kusetshenziswa i-GMFCS, futhi imodeli yokusebenza kwemoto ikalwa nge-Gross Motor Function Measure (GMFM). Amamodeli amane ahlolwe ukuze akhe amajika achaza ubudlelwano obungaqondile phakathi kweminyaka yobudala kanye nemodeli yokusebenza kwemoto. Imodeli lapho kokubili ipharamitha yomkhawulo (isikolo esikhulu se-GMFM) kanye nepharamitha yesilinganiso (izinga okutholwa ngalo amaphuzu aphezulu e-GMFM) zihluka kuleveli ngayinye ye-GMFCS echaze u-83% wokuhluka kuzikolo ze-GMFM.
Isifo sika-Huntington (HD) sibangelwa ukwanda okungavamile kokuphindaphinda kwe-CAG ku-huntingtin yombhalo wofuzo. Ukuthuthukiswa kwezindlela zokwelapha ze-HD kudinga ukuhlolwa kwangaphambili kwezidakamizwa kumamodeli ezilwane akhiqiza kabusha ukungasebenzi kanye nesifo sesifunda esithile esibonwa ku-HD. Senze imodeli entsha ye-knock-in yemoto ye-HD enegundane le-chimeric/i-exon 1 yomuntu equkethe izimpinda eziyi-140 ze-CAG ezifakwe kufuzo lwe-murine huntingtin. Lawa magundane abonise ukwanda komsebenzi we-locomotor kanye nokukhuliswa enyangeni engu-1 ubudala, okulandelwa ukungenzi lutho ezinyangeni ezi-4 kanye nokungahambi kahle kokuhamba ngonyaka ongu-1. Izimpawu zokuziphatha zandulela ukuphazamiseka kwe-neuropathological, okwaba namandla futhi kwanda kuphela ezinyangeni ezi-4 ubudala. Lokhu kwakuhlanganisa amabala enuzi okuzingela kanye ne-huntingtin equkethe i-nuclear ne-neuropil aggregates eyavela okokuqala ku-striatum, i-nucleus accumbens, ne-olfactory tubercle. Kuyathakazelisa ukuthi izifunda ezine-pathology yakuqala zonke zithola okokufaka okuminyene kwe-dopaminergic, okusekela ukuqoqwa kobufakazi bendima ye-dopamine ku-HD pathology.
Idatha yefrikhwensi yefomethi ibikwa yonkamisa base-Swedish abakhiqizwe bobabili abane-mandible engaguquki futhi engavinjelwe. Izilinganiso zenziwe ekuqaleni kwe-glottal pulse ukuze kulinganiselwe ukuchazwa kwemiphumela ezindleleni zempendulo ezingahlolisisi. Imiphumela ibonise ukuthi naphezu kokuvuleka kwemihlathi okungekona kwemvelo, izifundo zikwazile ukukhiqiza amaphethini ka-F ngaphakathi kwebanga lokuhluka konkamisa abavamile. Imiphumela ichazwa ngokuqagela ukuthi ukufunda "ngokuphazima kweso" kwemisebenzi engajwayelekile, njengokuphindaphinda onkamisa abangaguquki, kungenzeka ngoba ukuhlelwa kwemotor yenkulumo evamile "kuyisinxephezelo" kunokuba kubangelwa noma yiziphi izikhulumi ezidweba ulwazi olufanayo lwesikhathi esidlule noma ukubiza imodeli ekhethekile yezinqubo zezimoto ezihlukile kulezo zenkulumo yemvelo. Okusho ukuthi, isebenza ngendlela ezwelayo ukuze kuzuzwe izinjongo eziqondiswe kumlaleli. Njengoba "izimo" zakha isigaba esingapheli semicimbi uhlelo kumele lube "lokudala," noma lukwazi ukuphatha izimo ezingakaze zenzeke ngaphambili.
Ucwaningo lwamanje luphakamisa imodeli ekwazi ukukhiqizwa kabusha yokuwohloka kokuhlolwa kwemodeli yama-motor neurons kugundane. Ukuvuswa kwezimpande ze-ventral kumodeli ye-lumbar cord transects yabantu abadala kuma-axon e-motor at the root exit futhi kuholela ekubuyiseleni ukufa kweseli kwe-80% yemodeli yama-motor neurons amasonto angu-2 kamuva; lo mphumela ulandela uchungechunge lwezinguquko ze-retrograde, okuhlanganisa i-chromatolysis, ukulahlekelwa kwe-transmitter phenotype, kanye nokuqoqwa kwe-phosphorylated neurofilaments ku-perikarya. Amaseli e-glial abuthwe endaweni yokulimala okubuyiselwa emuva aveza womabili ama-epitopes aqondene ne-microglia (njengoba kuboniswa yi-OX-42 immunoreactivity) nomaka be-macrophage-specific (isb, i-ED-1 immunoreactivity). Omaka be-Macrophage-specific baba namandla kakhulu ezinsukwini ze-7 postaxotomy futhi banikeze ubufakazi obengeziwe be-phagocytosis esebenzayo yama-neurons alimele. I-ventral root avulsion iyimodeli ewusizo kakhulu yokuhlola izindlela zokufa kwe-motor neuron kanye nokuhlola ikhono lama-trophic factor kanye namanye ama-ejenti ukulondoloza i-phenotype nokukhuthaza osindile.
Ubufakazi obuningi buye babonisa ukuthi i-cerebellum idlala indima ebalulekile ekukhiqizeni ukunyakaza. Isici esibalulekile sokuphuma kwemoto isikhathi sayo maqondana nezisusa zangaphandle noma kwezinye izingxenye zomnyakazo. Ucwaningo lwangaphambilini luphakamisa ukuthi i-cerebellum idlala indima ngesikhathi sokunyakaza. Lapha sichaza imodeli yenethiwekhi ye-neural esuselwe kunhlangano ye-synaptic ye-cerebellum engakhiqiza izimpendulo ezinesikhathi ebangeni lamashumi ama-milliseconds ukuya kumasekhondi. Ngokuphambene namamodeli angaphambilini, ukubhala ikhodi yesikhashana kuvela ku-dynamics ye-cerebellar circuitry futhi akuxhomekile ekubambezelekeni kokwenziwa, izinhlu zama-elementi anokushintshana kwesikhathi okuhlukile, noma isibalo sama-elementi azungezayo kumafrikhwensi ahlukene. Kunalokho, isikhathi sikhishwa ku-vector ye-granule cell cell. Isethi engaphansi yamaseli e-granule asebenzayo iyashintshashintsha isikhathi ngenxa yempendulo engalungile yeseli ye-granule—Golgi—granule.
I-Spinal muscular atrophy (SMA) ibangelwa ukuguqulwa kwe-homozygous noma ukususwa kwe-SMN1 gene encoding survival of motor neuron (SMN) protein, okuholela ekulahlekeni okukhethekile kwama-alpha-motor neurons. Abantu ngokuvamile banekhophi eyodwa noma ngaphezulu yofuzo lwe-SMN2, isifunda sekhodi esicishe sifane ne-SMN1, ngaphandle kokuthi ukuguqulwa kwephoyinti kubangela ukuhlukana kuphume i-exon 7 kanye nokukhiqizwa kwephrotheni engasebenzi kakhulu ye-SMNDelta7. Ukwakhiwa kwezidakamizwa ezinciphisa ukugoqa kwe-SMN2 okuphambene kuyindlela yokwelapha ekhangayo ye-SMA. I-steric block antisense oligonucleotide (AO) isanda kwakhiwa evimbe i-intronic splice suppressor element, kanye nokufakwa okuthuthukisiwe kwe-SMN2 exon 7 kuma-fibroblasts esiguli se-SMA. Lapha, sibonisa ukuthi ukulethwa ngezikhathi ezithile kwe-intracerebroventricular (ICV) yale AO kubangele ukwanda kwenkulumo ye-SMN ebuchosheni nasemgogodleni kuze kufike ku-50% wezinga lama-littermates anempilo. I-PCR yesikhathi sangempela yemibhalo ye-SMN2 iqinisekise ukukhuphuka okuphakathi kwe-AO kwe-SMN yobude obugcwele.
Kwakhiwa imodeli yomugqa yesikhathi nokulungiswa kwamaphutha okuhloswe ngayo ukuchaza izindlela ezingaphansi kokusebenza kwesihloko kupharadigm yokuhlola, lapho umsebenzi kuwukuvumelanisa ukulandelana kwezenzo zemoto ngokulandelana kwestimu. Imodeli iqukethe izindlela ezimbili zokulungisa amaphutha: (1) ukulungiswa kwesikhathi (imvamisa ehlanekezelwe) yokulandelana kwezimpendulo; (2) izilungiso zokushintshwa kwesigaba salokho kulandelana (iphutha lokuvumelanisa). Kuleli phepha, kuhlaziywa umthelela wokuguquguquka kwemodeli ye-physiologically justifiable kanye nezimo zokuqala ngokulandelana kwempendulo yesimo esingashintshi kanye nokuzinza kokusebenza kwemodeli. Imodeli izinzile ezinzuzweni zokulungiswa kwamaphutha ebangeni elisuka ku-0 kuye ku-2. Ukuqhathanisa nedatha yobufakazi eyaziwayo isekela umbono wokuthi amanani anengqondo angaphansi kuka-1. Ngaphezu kwalokho, enye indlela yemodeli yomugqa eyisisekelo yethulwa lapho uhlamvu olungaba khona lwe kuxoxiswana ngenqubo yokutholwa kwephutha lokuvumelanisa.
Kuhlongozwa imodeli yesikhathi esiyiluphu evaliwe ehlanganisa izenzakalo ezimbalwa ezibonwa emisebenzini edinga ukukhiqizwa kokulandelana kwezenzo zemoto ngokuvumelanisa nokulandelana kwezisusa. Ngokuphambene namamodeli wangaphambilini, okuguquguqukayo okutholakala ohlelweni lwezinzwa olumaphakathi lwesihloko (iziguquguquko zangaphakathi) kanye neziguquguqukayo ezilinganisekayo zangaphandle ziyahlukaniswa, futhi kufakwe okuguquguqukayo okuningana okuvumelana ne-physiologically kwangaphakathi. Imodeli ithatha ubukhona (a) bomgcini wesikhathi wangaphakathi okhiqiza isikhawu sereferensi esisetshenziswa kuyunithi yokulawula imoto ukuze kubekwe isikhathi somyalo wemoto olandelayo; (b) i-intrinsic (isihloko) synchrony encike olwazini oluthile lwangemuva (impendulo) mayelana nokuqala okwenziwe kakade kwesenzo semoto. Indlela yokulungisa iphutha yezindlela ezimbili iyacatshangelwa: (1) ukulungiswa kwenkathi (imvamisa ehlanekezelwe) — isikhawu sereferensi (inkathi) sisethwa ekuqaleni komsebenzi ngokwesikhawu (s) sokuqalisa kwe-interstimulus futhi kamuva silungiselwe ukwehluka. .
Izilungiseleli zikaphethiloli zingamamodeli wesinqumo (imikhiqizo yesofthiwe) aziwa ngokwandayo njengamathuluzi okuphatha uphethiloli asebenzayo ngabathwali bamaloli base-US. Kusetshenziswa idatha yentengo yakamuva yazo zonke izitobhi zamaloli, lawa mamodeli abala ishejuli yamafutha esezingeni eliphezulu yomzila ngamunye obonisa: (i) yiziphi izitobhi zamaloli okufanele zisetshenziswe, kanye (ii) nokuthi ungakanani uphethiloli ongathengwa esitobhini esikhethiwe( s) ukunciphisa izindleko zokugcwalisa amafutha. Kodwa-ke, ngendlela yamanje, lawa mamodeli anciphisa kuphela izindleko zikaphethiloli, futhi aziba noma abukele phansi ezinye izindleko ezithintwa ukuhlukahluka kwesinqumo samamodeli. Ngokwesisekelo sezingxoxo nabaphathi benkampani yenethiwekhi, abashayeli bamaloli, nabathengisi be-fuel-optimizer, lesi sihloko siphakamisa imodeli ebanzi yokuthuthukisa uphethiloli wenkampani yenkampani yenethiwekhi ecabangela zonke izindleko ezithintwa ukukhetha okuhlukile kwemodeli. Imiphumela yokulingisa isho ukuthi imodeli ehlongozwayo ayitholi nje kuphela izindleko eziphansi zokusebenza kwemoto kunezilungiseleli zikaphethiloli ezithengiswayo, kodwa futhi inikeza izixazululo ezifiseleka kakhulu ngokombono wabashayeli.
Ukufakwa kwe-intraspinal kwamangqamuzana e-neural stem amelela indlela ethembisayo yokukhuthaza ukubuyiswa komsebenzi ngemva kokulimala komgogodla. Ukwelashwa okunjalo kungase kusebenze: I) ukuhlinzeka ngosekelo lwe-trophic ukuze kuthuthukiswe ukusinda kwama-neurons aphethe; II) ukuthuthukisa ubuqotho besakhiwo se-parenchyma yomgogodla ngokunciphisa i-syringomyelia kanye nezibazi ezindaweni ezilimele ngokuhlukumezeka; kanye ne-III) ihlinzeka ngezibalo ze-neuronal ukuze yenze ukudluliselwa okunamandla ngama-axon abamba, ama-segmental interneurons, kanye/noma ama-α-motoneurons. Lapha sibonise umphumela wokuxhunyelelwa kwe-intraspinal yebanga lomtholampilo le-fetus spinal cord-derived neural stem cell (HSSC) ekubuyiseleni umsebenzi wezinzwa kumodeli yegundane lokulimala kokucindezela kwe-lumbar (L3). Amagundane esifazane aseSprague–Dawley anezinyanga ezintathu ubudala athole ukulimala komgogodla we-L3. Ezinsukwini ezintathu emva kokulimala, izilwane zazingahleliwe futhi zithole imijovo ye-intraspinal ye-HSSC, imidiya kuphela, noma ayikho imijovo. Zonke izilwane zazingagxiliwe nge-tacrolimus, i-mycophenolate mofetil, ne-methylprednisolone acetate kusukela ngosuku lokuxhunyelelwa kwamaseli futhi zasinda amasonto ayisishiyagalombili.
Sibonise ngaphambilini ukuthi ukuphathwa kwe-quercetin ngemva kokulimala komgogodla kumodeli yegundane kubangele ukubuyiswa okuphawulekayo komsebenzi wemoto. Kumodeli efanayo yokulimala kokucindezelwa komgogodla, manje sesihlobanise ubude besikhathi sokwelashwa nezinga lapho ukusebenza kwemoto kutholwa khona. IZINDLELA: Amagundane angama-Wistar angamaduna angamashumi ayisikhombisa nane abelwa amaqembu ayisishiyagalombili okuhlola. Ukulimala kwe-Mid-thoracic yomgogodla kwakhiqizwa ezilwaneni zamaqembu ayisikhombisa. I-Quercetin ilawulwa nge-intraperitoneally kumthamo ngamunye we-25 micromol kg (-1). Ukuqala kokwelashwa kwaba ihora elingu-1 ngemva kokulimala. Ubude bokwelashwa babusuka kumjovo owodwa kuye ezinsukwini eziyi-10, nemijovo yokujova izikhathi ezimbili noma ezintathu ngosuku. Izikolo ze-BBB (i-Basso, i-Beattie ne-Bresnahan) zatholwa futhi ukulondolozwa kwezicubu endaweni yokulimala kwahlaziywa. IMIPHUMELA: Asikho ezilwaneni ezilawulwayo ezingalashwa ezathola ukusebenza kwemoto okwanele ukuhamba. Lapho i-quercetin isetshenziswa kabili ngosuku esikhathini esiyizinsuku ezi-3 noma eziyi-10, cishe amaphesenti angama-50 ezilwane athola ukunyakaza okwanele kokuhamba.
Ukuhlaziywa kwesimo esizinzile kwenziwa kumodeli ye-kinetic ye-switch complex ye-flagellar motor ye-Halobacterium salinarum (Nutsch et al. [16]). Ubukhona kanye nokuhluka kwesimo esihle sokuqina kwesistimu kuyasungulwa futhi kuboniswa ukuthi kungani isimo esizinzile sigxile esigabeni esinekhono, isimo senjini lapho ekwazi khona ukuphendula ekuvuseleleni ukukhanya. Kuyaboniswa futhi ukuthi kungani isimo esizinzile sishintshela esigabeni sokuphikisa lapho inani lesimo esizinzile lesilawuli sokuphendula i-CheYP likhuphuka. Lo msebenzi uyingxenye eyodwa yokumodela kubhayoloji yezinhlelo lapho izakhiwo zezibalo zemodeli zisungulwa.
Uhlu oluphelele lwezici eziyimbangela ku-Amyotrophic lateral sclerosis (ALS) lusalokhu lungaqondakali, kodwa ukucindezeleka okwenziwe nge-oxidative kubonwa njengento enomthelela. Izinguquko ku-Cu/Zn superoxide dismutase 1 (SOD-1), ezihlotshaniswa ne-ALS yomndeni, zikhuthaza ukulimala kwe-oxidative okusabalele. Amagundane aveza amagundane e-G93A e-SOD-1 ashintshashintshayo abonisa izici eziningi ze-ALS futhi awusizo ekuthuthukisweni kokwelapha. Ukwengezwa kokudla nge-S-adenosyl methionine (SAM) kunikeze imiphumela eminingi ye-neuroprotective kumamodeli wamagundane we-pathology ehlobene neminyaka. Sihlole lapha ukuthi ukuxhaswa kwe-SAM kungathinta yini inkambo ye-motor neuron pathology kumagundane aveza i-SOD-SAM ebambezelekile yomuntu ukubambezeleka kwesifo esiqala ngamaviki e-2-3. I-SAM iphinde yabambezeleka izimpawu zokuwohloka kwemizwa kulawa magundane naku-ALS, okuhlanganisa nokuvimbela ukulahleka kwama-motor neurons, nokunciphisa i-gliosis, ukuhlanganisa kwe-SOD-1, amaprotheni.
Ukuhlaziywa kwe-Electromyographical kokulahlekelwa kweyunithi yemoto ebonisa izimpawu ngaphambili kumodeli yegundane elishintshashintshayo le-SOD1 le-amyotrophic lateral sclerosis (ALS) kuveze okutholakele okuphikisanayo mayelana nokuqala kanye nesikhathi. Sirekhode amandla e-isometric emisipha ye-hindlimb kanye neyunithi yemoto ukuze sinqume inombolo yeyunithi yemoto nosayizi phakathi nesikhathi sokuphila samagundane. Izinombolo zeyunithi yezimoto ku-fast-twitch tibialis anterior, extensor digitorum longus kanye nemisipha ye-gastrocnemius ephakathi zehlile kusukela ezinsukwini ze-40 ubudala, izinsuku ezingu-50 ngaphambi kokubikwa kwezimpawu ezicacile kanye nokulahlekelwa kwe-motoneuron. Izinombolo zeyunithi yezimoto zehla ngemva kwezimpawu ezisobala kumsipha we-soleus onyakaziswa kancane. Amandla emisipha ehlile ngokuhambisana nezinombolo zeyunithi yezimoto, okubonisa ukunxeshezelwa okuncane noma ukungabikho kokusebenza ngokumila. Ukwehla kwangaphambi kwesikhathi okuqondene nemisipha kwakungenxa yokuba sengozini okukhethekile kwamayunithi amakhulu, asheshayo ezimoto, avinjwe ama-motoneurons amakhulu. Ama-motoneurons amakhulu yingakho esengozini enkulu ku-ALS nge-die-back eyenzeka ngaphambi kwezimpawu ezisobala. Siphetha ngokuthi usayizi wama-motoneurons, ama-axon awo, kanye nosayizi weyunithi yenjini kubalulekile.
I-Urinary incontinence yisimo esiwohlozayo esithinta ngokuyinhloko abantu asebekhulile. Inqubo eyodwa enkulu iphumela ekuwohlokeni okungapheli kwe-striated urethral sphincter ene-fibrosis ehambisanayo. Ababhali baphenye isiphetho samaseli e-muscle precursor cell (MPC) afakwe kumodeli yokulimala kwe-urethral sphincter ekhiqiza kabusha izinguquko ze-histopathologic zokungaphumeleli kwe-sphincter. I-striated urethral sphincter yamagundane abesilisa amadala yonakaliswe yi-electrocoagulation. I-MPC yahlukaniswa ne-myofiber explants, yangenwa i-adenovirus ethwele i-transgene encoding beta-galactosidase, futhi yajova ku-sphincter yesilwane esifanayo ezinsukwini ezingu-37 ngemva kokulimala. Izilwane zabulawa ezinsukwini ezi-5 nezingu-30 ngemuva kokujova ukuze kuhlolwe ukusebenza kwe-sphincter kanye nokwakhiwa kwamayunithi ezimoto. I-Electrocoagulation ibangele ukubhujiswa okungenakuhlehliswa kokubili kwe-sphincteric myofibers kanye neziphetho zemizwa, ngokungakwazi ukusebenza kwe-sphincter eyonakele ukuze kugcinwe ukwanda kwengcindezi yesinye; i-atrophy ne-fibrosis ithuthukiswe ngemva kwenyanga engu-1.
I-childhood motor neuron disease i-spinal muscular atrophy (SMA) iphumela ekukhulumeni okuncishisiwe kofuzo lwe-survival motor neuron (SMN). Ucwaningo lwangaphambilini olusebenzisa amamodeli e-in vitro kanye nezinto eziphilayo eziphansi luphakamise ukuthi amazinga aphansi we-Smn protein aphazamisa izinqubo zokukhula ngaphambi kokubeletha kuma-motor neurons aphansi, abe nomthelela ekukhuleni kwe-neuronal, i-axon branching kanye nokuxhumana kwe-neuromuscular. Izinga lezi zindlela zokuthuthuka ezinomthelela ngayo ekubeni sengozini okukhethekile kanye ne-pathology ohlelweni lwe-neuromuscular mammalian in vivo alikacaci. Lapha, siphenye ukuthuthukiswa kwezimpawu zangaphambi kokuxhuma kwe-neuromuscular kubantu abasengozini ehlukile ye-motor neuron ku-Smn(-/-); amagundane e-SMN2, imodeli ye-SMA eqinile. Sibonisa ukuthi amazinga e-Smn ancishisiwe awanawo umthelela obonakalayo ku-morphological correlates yentuthuko yangaphambi kwezimpawu kumayunithi emoto asengozini noma azinzile, okubonisa ukuthi izinqubo zokuthuthuka ezingavamile zangaphambi kwezimpawu cishe akunakwenzeka ukuba zibe imfuneko yezinguquko ezilandelayo ze-pathological.
I-hypothesis eyinhloko yalolu cwaningo yayiwukuthi iphethini yemoto yokukhwehlela ikhiqizwa, okungenani ngokwengxenye, yinethiwekhi ye-medullary respiratory neuronal ukuphendula okokufaka okuvela "kukhwehlela" kanye ne-pulmonary stretch receptor relay neurons ku-nucleus tractus solitarii. Ukulingiswa kwekhompyutha kwemodeli yenethiwekhi esabalalisiwe enoxhumo oluhlongozwayo kusuka ku-nucleus tractus solitarii kuya kuma-ventrolateral medulary respiratory neurons kukhiqize amaphethini emoto aphefumulayo anjengokukhwehlela. Izimpendulo ezibikezelwe "zezinhlobo" ezihlukahlukene zama-neurons (I-DRIVER, I-AUG, I-DEC, E-AUG, ne-E-DEC) ezithathwe ekulingiseni zahlolwa ku-vivo. Izimpendulo ezihambisanayo nezilandelanayo zama-neuron anezimpawu ezisebenzayo zokuphefumula zaqashwa ngesikhathi sokukhwehlela okungelona iqiniso kumakati e-decerebrate, akhubazekile, angena umoya. Amaphethini anjengokukhwehlela emithanjeni ye-phrenic kanye ne-lumbar avuswe ukukhuthazwa komshini we-intrathoracic trachea. Amaphethini okuphuma okushintshiwe akalwa ezinhlotsheni eziningi zama-neurons okuphefumula ngesikhathi sokukhwehlela okungokomfanekiso.
I-autosomal recessive mutation mnd2 iphumela ekuqalekeni kwesifo semotor neuron esinokukhubazeka okuqhubekayo ngokushesha, ukuwohloka okukhulu kwemisipha, ukuhlehla kwe-thymus nobende, nokufa ngaphambi kwezinsuku ezingama-40 ubudala. i-mnd2 imakwe ku-chromosome 6 yegundane ngohlelo lofuzo: centromere-Tcrb-Ly-2-Sftp-3-D6Mit4-mnd2-D6Mit6, D6Mit9-D6Rck132-Raf-1, D6Mit11-D6Mit12-D6Mit14. i-mnd2 itholakala phakathi kweqembu lokuxhumanisa elondolozwe elinama-homolog ku-chromosome yomuntu 2p12-p13. Ama-neuron emisipha yomgogodla wezilwane ezithintekile i-homozygous avuvukele futhi anebala elibuthakathaka, futhi i-electromyography yembula umsebenzi ozenzakalelayo wokuwohloka kwemisipha. I-Myelin staining yayivamile kuyo yonke i-neuraxis. Ukubhekwa komtholampilo kuhambisana nokungajwayelekile okuyisisekelo kokusebenza kwe-motor neuron ephansi. Le modeli yezilwane entsha izoba wusizo ekuhlonzeni ukukhubazeka kofuzo okubangela isifo se-motor neuron kanye nokuhlolwa kwezindlela zokwelapha ezintsha.
Isifo sikaParkinson (PD) yisifo esivamile se-neurodegenerative esibonisa ukungasebenzi kahle kwezimoto, njengokundindizela, i-akinesia kanye nokuqina. Ocwaningweni lwamanje, siphenye ukuthi ukuhlolwa kokubhukuda kungasetshenziswa yini njengenye yezindlela zokuqapha ukuziphatha ukuze kufundwe ukukhubazeka kwezimoto ku-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in izinhlobo ezimbili zamagundane, i-Balb/c ne-C57BL/6. Amagundane alashwe ngemithamo ehlukene ye-MPTP (i-10, i-20 ne-30 mg/kg, kabili, i-16 h ngokuhlukana), futhi afakwa ngaphansi kokuhlolwa kokubhukuda ngosuku lwesithathu lomjovo wokuqala we-MPTP. Ukundindizela okubangwa yi-MPTP kwaqashwa ngemizuzu engama-30, futhi i-akinesia nokuqina okuthuthukisiwe kwacwaningwa emahoreni ama-3 ngemva kokwelashwa kwesibili kwe-MPTP. Ngenkathi ukundindizela kanye ne-akinesia ekhiqizwayo kuncike kumthamo kanye namandla okundindizela aqhathaniswa nezinhlobo ezimbili zamagundane afundwayo, impendulo yokugcina ku-C57BL/6 yayincane kakhulu kunaleyo ebonwe e-Balb/c. Ukuqina okuboniswe ku-Balb/c amagundane bekuncike kumthamo, kodwa hhayi ku-C57BL/6.
Ubufakazi obuhlukahlukene buphakamisa ukuthi i-amyotrophic lateral sclerosis (ALS) ithinta ngokukhetha ukusebenza kwe-motor neuron, kodwa ukuguqulwa kwe-electrophysiological of single motor neurons ku-ALS kusazobhalwa. Emsebenzini wamanje, ukuthakaseleka kwama-motor neurons kuhlolwe kumodeli yegundane elishintshashintshayo lohlobo lomndeni we-ALS, elihlotshaniswa nokuguqulwa kwe-Cu,Zn superoxide dismutase (Gly 93→ Ala). Ukurekhodwa kwe-patch-clamp kwamandla we-membrane kuma-transgenic ama-motor neurons kubonise ukuthi avutha ngokunyuka kwemvamisa kanye nobude besikhathi esifushane uma kuqhathaniswa nama-motor neurons avela kumagundane okulawula. Izici ze-membrane ye-passive yalezi zinzwa zazilingana nokho. Imiphumela enjalo iphakamisa ukuthi ukuguquguquka kwe-motor neuron excitability kuhambisana nokuguqulwa okuhlobene ne-ALS futhi okungase kube nomthelela ku-pathogenesis yalesi sifo.
Ukwelashwa kokubuyisela amaseli kuye kwaphakanyiswa kabanzi njengokwelapha izifo eziningi kuhlanganise nesifo se-motor neuron. Izinhlobonhlobo zamangqamuzana anikelayo ahlolelwe ukwelashwa okuhlanganisa namalungiselelo angawodwa ukusuka kumnkantsha wamathambo kanye nentambo yomgogodla yombungu. Omunye umthombo wamaseli, amaseli e-Sertoli, asetshenziswe ngempumelelo kumamodeli esifo sikashukela, isifo sikaParkinson kanye nesifo sikaHuntington. Ikhono lalawa maseli ukukhiqiza amaprotheni e-cytoprotective kanye nendima yawo 'njengamaseli abahlengikazi' asekela umsebenzi wezinye izinhlobo zamaseli kumasende aphakamisa ukusetshenziswa kwawo okungaba khona njengamaseli e-neuroprotective. Ucwaningo lwamanje luhlola ikhono lamaseli e-Sertoli ajovwe ku-parenchyma yomgogodla ukuze avikele ama-motor neurons kumodeli yegundane ye-amyotrophic lateral sclerosis. Amagundane angamashumi ayisikhombisa e-transgenic aveza i-mutant (G93A) yomuntu i-Cu-Zn superoxide dismutase (SOD1) athole umjovo womgogodla we-Sertoli-enothiswe ngamaseli e-testicular ku-L4-L5 ventral uphondo (ingqikithi yamaseli angu-1 × 105) ngaphambi kokuqala kwezimpawu zomtholampilo. .
Imodeli yegundane yokwenziwa ye-bacterial chromosome transgenic (BACHD) esanda kwakhiwa ikhiqiza izici ze-phenotypic ze-HD okuhlanganisa kakhulu ukuhlanganisa amaprotheni ahlobene ne-neuropil kanye nokungasebenzi kahle kwemoto okune-neurodegenerative pathology. Ukungasebenzi kahle kwezimoto kukhonjiswe ukuthi kwandulela i-neuropathology kumagundane e-BACHD. Ngakho-ke siphenye ukuqhubeka kwe-synaptic pathology kumaseli e-pyramidal kanye ne-interneurons ye-superficial motor cortex yamagundane e-BACHD. Ukurekhodwa kwe-clamp ye-cell-cell patch kwenziwa kumaseli e-2/3 eyinhloko ye-motor cortical pyramidal kanye ne-parvalbumin interneurons evela kumagundane e-BACHD ezinyangeni ezi-3, lapho amagundane eqala ukubonisa ukungasebenzi kahle kwemoto, futhi ezinyangeni ezingu-6, lapho ukungasebenzi kwemoto kubi kakhulu. .
I-motor neuron degeneration mutation (Mnd) ibangela ukuqala sekwephuzile, ukonakala okuqhubekayo kwama-neurons emoto aphezulu naphansi kumagundane. Ngemva kokusungula izimo zofuzo nezemvelo ezihlukanisa i-phenotypes ye-Mnd/Mnd kusukela ku-+/Mnd amagundane, i-Mnd yaklanywa imephu yaba yi-Chr 8 eseduze, kusetshenziswa ama-retroviruses angapheli njengomaka. Indawo yemephu iqinisekiswe ngomaka be-polymorphic abengeziwe. I-outcross/intercross matings kuhlobo lwe-AKR/J, olwasetshenziswa ukulandela ukuhlukaniswa kwezimpawu ze-retroviral maqondana ne-Mnd, kuphinde kwembula ukuba khona komphumela wesikhathi. Cishe ingxenye eyodwa kwezine yenzalo ye-Mnd/Mnd F2 ethintekile yabonisa isifo esisheshayo. Imodeli yegundane le-Mnd kufanele ivumele ukucwaninga kwezinqubo ezithinta ukuqala nokuqhubekela phambili kokuwohloka okuthile kwe-neuronal kuzo zombili izifo zezilwane nezomuntu.
Ukusungula amamodeli amangqamuzana omuntu e-spinal muscular atrophy (SMA) ukuze alingise ama-phenotypes aqondene ne-motor neuron kubambe isihluthulelo sokuqonda i-pathogenesis yalesi sifo esibhubhisayo. Lapha, sakha imodeli yamaseli emele eduze kakhulu ye-SMA ngokuwisa isakhi sofuzo esinquma isifo, i-survival motor neuron (SMN), kuma-human embryonic stem cell (hESCs). Ucwaningo lwethu ngale modeli yeseli lubonise ukuthi ukudicilela phansi kwe-SMN akukuphazamisi ukungeniswa kwe-neural noma ukucaciswa kokuqala kwama-spinal motor neurons. Ngokuphawulekayo, ukuphuma kwe-axonal ye-spinal motor neurons kwalimala kakhulu futhi lawa ma-neurons alingisa izifo abe esewohloka. Ngaphezu kwalokho, lezi phenotypes zesifo zidalwe ubude obugcwele be-SMN (SMN-FL) kodwa hhayi i-SMN-Delta 7 (entula i-exon 7) i-knotype, futhi yayiqondile kuma-neuron motor yomgogodla. Ukubuyisela ukubonakaliswa kwe-SMN-FL kuthuthukise ngokuphelele zonke izifo ze-phenotypes, okuhlanganisa ukukhubazeka okuthile kwe-axonal nokulahlekelwa kwe-motor neuron. Ekugcineni, ukwehla kwe-SMN-FL kuholele ekucindezelekeni okweqile kwe-mitochondrial oxidative.
