Cov noob caj noob ces ntawm Autosomal Recessive Polycystic raum Kab Mob --ARPKD
Mar 30, 2022
Hu rau: Audrey Hu Whatsapp / hp: 0086 13880143964 Email:audrey.hu@wecistanche.com
Paraskevi Goggolidou *, Taylor Richards
Abstract:
ARPKD yog ib hom kab mob caj cesmob raumuas tshwm sim los ntawm ob sab o ntawm lub raum cystic thiab daim siab fibrosis. Nws qhia tau hais tias muaj ntau yam mob hnyav, nrog rau 30 feem pua ntawm cov tib neeg tuag ntxov thiab feem ntau muaj qhov pom zoo yog tias lawv muaj sia nyob thawj xyoo ntawm lub neej. Cov laj thawj rau qhov kev hloov pauv no tseem tsis paub meej. Ob lub noob tau pom tias ua rau ARPKD thaum hloov pauv, PKHD1, kev hloov pauv uas ua rau feem ntau ntawm ARPKD thiab DZIP1L, uas cuam tshuam nrog ARPKD nruab nrab. Qhov kev tshuaj xyuas me me no yuav tshawb txog cov noob caj noob ces ntawm ARPKD thiab sib tham txog cov kev hloov pauv caj ces thiab cov phenocopies uas tuaj yeem cuam tshuam rau kev kuaj mob.
Ntsiab lus:Autosomal recessive polycysticmob raum(ARPKD), PKHD1, DZIP1L, Modifier noob, Phenocopy Fibrocystin
cistanche tubulosa cov txiaj ntsig thiab kev phiv
1. Taw qhia
Autosomal Recessive Polycystic CovKab mob raum(ARPKD) yog ib daim ntawv tsis tshua muajmob raum mob(CKD) tus yam ntxwv los ntawm lub xub ntiag ntawmcystic raum. Qhov tshaj tawm tshaj tawm ntawm ARPKD feem ntau lees paub tias yog ~ 1: 20, 000 hauv Europe [1]. ARPKD feem ntau tshwm sim thaum ntxov hauv lub neej thiab feem ntau kuaj pom nyob rau hauv lub sij hawm neonatal/perinatal los yog thaum yau [1-10]. Txawm li cas los xij, cov tib neeg uas muaj tus neeg laus pib pib ARPKD kuj tau tshaj tawm, qhia txog qhov sib txawv ntawm qhov kev nthuav qhia kab mob [2,8–10]. Thawj xyoo yog qhov tseem ceeb rau cov neeg kuaj pom thaum ntxov hauv lub neej, nrog kev pom kev tuag ntawm ~ 30-40 feem pua [1]. Txawm li cas los xij, rau cov uas muaj sia nyob rau lub sijhawm pib no, 1- xyoo thiab 10- xyoo muaj sia nyob tau kwv yees li ntawm 85 feem pua thiab 82 feem pua, raws li [1]. Tsis muaj haiv neeg lossis poj niam txiv neej tsis ncaj ncees tau raug tshaj tawm hauv kev txhim kho lossis kev nce qib ntawm ARPKD [1–6,8–10].
Qhov kev nthuav qhia phenotypic ntawm ARPKD yog qhov sib txawv heev, nrog rau cov neeg kuaj pom thaum ntxov hauv lub neej ua rau pom lub raum mob hnyav dua piv rau cov uas feem ntau kuaj pom thaum muaj hnub nyoog laus dua. Lub raum phenotype suav nrog kev tsim cov hlwv nyob rau hauv lub distal tubules thiab sau cov ducts ntawm nephron [1]. Raws li qhov tshwm sim ntawm kev loj hlob cyst, cov tib neeg loj hlob, echogenic ob lub raum uas muaj qhov tsis zoo corticomedullary sib txawv, tab sis khaws ib lub raum zoo [1,11]. Vim yog lub raum hloov pauv uas tshwm sim vim ARPKD, lub raum feem ntau tau piav qhia tias muaj "ntsev thiab kua txob" qauv hauv ultrasounds [12,13]. Lub raum ua haujlwm yuav ua rau muaj kev loj hlob zuj zus vim yog tsim cov kab mob macroscopic thiab interstitial fibrosis thiab nyob ib ncig ntawm 50 feem pua ntawm cov neeg mob yuav nce mus rau CKD theem 5 los ntawm cov neeg laus.
suab puam cistanche cov txiaj ntsig
Cov txheej txheem hauv qab tsim cov kab mob hauv lub raum hauv ARPKD tsis to taub tab sis lawv tau cuam tshuam nrog lwm cov tswv yim nrog cov teeb meem ciliary, yog li tus cwj pwm ntawm ARPKD ua Ciliopathy [14-18]. Ntau yam kab mob hauv lub raum cyst kuj tshwm sim, xws li nephronophthisis, Joubert syndrome thiab Bardet-Biedl syndrome yog tshwm sim los ntawm kev hloov pauv hauv cov noob uas nws cov proteins hauv zos los yog xav tau thawj cilia rau kev taw qhia [15,16]. ARPKD yog tshwm sim los ntawm kev hloov pauv hauv Polycystic raum thiab Kab Mob Siab 1 (PKHD1) lossis tsawg dua hauv DAZ cuam tshuam zinc ntiv tes protein 1 (DZIP1L) [17–20]. Cov noob no encode Fibrocystin (FPC) thiab DZIP1L feem, ob qho tib si ntawm qhov chaw rau cilia [17–19]. Cov haujlwm ntawm FPC tsis nkag siab tag nrho. Txawm li cas los xij, vim nws cov ciliary localization thiab cov qauv homology, nws yuav ua raws li ciliary receptor protein, whereas DZIP1L localises mus rau ciliary hloov chaw, uas nws plays lub luag hauj lwm nyob rau hauv thauj cov noob khoom rau hauv ciliary axoneme [17-19]. Zoo li ARPKD, Autosomal Dominant Polycystic Kidney Disease (ADPKD), lwm tus kab mob polycystic raum tab sis ntawm cov qub txeeg qub teg, yog tshwm sim los ntawm kev hloov pauv hauv PKD1 thiab PKD2 uas encode Polycystin 1 (PC1) thiab Polycystin 2 (PC2) cov proteins uas tsim ib qho chaw ua haujlwm. rau thawj cilia [1,14–16]. PC2 yog ib qho kev thauj khoom ion thiab kev sib cuam tshuam ntawm FPC thiab PC2 tau pom tias tshwm sim hauv cilia, qhov twg ob lub proteins tsim ib qho nyuaj thiab tsav PC2 channel kev ua haujlwm [14,21]. Txawm li cas los xij, qhov tseem ceeb ntawm qhov kev sib raug zoo no hauv qhov kev tshwm sim ntawm PKD tsis paub tias poob ntawm PC2 binding domain hauv FPC tsis ua rau PKD hauv nas [14]. FPC thiab PC1 tsis tshwm sim los koom nrog txoj hauv kev zoo sib xws raws li RNA-sequencing thwmsim ua nyob rau hauv murine qauv [22]. Txawm li cas los xij, cov nas digenic thiab nas nrog kev hloov pauv hauv Pkhd1 thiab Pkd1 muaj qhov tshwm sim sai thiab hnyav ntawm PKD, qhia txog kev sib koom ua ke ntawm ob lub noob [14,22]. Txawm hais tias qhov poob ntawm FPC kev qhia tsis cuam tshuam rau qhov kev qhia lossis hauv cheeb tsam ntawm PC1 / PC2 complex, nws tseem muaj peev xwm hais tias PC1, PC2 thiab FPC koom nrog kev sib cuam tshuam ntawm cov noob caj noob ces, nrog rau cov ciliary compartment tau qhia tias yog lub hom phiaj dysregulated hauv murine qauv. nrog kev hloov pauv hauv Pkd1 lossis Pkhd1 [14,22]. Kev poob ntawm DZIP1L tau tshaj tawm tias inhibit qhov chaw ntawm PC1 thiab PC2 rau ciliary axoneme [17]. Nyob rau hauv lem, qhov no tshwm sim nyob rau hauv tsub zuj zuj ntawm lub PC1 thiab PC2 nyob rau hauv lub ciliary basal lub cev / hloov chaw [17]. Interestingly, tsis muaj kev cuam tshuam ntawm ob ARPKD noob PKHD1 thiab DZIP1L tau kuaj pom [17]. Yog li, txawm hais tias ARPKD qhia tau hais tias zoo sib xws rau ADPKD, nrog dysregulated ciliary pathways, proliferation, apoptosis thiab kua secretion pom nyob rau hauv ob qho tib si, lawv tau txais txawv histopathological nta thiab cellular yam ntxwv [1,14–16]. Ib qho piv txwv ntawm qhov sib txawv no yog dysregulated non-canonical Wnt / Planar Cell Polarity (PCP) signaling, qhia hauv ARPKD [23] tab sis tsis yog ADPKD, qhia tias txawm tias Polycystins, FPC thiab DZIP1L tuaj yeem cuam tshuam thiab tau txais cov haujlwm ntsig txog cilia, cov no. functions tsis tas yuav converge.
Covraum puasuas tuaj yeem tshwm sim los ntawm ARPKD tsis yog ib qho tsos mob ntawm tus kab mob, nrog rau lub raum qhia ntxiv ntawm kev kub siab thiab lub siab tsis xws luag, txawm hais tias tom kawg yuav tsis tas yuav ua rau pom tseeb cov tsos mob [1,8,11,24]. Cov tib neeg uas muaj kev nthuav qhia ntawm ARPKD tuaj yeem tshwm sim nrog oligohydramnios, uas tuaj yeem ua rau muaj qhov tshwm sim ntawm Potter Syndrome [1]. Potter Syndrome yog txuam nrog pulmonary hypoplasia, cov yam ntxwv ntawm lub ntsej muag thiab tus txha nraub qaum, ceg thiab ko taw tsis xws luag [1]. Kev tuag vim kev nyuaj siab ntsws kuj tuaj yeem tshwm sim thaum lub sij hawm neonatal [1,24]. Lub siab phenotypes vim yog ductal phaj malformations thaum ntxov ntawm txoj kev loj hlob thiab ua rau cov tsos ntawm congenital daim siab fibrosis [1,8,24]. Ntau qhov ua rau tuag taus muaj feem cuam tshuam nrog kev nthuav qhia daim siab thiab suav nrog portalntshav siab, variceal los ntshav, oesophageal txawv, cholangitis thiab hypersplenism [1,8,24].
cistanche cov txiaj ntsig kev noj qab haus huv: kho mob raum kab mob
2. PKHD1 thiab DZIP1L- ob lub noob tseem ceeb hauv ARPKD
PKHD1 yog cov noob nyob hauv chromosome 6p12 thiab nws muaj tag nrho ntawm 86 exons [19,20,25]. Cov noob txhais ob peb cov protein isoforms ntawm qhov sib txawv ntawm qhov loj me, uas nws lub luag haujlwm tsis tau nkag siab tag nrho [26–28]. Qhov qhib nyeem ntawv ntev tshaj plaws ntawm PKHD1 yog 67 exons ntev thiab encodes cov protein FPC [18,19]. Cov kev qhia ntawm PKHD1 zoo nkaus li tsis yog tsuas yog cov ntaub so ntswg tshwj xeeb xwb tab sis kuj yog cov cell-hom tshwj xeeb, feem ntau pom nyob rau hauv cov ductal hlwb ntawm lub raum (suav cov duct), siab (kua duct) thiab pancreas (pancreatic islets) thiab lawv cov precursors. thaum lub sij hawm kev loj hlob [18,27–29]. FPC tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev loj hlob ntawm lwm yam kabmob, xws li lub ntsws [26,28]. Isoforms ntawm FPC tau qhia nyob rau hauv ntau yam subcellular compartments, nrog rau cov thawj cilia, plasma membrane, cytoplasm, Endoplasmic Reticulum thiab Golgi [18,27,29–31].
FPC yog 4074 amino acid ntev protein, muaj ob lub ntsiab lus [19,20] (Fig. 1). Thawj cov ntsiab lus tseem ceeb ntawm FPC yog lub npe loj tshaj plaws uas suav nrog thaj tsam N-terminal thiab muaj ntau qhov kev txaus siab, xws li IPT, G8 thiab Parallel Beta Helices [18,19,32]. Qhov thib ob tseem ceeb tivthaiv yog ib tug luv luv intracellular C-terminal domain nrog ib tug cilia localization ib theem zuj zus, uas tej zaum yuav tsav lub internal protein-protein kev sib cuam tshuam xws li ib tug nrog PC2 thiab nws yuav raug tso tawm rau ib tug tam sim no tsis paub lub hom phiaj tom qab Notch-zoo li proteolytic cleavage [ 21, 30, 33–35] ib. Lub luag haujlwm ntawm cov protein tam sim no tsis paub. Txawm li cas los xij, vim nws cov duab thiab qhov chaw nyob, nws yog qhov kev xav los ua lub luag haujlwm ntawm receptor protein thiab tuaj yeem koom nrog hauv kev tswj cov cell tsim, proliferation, apoptosis, adhesion thiab signaling [18–21,23,30,33,35– 37] ib.
ARPKD qhov tshwm sim tshwm sim los ntawm kev hloov pauv hauv PKHD1 yog qhov sib txawv heev tab sis nws feem ntau cuam tshuam nrog ob lub raum thiab kab mob siab. Qhov hnyav ntawmraumkab mobfeem ntau muaj feem xyuam rau lub hnub nyoog ntawm kev tuag / kev kuaj mob, nrog kev tuag perinatal yog qhov kev nthuav qhia kab mob hnyav tshaj plaws [3–6,8–10,38–42]. Tam sim no tsis muaj kev paub txog kev sib raug zoo ntawm qhov kev nthuav qhia ntawm qhov hnyavraumkab mobkab mob siab heev [8]. Feem ntau cov tib neeg uas pom muaj kab mob raum hnyav, piv txwv li perinatal ciaj sia taus, kuj yuav tsim ib lub siab phenotype [8]. Txawm li cas los xij, kev sib xyaw ua ke ntawm qhov hnyavraumkab mobnrog mob siab mob siab, mob raum mob me nrog mob siab mob hnyav thiab ob lub raum thiab kab mob siab tau raug tshaj tawm [8]. Dab tsi ua rau qhov sib txawv no tsis to taub tag nrho. Txawm li cas los xij, qhov sib txawv tau raug txheeb xyuas ntawm qhov mob hnyav (perinatal demise vs perinatal survival) thiab hom kev hloov pauv los ntawm ib tus neeg [3–6,8,9,38,41]. Lub xub ntiag ntawm ob lub truncating mutations yog txuam nrog cov phenotype loj tshaj plaws. Hauv qhov sib piv, muaj ob qhov kev hloov pauv tsis zoo lossis kev hloov pauv tsis zoo uas tau txais los ntawm ib sab ntawm kev txiav tawm feem ntau cuam tshuam nrog qhov tsis tshua muaj phenotype [3–6,8,9,38,41]. Qee qhov kev hloov pauv tsis zoo tau txuas mus rau qhov muaj feem cuam tshuam loj heev, tab sis tsis muaj kev sib koom ua ke ntawm kev hloov pauv qhov chaw nyob hauv PKHD1 thiab qhov mob hnyav [3–6,8,38,42]. Tseem tsis muaj kev sib koom ua ke ntawm kev hloov pauv thiab seb ib tus neeg puas yuav muaj lub siab tseem ceeb phenotype [5].
Hauv ARPKD, feem ntau cov kev hloov pauv tau tawg mus thoob plaws cheeb tsam extracellular ntawm FPC uas tsis muaj pawg nyob rau hauv ib cheeb tsam ntawm FPC hais txog ib qho phenotype [3–8,40]. Kev txiav txim siab txog kev sib raug zoo ntawm ib tus neeg qhov kev hloov pauv thiab lawv qhov kev nthuav qhia kab mob yog qhov nyuaj los ntawm qhov tsawg zaus ntawm kev hloov pauv feem ntau thiab qhov tsis zoo ntawm cov qub txeeg qub teg [3,4,6,8]. Qhov no cuam tshuam ntxiv los ntawm qhov nyuaj ntawm PKHD1 kev qhia, peb tsis muaj kev nkag siab txog cov qauv protein / kev ua haujlwm ntawm FPC thiab intrafamilial variability [3–5,7,8,26]. Qee qhov kev hloov pauv muaj qhov tshwm sim ntau dua hauv cov pej xeem, qee qhov raug ntaus nqi los ntawm tus tsim teebmeem [2–7,9,10,38,41–43]. Qhov kev hloov pauv T36M muaj qhov tshwm sim ntau tshaj plaws, suav txog kwv yees li 20 feem pua ntawm tag nrho ARPKD mob thiab feem ntau cuam tshuam nrog kev mob hnyav [3,5,6,38,40,41,44,45]. Thawj qhov kev tshuaj ntsuam exon algorithm tau pom zoo los ntawm Bergmann thiab cov npoj yaig [45] thiab lawv pom tias thaum kuaj xyuas lawv cov seem 9 exon, lawv tuaj yeem ntes 50 feem pua ntawm tag nrho cov kev hloov pauv hauv lawv pawg. Lawv qhov kev tshawb pom kev ua tau zoo tuaj yeem nthuav dav mus rau kwv yees li 80 feem pua thaum npog lawv sab saum toj 27 exons [45]. Ib qho tshwm sim nyob rau hauv ntau ntawm cov exon profiles yog qhov muaj peb qhov loj tshaj exons (exons 32, 58 thiab 61) nrog rau exon 3, qhov twg T36M kev hloov pauv tshwm sim [9,10,39,44,45]. Cov txiaj ntsig zoo sib xws tau pom hauv lwm cov ntawv tshaj tawm tab sis muaj qhov sib txawv ntawm exon zaus thiab feem pua ntawm cov kev pab cuam thiab tej zaum yuav qhia qhov txawv ntawm kev hloov pauv los ntawm cov pej xeem, raws li pom hauv Spanish, Dutch, Italian thiab Oman pawg [9,10,39,44].
cistanche tubolosa cov txiaj ntsig kev noj qab haus huv: txhim kho lub raum ua haujlwm
Tsis tas li ntawd, txawm hais tias tam sim no tseem tsis tau paub txog FPC hotspot cuam tshuam nrog qhov tshwm sim ntawm tus kab mob, qee qhov kev tshawb fawb tau sim txheeb xyuas cov qauv ntawm txoj haujlwm ntawm kev hloov pauv ntawm PKHD1 thiab qhov mob hnyav [3,6,43,46]. Kev hloov pauv hauv cheeb tsam ntawm 700-2000 amino acids ntawm FPC tau pom tias ua rau lub raum mob me me piv rau cov kev hloov pauv hauv lwm thaj tsam ntawm FPC [6,46]. Tsis tas li ntawd, cov tib neeg uas muaj kev hloov pauv nyob ib puag ncig FPC amino acids 2600-4074 tuaj yeem txhim kho lub siab phenotype [43,46]. Txawm li cas los xij, kev tshawb fawb ntxiv tam sim no xav tau los lees paub cov kev sib raug zoo no. Qhov tshwm sim tiag tiag ntawm cov kev hloov pauv ntawm cov saw-tam sim no piv rau qhov kev hloov pauv tsis zoo tam sim no tsis paub, nrog ntau qhov sib txawv ntawm cov kev tshawb fawb [3,4,6–8,38,41]. Cov kev tshawb fawb uas muaj cov neeg mob raum hnyav dua muaj feem ntau ntawm cov saw-tawm kev hloov pauv [4,7,8]. Txawm hais tias muaj kev txhim kho hauv kev kuaj caj ces ntawm cov neeg mob ARPKD, tsis yog txhua qhov kev hloov pauv tuaj yeem txheeb xyuas tau. Qee cov neeg mob ARPKD tuaj yeem muaj kev hloov pauv hauv thaj chaw intronic, cov chaw sib txuas lossis thaj chaw tswj hwm [5,10,39–42,47]. Qee tus neeg yuav muaj kev hloov pauv loj rau cov qauv ntawm PKHD1, xws li cov txheej txheem kev sib txuas lus tsis pom lawv [9,10,39]. Qhov kev kawm yuav nyuaj ntxiv los ntawm ARPKD phenocopies, kev hloov pauv hauv lwm cov noob hloov pauv lossis kev kuaj tsis raug.
Kev hloov pauv hauv DZIP1L tsuas yog raug txheeb xyuas hauv qee tus neeg uas muaj ARPKD nruab nrab [17]. Txawm hais tias lub raum tshwm sim cuam tshuam nrog kev hloov pauv hauv DZIP1L yog tus cwj pwm zoo dua, peb txoj kev nkag siab ntawm cov txiaj ntsig ntawm DZIP1L kev hloov pauv thiab lawv lub peev xwm ua rau lub siab phenotype tsis meej. Cov nas nqa cov kev hloov pauv hauv Dzip1l qhia ductal phaj malformations tab sis tsis muaj lub siab mob hnyav dua [17]. Qhov tsis muaj xws li qhov tsis xws luag tau raug pom zoo los ntawm cov nas thaum ntxov [17]. Tsis tas li ntawd, tsuas yog ib pawg me me ntawm ARPKD cov neeg mob tau tshaj tawm tias muaj kev hloov pauv hauv DZIP1L thiab ntawm pawg kawm hauv [17], tsuas yog ib tus neeg mob tau tshaj tawm lub siab tsis zoo thaum lub sijhawm kawm.
3. Phenocopies, modifier noob thiab cov toj roob hauv pes nyuaj ntawm cov kab mob mechanisms
Nws yog li ntawd los ua pom tseeb los ntawm saum toj no hais tias ib tug complex toj roob hauv pes yog tshwm sim nyob rau hauv ARPKD. ARPKD phenocopies tau raug txheeb xyuas nyob rau hauv ntau lub qauv qauv, qhov tseem ceeb tshaj plaws ntawm cov uas muaj feem xyuam nrog thaum ntxov-pib ADPKD [48–50]. Txawm li cas los xij, ADPKD tsis yog tib qho piv txwv ntawm ARPKD phenocopying, nrog Nephronophthisis, HNF-1 thiab ntau dua tsis ntev los no CYS tau tshaj tawm [48,49,51]. Tsis tas li ntawd, nws muaj peev xwm hloov pauv hauv PKHD1 rau phenocopy lwm yam ciliopathies, tshwj xeeb tshaj yog, PKHD1 kev hloov pauv tau raug tshaj tawm hauv cov neeg mob ADPKD uas tsis muaj kev hloov pauv hauv PKD1 thiab PKD2, qhia txog kev sib raug zoo ntawm ntau cov noob, kev hloov pauv uas ua rau Ciliopathies [52] , 53] ib.
Lub luag haujlwm ntawm kev hloov pauv caj ces kuj tau tshwm sim tsis ntev los no, nrog rau kev ua haujlwm los ntawm peb lub chaw kuaj mob txheeb xyuas ATMIN ua qhov hloov pauv muaj peev xwm ntawm ARPKD [23]. Admin yog DNA kev puas tsuaj teb cov protein uas tseem tuaj yeem ua raws li qhov hloov pauv [54]. ATM tau raug pom zoo los tswj cov kev qhia ntawm DYNLL1 los ntawm qhov kev tawm tswv yim tsis zoo uas ATMIN ncaj qha khi rau DYNLL1 tus txhawb nqa cheeb tsam thiab thaum DYNLL1 ncav cuag qhov pib, qhov khi ntawm DYNLL1 ncaj qha rau ATMIN inhibits ATMIN lub peev xwm los khi rau DYNLL1 txhawb nqa [5 —57]. Kev sib raug zoo ntawm ATMIN DYNLL1 tau pom tias yog qhov tseem ceeb rau kev loj hlob ntawm cov ntaub so ntswg thiab tuaj yeem ua lub luag haujlwm hauv kev tsim cilia [58]. Admin kuj tau pom tias yog ib qho tseem ceeb rau nas raum kev loj hlob los ntawm modulating Wnt signaling [59]. Admin modulation cuam tshuam rau Pkhd1 thiab cuam tshuam cov cellular proliferation thiab adhesion, ua rau cov tsis-canonical Wnt/Planar Cell Polarity (PCP) signaling hauv ARPKD [23]. Cov txheej txheem ntawm Admin-Pkhd1 kev sib cuam tshuam yuav cuam tshuam cov caj ces lossis lwm yam kev sib cuam tshuam ntawm cov protein sib cuam tshuam lossis cov txheej txheem kev hloov pauv / txhais lus vim Admin tsis ncaj qha khi rau C-terminus ntawm Fibrocystin [23]. Tus AtminGpg6 nas, uas phenocopies ARPKD los ntawm kev nthuav tawm lub raum, daim siab thiab lub ntsws phenotype tuaj yeem ua pov thawj cov cuab yeej muaj txiaj ntsig hauv kev nkag siab zoo dua cov kab mob thiab lub luag haujlwm ntawm cov tshuaj hloov caj ces hauv ARPKD [23,58,59]. Nws yuav tsum raug sau tseg tias nyob rau hauv cov qauv tsiaj cov keeb kwm yav dhau los kuj tshwm sim los cuam tshuam rau cystic raum mob hnyav [60], yog li ua rau kev txhais cov ntsiab lus nyuaj. HNF-1 yog lwm tus neeg sib tw hloov pauv noob hauv ARPKD uas tuaj yeem ua rau mob ntshav qab zib thaum ntxov ntawm cov menyuam yaus (MODY5) thiab kev loj hlob ntawm lub raum hauv lub raum thiab tuaj yeem phenocopy ARPKD [48,49]. Tsis tas li ntawd, cov nas transgenic nrog kev hloov pauv hauv Hnf1 tsim cov kab mob hauv lub raum thiab Hnf1 tau pom tias yuav tswj hwm Pkhd1 [61,62]. Kev poob ntawm Hnf1 los yog nws C-terminus ua rau downregulation ntawm Pkhd1 nyob rau hauv transgenic nas, hais txog qhov zoo sib xws nyob rau hauv lub molecular txoj kev ntawm lub raum cyst tsim nyob rau hauv ob yam kab mob [61,62].
Tsis tas li ntawd, ntau txoj hauv kev taw qhia tau raug txheeb xyuas kom tsis raug cai hauv ARPKD thiab cov no tau raug tshuaj xyuas zoo hauv [14,23,63]. Peb tus kheej txoj haujlwm tau nthuav tawm lub luag haujlwm tseem ceeb rau qhov tsis yog-canonical Wnt / PCP signaling hauv ARPKD [23]. Qhov tseem ceeb nce WNT5A, VANGL2 thiab SCRIBBLE qhia tau pom nyob rau hauv ARPKD ob lub raum piv rau cov hnub nyoog-matched noj qab haus huv tswj, uas ua ke nrog ib tug striking nce nyob rau hauv E-cadherin, taw tes rau lub luag hauj lwm tseem ceeb ntawm non-canonical Wnt signaling nyob rau hauv ARPKD. Kev ua haujlwm ntxiv tam sim no tau ua tib zoo txheeb xyuas cov haujlwm no thiab txiav txim siab cov txheej xwm hierarchy.
cistanche testosterone: kho mob raum
4. Cov lus xaus
Raws li ARPKD yog ib yam kab mob tsis tshua muaj nrog cov txheej txheem sib txawv thiab muaj ntau hom kab mob thiab kab mob sib txawv ntawm cov pej xeem, nws yog ib qho tseem ceeb uas tsim tau zoo thiab tswj xyuas cov kev tshawb fawb ntev, kom muaj peev xwm ua kom tiav cov kab mob thiab cuam tshuam rau kev kuaj mob, prognosis, thiab kev kho mob. ARPKD tsiaj qauv tuaj yeem pab tau zoo hauv cov kev taw qhia no txawm hais tias, rau lub sijhawm no, tsis muaj ib tus qauv tsiaj uas tau rov qab ua tiav ARPKD, txhais tau hais tias cov qauv no tsis muaj nuj nqis hauv kev qhia txog kab mob, lawv daim ntawv thov yuav tsum tau sim hauv tib neeg kev tshawb fawb. Txawm hais tias nws ntseeg tau tias tsis muaj qhov tseem ceeb ntawm poj niam txiv neej lossis haiv neeg kev tsis ncaj ncees hauv ARPKD, kev tshawb fawb nrog ntau tus neeg thiab ntau haiv neeg ntawm cov neeg koom yuav tsum tau ua rau cov lus nug no kom teb tau meej. Qhov tshwm sim ntau zuj zus ntawm kev sau npe hauv tebchaws thiab thoob ntiaj teb rau cov kab mob tsawg tuaj yeem pab txuas qhov sib txawv no hauv kev sau cov ntaub ntawv thiab nws tseem tuaj yeem pab tsim cov kev tshawb fawb ntev uas qhia txog ARPKD prognosis thiab pab nrog cov tshuaj kho tus kheej. Cov ntaub ntawv khaws tseg rau kev sau npe thiab biobanks tseem yuav tsum yog homogeneous thiab muaj txiaj ntsig zoo sib xws kom nws ua raws li cov qauv uas tuaj yeem tso cai rau kev sib faib cov ntaub ntawv thiab kev sib koom ua ke ntawm cov ntaub ntawv no. Qhov tseem ceeb tshaj plaws yuav tsum tau muab tso rau hauv kev sib koom tes hauv thiab thoob plaws lub teb chaws thiab cov teb chaws, thiaj li muaj peev xwm sib txuas tag nrho cov ntaub ntawv ntawm ARPKD thiab ua tiav lub zog ntawm cov lej uas tsis tshua muaj kab mob xav tau. Kev paub txog kev hloov pauv los ntawm lwm cov kab mob tsis tshua zoo sib xws xws li Nephronophthisis, tuaj yeem ua kom muaj kev nkag siab zoo ntawm cov kab mob thiab txo qis kev kuaj mob. Qhov tseem ceeb tseem ceeb kuj tseem yuav raug muab rau cov neeg kwv yees txog kev kis kab mob thiab kev txheeb xyuas cov biomarkers tshiab uas tuaj yeem qhia tsis yog ARPKD kev loj hlob nkaus xwb tab sis kuj kho. Muaj ntau yam teeb meem cuam tshuam nrog kev ua haujlwm ntawm cov kab mob tsawg, txawm li cas los xij, lub suab pib hauv av tau ua tiav hauv ARPKD thiab nrog kev sib koom ua ke, strides hauv ARPKD kuaj mob, kev kuaj mob thiab kev kho mob yuav pom zoo.
Tshaj tawm ntawm kev sib tw txaus siab
Taylor Richards qhia txog kev txhawb nqa nyiaj txiag yog muab los ntawm PKD kev siab hlub UK. Paraskevi Goggolidou qhia txog kev txhawb nqa nyiaj txiag yog muab los ntawm PKD Charity UK. Paraskevi Goggolidou qhia txog kev txhawb nqa nyiaj txiag tau muab los ntawm Lub Tsev Haujlwm ntawm Biomedical Science.
Kev lees paub
PG thiab TR tau txais nyiaj los ntawm PKD kev siab hlub UK (grant ref: S Los ntawm: 'Cov caj ces ntawm Autosomal Recessive Polycystic raum Kab Mob' los ntawmParaskevi Goggolidou *, Taylor Richards ---BBA - Molecular Basis of Disease 1868 (2022) 166348