ʻO ke kila kila 347 / 347H Welded coil Tubes zhemical component, ʻO ke kuleana o ka dystrophin glycoprotein complexes i ka mechanotransduction o nā ʻiʻo ʻiʻo.

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ʻO Dystrophin ka protein nui o ka dystrophin-glycoprotein complex (DGC) i loko o ka ʻiʻo iwi a me nā cardiomyocytes.Hoʻopaʻa ʻo Dystrophin i ka cytoskeleton actin i ka matrix extracellular (ECM).ʻO ka haki ʻana o ka pilina ma waena o ka matrix extracellular a me ka cytoskeleton intracellular hiki ke loaʻa nā hopena pōʻino no ka homeostasis o nā ʻiʻo muscular skeletal, e alakaʻi ana i kekahi mau muscular dystrophies.Eia kekahi, ʻo ka nalowale o nā DGC hana e alakaʻi i ka cardiomyopathy holomua holomua a me ka make mua.Hana ʻo Dystrophin ma ke ʻano he pūnāwai molekula a he mea nui ka DHA i ka mālama ʻana i ka pono o ka sarcolemma.Eia kekahi, ke hōʻiliʻili nei nā hōʻike e pili ana i ka DGC i ka hōʻailona mechanistic, ʻoiai ʻaʻole maopopo ʻole kēia kuleana.Ke manaʻo nei kēia ʻatikala loiloi e hāʻawi i kahi ʻike hou o DGC a me kā lākou kuleana i ka mechanotransduction.Kūkākūkā mua mākou i ka pilina paʻakikī ma waena o nā mechanics cell muscle a me ka hana, a laila e nānā i ka noiʻi hou e pili ana i ke kuleana o ka dystrophin glycoprotein complex i ka mechanotransduction a me ka mālama ʻana i ka pono biomechanical cell muscle.ʻO ka mea hope loa, ke nānā nei mākou i nā puke o kēia manawa e hoʻomaopopo i ke ʻano o ka hoʻopili ʻana o ka hōʻailona DGC me nā ala mechanosignaling e hōʻike i nā wahi e hiki mai ana, me ka nānā pono ʻana i ka cardiomyopathy.
Ke kamaʻilio mau nei nā kelepona me ko lākou microenvironment, a he mea pono ke kamaʻilio ʻelua ala ma waena o lākou no ka wehewehe ʻana a me ka hoʻohui ʻana o ka ʻike biomechanical.Mālama ʻo Biomechanics i nā hanana nui ma hope (e laʻa, cytoskeletal rearrangements) ma ke kaohi ʻana i ka phenotype cellular holoʻokoʻa i ka lewa a me ka manawa.ʻO ke kikowaena o kēia kaʻina hana i loko o ka cardiomyocytes ka ʻāina kumu kūʻai, ka ʻāina kahi e hoʻopili ai ka sarcolemma i kahi sarcomere i haku ʻia me nā paʻakikī integrin-talin-vinculin a me dystrophin-glycoprotein (DGC).Hoʻopili ʻia i ka cytoskeleton intracellular, hoʻolaha kēia mau mea hoʻopili kikoʻī (FAs) i kahi cascade o nā hoʻololi cellular biomechanical a biochemical e hoʻomalu i ka ʻokoʻa, proliferation, organogenesis, migration, holomua maʻi, a me nā mea hou aku.ʻO ka hoʻololi ʻana o nā mana biomechanical i loko o ka biochemical a/a i ʻole (epi) hoʻololi genetic i kapa ʻia ʻo mechanotransduction1.
Ua ʻike lōʻihi ʻia ka integrin transmembrane receptor 2 e hoʻopaʻa i ka matrix extracellular i loko o nā cell a hoʻopaʻa i ka hōʻailona o loko a me waho.I ka like me nā integrins, hoʻopaʻa nā DGC i ka ECM i ka cytoskeleton, e hoʻokumu i kahi loulou koʻikoʻi ma waena o waho a me loko o ka cell3.Hōʻike mua ʻia ka dystrophin lōʻihi piha (Dp427) i loko o ka puʻuwai a me ka ʻiʻo iwi, akā ʻike pū ʻia i loko o nā ʻiʻo o ka ʻōnaehana nerve waena, me ka retina a me ka kiko Purkinje4.ʻO nā hoʻololi i loko o nā integrins a me DGC i manaʻo ʻia ʻo ia nā kumu o ka muscular dystrophy a me ka progressive dilated cardiomyopathy (DCM) (Table 1)5,6.ʻO ka mea nui, nā hoʻololi DMD e hoʻopili ana i ka pūmua dystrophin waena DGC ke kumu o Duchenne muscular dystrophy (DMD)7.Hoʻokumu ʻia ka DGC i kekahi mau subcomplexes me α- a me β-dystroglycan (α/β-DG), sarcoglycan-spanin, dystrophin, a me dystrophin 8.
ʻO Dystrophin kahi protein cytoskeletal i hoʻopaʻa ʻia e DMD (Xp21.1-Xp22) e pāʻani ana i kahi kuleana nui i ka mālama ʻana i ka DGC.Mālama ʻo DGC i ka pono o ka sarcolemma, ka membrane plasma o ka ʻiʻo ʻiʻo striated.Hoʻemi hou ʻo Dystrophin i ka pōʻino i hoʻokumu ʻia e ka ʻoki ʻana ma o ka hana ʻana ma ke ʻano he pūnāwai molecular a me ka scaffold molekula9,10.Loaʻa i ka dystrophin piha ka lōʻihi he 427 kDa, akā naʻe, ma muli o ka nui o nā mea hoʻolaha kūloko i DMD, aia kekahi mau isoforms ʻoki maoli ʻia, me Dp7111.
Ua hōʻike ʻia nā protein accessory i localized i dystrophin, me nā mechanotransducers ʻoiaʻiʻo e like me neuronal nitric oxide synthase (nNOS), Yes-associated protein (YAP), a me caveolin-3, no laila e hōʻike ana i nā mea nui o ka hōʻailona kelepona.Nā hui 12, 13, 14. Ma waho aʻe o ka hoʻopili ʻana, kahi mīkini cellular e pili ana i ka pilina ma waena o nā cell a me ka matrix, i hana ʻia e nā integrins a me kā lākou mau pahuhopu i lalo, ʻo kēia mau mea paʻakikī ʻelua e hōʻike ana i ka pilina ma waena o ka "loko" a me "waho" o ke kelepona. .He mea koʻikoʻi ka pale ʻana i kēia mau hoʻopili kikoʻī mai ka luku ʻole ʻia i ke ʻano o ke kelepona a me ke ola.Eia kekahi, kākoʻo ka ʻikepili i ka dystrophin he modulator o nā kaila ion mechanosensitive, e komo pū ana i nā kahawai i hoʻāla ʻia, ʻoi aku ka L-type Ca2 + a me nā ala TRPC 15.
ʻOiai he mea koʻikoʻi ka dystrophin no ka hana homeostatic o nā puʻupuʻu ʻiʻo striated, ʻaʻole maopopo loa nā mīkini kākoʻo pololei, ʻoi aku ka hana o ka dystrophin a me kona hiki ke hana ma ke ʻano he mechanosensor a me ka pale mechanical.Ma muli o ka nalowale o ka dystrophin, ua ala mai kekahi mau nīnau i pane ʻole ʻia, e like me: ua kuhi hewa ʻia nā protein mechanosensitive e like me YAP a me AMPK i ka sarcolemma;Aia nā kamaʻilio cross me nā integrins, nā kūlana e hiki ke alakaʻi i ka mechanotransduction maʻamau?Hiki i kēia mau hiʻohiʻona ke kōkua i ka phenotype DCM koʻikoʻi i ʻike ʻia i nā maʻi me DMD.
Eia kekahi, ʻo ka hui ʻana o nā hoʻololi i nā biomechanics cellular me ka phenotype DMD holoʻokoʻa he mau hopena koʻikoʻi koʻikoʻi.ʻO DMD kahi muscular dystrophy pili X e pili ana i nā kāne 1: 3500-5000, i hōʻike ʻia e ka nalo mua o ka neʻe (<5 mau makahiki) a me ka DCM holomua me kahi prognosis ʻoi aku ka maikaʻi ma mua o DCM o nā etiologies16,17,18.
ʻAʻole i wehewehe piha ʻia ka biomechanics o ka nalowale o ka dystrophin, a ma ʻaneʻi mākou e nānā i nā hōʻike e kākoʻo ana i ka manaʻo he hana maoli ka dystrophin i kahi hana mechanoprotective, ʻo ia hoʻi ka mālama ʻana i ka pono o ka sarcolemma, a he mea koʻikoʻi i ka mechanotransduction.Eia hou, ua nānā mākou i nā hōʻike e hōʻike ana i ka crosstalk koʻikoʻi me nā integrins, e hoʻopaʻa pono ana i ka laminin α7β1D i loko o nā puʻupuʻu muscle striated.
ʻO ka hoʻokomo ʻana a me ka holoi ʻana ke kuleana no ka nui o nā hoʻololi ʻana ma DMD, me 72% o nā hoʻololi ʻana i hoʻokumu ʻia e ia mau hoʻololi.ʻO ka maʻi maʻi, hōʻike ʻo DMD i ka wā kamaliʻi (≤5 mau makahiki) me ka hypotension, hōʻailona maikaʻi o Gower, lohi i ka holomua o nā hoʻololi pili makahiki, hiki i ka noʻonoʻo, a me ka atrophy ʻiʻo iwi.ʻO ka pilikia hanu i ka wā kahiko ke kumu nui o ka make i nā maʻi DMD, akā ʻoi aku ka maikaʻi o ka mālama ʻana i ke kākoʻo (corticosteroids, hoʻomau mau ʻana i ke ea ea maikaʻi) ua hoʻonui i ke ola o kēia mau maʻi, a ʻo ka makahiki waena o nā maʻi DMD i hānau ʻia ma hope o 1990 he 28.1 makahiki 20 ,21 ..Eia naʻe, i ka piʻi ʻana o ke ola o ka mea maʻi, ʻoi aku ka ʻino o ka prognosis o ka holomua DCM i ka hoʻohālikelike ʻia me nā cardiomyopathies16 ʻē aʻe, e alakaʻi ana i ka pau ʻole o ka naʻau, ʻo ia ke kumu nui o ka make, e helu ana ma kahi o 50% o DMD deaths17,18.
Hōʻike ʻia ka Progressive DCM e ka hoʻonui ʻana i ka ventricular dilatation hema a me ka hoʻokō ʻana, ventricular thinning, hoʻonui i ka fibrofatty infiltration, hoʻemi i ka hana systolic, a me ka hoʻonui pinepine ʻana o nā arrhythmias.ʻO ka degere o ka DCM i nā maʻi me DMD ua aneane āpau i ka hopena o ka wā ʻōpio (90% a i 18 mau makahiki), akā aia ma kahi o 59% o nā maʻi ma o 10 mau makahiki o ka makahiki8,22.He mea koʻikoʻi ka hoʻoponopono ʻana i kēia pilikia no ka mea ke emi mau nei ka haʻihaʻi ejection ventricular hema ma kahi o 1.6% i kēlā me kēia makahiki23.
He mea maʻamau ka arrhythmias puʻuwai i nā poʻe maʻi me DMD, ʻoi aku ka nui o ka tachycardia sinus a me ka tachycardia ventricular, a ʻo ia ke kumu o ka make puʻuwai koke22.ʻO Arrhythmias ka hopena o ka fibrofatty infiltration, ʻoi loa i ka subbasal left ventricle, e hōʻino ana i ka circuitry hoʻihoʻi a me ka [Ca2 +] i hoʻoponopono i ka dysfunction a me ka ion channel dysfunction24,25.He mea koʻikoʻi ka ʻike ʻana i ka hōʻike ʻana o ka naʻau lapaʻau, no ka mea, hiki i nā hoʻolālā lapaʻau mua ke hoʻopaneʻe i ka hoʻomaka ʻana o ka DCM koʻikoʻi.
Hōʻike ʻia ke koʻikoʻi o ka mālama ʻana i ka maʻi maʻi puʻuwai a me ka maʻi ʻiʻo o ka iwi i loko o kahi noiʻi hoihoi i hoʻohana i kahi kiʻi kiʻi o DMD i kapa ʻia ʻo mdx26 e aʻo ai i nā hopena o ka hoʻomaikaʻi ʻana i ka ʻiʻo ʻiʻo ʻiʻo me ka ʻole o ka hoʻoponopono ʻana i nā pilikia naʻau i loaʻa ma DMD.Maʻaneʻi, ua hōʻike nā mea kākau i ka piʻi ʻana o ka 5-fold paradoxical i ka maʻi maʻi maʻi ma hope o ka hoʻomaikaʻi ʻana i ka ʻiʻo iwi, a ua hōʻemi nui nā ʻiole i ka fraction ejection26.ʻO ka hoʻomaikaʻi ʻana i ka hana o ka ʻiʻo iwi e hiki ai i ka hoʻoikaika kino kino ke hoʻonui i ke koʻikoʻi ma ka myocardium, e maʻalahi ai i ka hana maʻamau.Hōʻike kēia i ke koʻikoʻi o ka mālama ʻana i nā poʻe maʻi DMD ma ke ʻano ākea a me ka mālama ʻana i ka lāʻau ʻiʻo ʻiʻo wale nō.
Hana nā DGC i kekahi mau hana ʻē aʻe, ʻo ia hoʻi, hāʻawi i ka paʻa i ka sarcolemma, lilo i scaffold molecular e hana ma ke ʻano he loulou hōʻailona, ​​​​e hoʻoponopono i nā kaila ion mechanosensitive, ke kumu o ka mechanotransduction costal, a komo i ka hoʻoili ʻana o ka ikaika lateral i ka ʻāina o ka iwi ʻaoʻao (Fig. 1b)..He kuleana koʻikoʻi ka Dystrophin i kēia hiki, a ma muli o ka nui o nā mea hoʻolaha i loko, aia kekahi mau isoforms like ʻole, e pāʻani ana kēlā me kēia i kahi ʻano ʻokoʻa i nā ʻāpana like ʻole.Kākoʻo ka hōʻike ʻokoʻa ʻokoʻa o nā isoform dystrophin like ʻole i ka manaʻo he hana ʻokoʻa kēlā me kēia isoform.No ka laʻana, hōʻike ka ʻiʻo puʻuwai i ka lōʻihi piha (Dp427m) a me ka isoform Dp71m pōkole o ka dystrophin, ʻoiai ʻo ka ʻiʻo iwi wale nō e hōʻike i ka mua o nā mea ʻelua.ʻO ka nānā ʻana i ke kuleana o kēlā me kēia subtype hiki ke hōʻike i kāna hana physiological wale nō, akā i ka pathogenesis o ka muscular dystrophy.
Hōʻike schematic o ka dystrophin lōʻihi piha (Dp427m) a me ka mea liʻiliʻi, ʻoki ʻia Dp71 isoform.ʻO Dystrophin he 24 spectrin hou i hoʻokaʻawale ʻia e ʻehā mau puka lou, a me kahi domain-binding domain (ABD), kahi waihona waiwai cysteine ​​​​(CR), a me kahi C-terminus (CT).Ua ʻike ʻia nā hoa paʻa koʻikoʻi, me nā microtubules (MTs) a me ka sarcolemma.Nui nā isoforms o Dp71, ʻo Dp71m e pili ana i ka ʻiʻo ʻiʻo a ʻo Dp71b e pili ana i ka isoform o ke kino.ʻO ka mea kūikawā, pili ka Dp71f i ka isoform cytoplasmic o nā neurons.b Aia ka dystrophin-glycoprotein complex (DHA) i loko o ka sarcolemma holoʻokoʻa.Hoʻololi nā mana biomechanical ma waena o ECM a me F-actin.E hoʻomaopopo i ka hiki ke kamaʻilio ma waena o nā DGC a me ka integrin adhesion, hiki i ka Dp71 ke pāʻani i kahi kuleana i nā adhesions focal.Hana ʻia me Biorender.com.
ʻO DMD ka maʻi muscular dystrophy maʻamau a ma muli o nā hoʻololi i DMD.Eia nō naʻe, no ka mahalo piha ʻana i kā mākou ʻike i kēia manawa i ka hana o ka anti-dystrophin, he mea nui ia e kau i loko o ka pōʻaiapili o DGC holoʻokoʻa.No laila, e wehewehe pōkole ʻia nā protein constituent ʻē aʻe.Ua hoʻomaka ʻia ke aʻo ʻia ʻana o ka pūmua o DGC i ka hopena o 1980s, me ka nānā pono ʻana i ka dystrophin.Ua hana ʻo Koenig27,28, Hoffman29 a me Ervasti30 i kahi ʻike koʻikoʻi ma o ka ʻike ʻana i ka dystrophin, he protein 427 kDa i loko o ka muscle striated31.
Ma hope mai, ua hōʻike ʻia nā subcomplexes ʻē aʻe e pili ana i ka dystrophin, me ka sarcoglycan, ka dystrophin transmembrane subcomplex, dysbrevin, a me syntrophins8, i hui pū ʻia i ke ʻano DGC o kēia manawa.E hoʻolaha mua kēia ʻāpana i nā hōʻike no ke kuleana o ka DGC i ka ʻike mechanosensory oiai e nānā pono ana i nā ʻāpana pākahi.
ʻO ka isoform dystrophin holoʻokoʻa i loaʻa i loko o ka ʻiʻo ʻiʻo striated ʻo Dp427m (e like me "m" no ka ʻiʻo e hoʻokaʻawale iā ia mai ka lolo) a he ʻano protein nui i ke ʻano o ke koʻokoʻo me ʻehā mau kikowaena hana i loaʻa ma lalo o ka cardiomyocyte sarcolemma, ʻoi aku ma ka ʻāina costal. 29, 32. Dp427m, i hoʻopili ʻia e ka DMD gene ma Xp21.1, he 79 exons i hana ʻia ma 2.2 megabases a no laila ʻo ia ka gene nui loa i kā mākou genome8.
Hoʻopuka kekahi mau mea hoʻolaha kūloko i DMD i nā isoforms dystrophin i kālai ʻia, ʻo kekahi o ia mau kiko kikoʻī.Hoʻohālikelike ʻia me Dp427m, ʻoki nui ʻia ʻo Dp71m a nele i kahi kikowaena spectrin repeat domain a i ʻole N-terminal ABD domain.Eia nō naʻe, paʻa ʻo Dp71m i ka ʻōnaehana paʻa C-terminal.I ka cardiomyocytes, ʻaʻole maopopo ka hana o Dp71m, akā ua hōʻike ʻia i ka localize ma T tubules, e hōʻike ana e kōkua paha ia i ka hoʻoponopono ʻana i ka hoʻohui ʻana o ka excitation-contraction 33,34,35.I ko mākou ʻike, ʻo ka loaʻa hou ʻana o Dp71m i loko o ka ʻiʻo cardiac ua loaʻa iki ka nānā ʻana, akā ke hōʻike nei kekahi mau haʻawina e pili ana ia me nā kahawai ion stretch-activated, a ua manaʻo ʻo Masubuchi e pāʻani paha ia i ka hoʻoponopono o nNOS33., 36. I ka hanaʻana pēlā, ua loaʻa iā Dp71 ka nānā nuiʻana i ka neurophysiology a me ka noiʻi platelet, nā wahi e hiki ai ke hāʻawi i kaʻike i kahi hana i loko o ka cardiomyocytes37,38,39.
I loko o ke kino nūnū, ua hōʻike nui ʻia ka Dp71b isoform, me 14 isoforms i hōʻike ʻia38.ʻO ka holoi ʻana i ka Dp71b, kahi mea hoʻoponopono koʻikoʻi o ka aquaporin 4 a me Kir4.1 potassium channel i loko o ka ʻōnaehana nūnū waena, ua hōʻike ʻia e hoʻololi i ka permeability pale koko-lolo40.Hāʻawi ʻia i ke kuleana o Dp71b i ka hoʻoponopono ion channel, hiki i ka Dp71m ke pāʻani like i ka cardiomyocytes.
ʻO ka loaʻa ʻana o DGC i loko o nā ganglia costal e hōʻike koke i kahi hana i ka mechanotransduction, a ʻoiaʻiʻo ua hōʻike ʻia e hui pū me ka integrin-talin-vinculin complexes 41.Eia kekahi, hāʻawi ʻia ʻo ka ʻāpana costal ka mea nui o ka transverse mechanotransduction, ʻo ka localization o Dp427m ma aneʻi e hōʻike ana i kāna kuleana i ka pale ʻana i nā cell mai ka pōʻino i hoʻoiho ʻia.Eia kekahi, pili pū ʻo Dp427m me actin a me ka cytoskeleton microtubule, a laila hoʻopau i ka pilina ma waena o ka intracellular environment a me ka extracellular matrix.
ʻO ka N-terminus i loaʻa ka actin-binding domain 1 (ABD1) he ʻelua calmodulin homology domains (CH) i koi ʻia no ka launa pū ʻana me F-actin a hoʻopaʻa i ka isoform γ-actin i ka sarcolemma42,43.Hiki i ka Dystrophin ke kōkua i ka viscoelasticity holoʻokoʻa o ka cardiomyocytes ma o ka hoʻopili ʻana i ka cytoskeleton subsarcolemmal, a ʻo kona localization i ka ganglia costal e kākoʻo i kona komo ʻana i ka mechanotransduction a me ka mechanoprotection44,45.
Aia i loko o ke kikowaena kikowaena he 24 spectrin-like repeat proteins, ʻo kēlā me kēia mea he 100 mau koena amino acid ka lōʻihi.Hoʻopili ʻia ka spectrin repeats me ʻehā mau hinge domain, e hāʻawi ana i ka maʻalahi o ka protein a me kahi kiʻekiʻe o ka extensibility.Hiki ke wehe hou i ka Dystrophin spectrin i loko o ka physiological range of forces (15-30 pN) e hoʻonui ana mai 21 nm a 84 nm, hiki ke loaʻa nā ikaika no ka hoʻemi ʻana o ka myosin 46.ʻO kēia mau hiʻohiʻona o ka spectrin repeat domain e ʻae i ka dystrophin e hana ma ke ʻano he molecular shock absorber.
ʻO ke koʻokoʻo waena o Dp427m e hōʻoia i kona localization i ka sarcolemma, ma ke ʻano, ma o ka hydrophobic a me nā pilina electrostatic me phosphatidylserine 47,48.ʻO ka mea e mahalo ai, ʻokoʻa ke ʻano o ke kikowaena o ka dystrophin me ka sarcolemma phospholipids i loko o nā ʻiʻo iwi a me ka puʻuwai, e hōʻike ana paha i nā ʻano punawai like ʻole.koʻikoʻi, ʻoiai ua pili pū nā ʻiʻo iwi me R10-R1249.
ʻO ka hoʻopaʻa ʻana i ka cytoskeleton γ-actin e koi i ka ABD2 spectrin e hana hou i ka ʻāpana 11-17, nona nā koena amino acid kumu a ʻokoʻa mai ka F-actin-binding CH domain.Hoʻopili pololei nā Microtubules me ke kikowaena kumu o ka dystrophin, pono kēia pilina i ke koena o ka spectrin e hana hou i ka 4-15 a me 20-23, a pono ke alo o ankyrin B e pale i ka hoʻokumu ʻana o nā microtubules ma kēia pūnaewele.ʻAʻole loaʻa nā paipu 50,51,52.Ua hōʻike ʻia kahi āpau ma waena o nā microtubules a me dystrophin e hoʻonui i ka pathology DMD ma o ka hoʻonui ʻana i nā ʻano oxygen reactive (X-ROS).
ʻO ka CR domain ma o ankyrin B kekahi heleuma no sarcolemmal phospholipids52.Pono ʻo Ankyrin-B a me ankyrin-G no ka hoʻokaʻawale ʻana i nā iwi ʻaoʻao o ka dystrophin / DGC, a ʻo kā lākou haʻalele ʻana e hopena i kahi ʻano sarcolemmal diffuse o DGC52.
Aia i loko o ka waihona CR kahi kāʻei hoʻopaʻa WW e pili pono ana me ke kumu paʻa PPxY o β-DG.Ma ka hoʻopili ʻana i ka complex dystrophin-glycan, hoʻopau ka dystrophin i ka loulou ma waena o loko a me waho o ka cell54.He mea koʻikoʻi kēia pilina no ka ʻiʻo striated, e like me ka mea i hōʻike ʻia e ka hoʻopau ʻana i ka pilina ma waena o ka ECM a me ka loko o ka cell e alakaʻi i ke ola-limiting muscular dystrophy.
ʻO ka hope loa, ʻo ka CT domain kahi ʻāina i mālama nui ʻia e hana i kahi helix coiled a koʻikoʻi no ka hoʻopaʻa ʻana i ka α-dystrobrevin a me α1-,β1-syntrophins55,56.Hoʻopili ʻo α-dystrobrevin i ka CT domain o dystrophin a hāʻawi i ke kū'ē hou aku i ka dystrophin i ka sarcolemma57.
I ka wā o ka ulu ʻana o ka embryonic a me ka fetal, ua hōʻike nui ʻia ʻo Utrophin i loko o nā ʻiʻo like ʻole, me nā pūnaewele endothelial, ʻiʻo nerve, a me ka ʻiʻo ʻiʻo striated58.Hōʻike ʻia ʻo Utrophin e UTRN aia ma ka chromosome 6q a he dystrophin autolog me 80% protein homology.I ka wā o ka hoʻomohala ʻana, ʻike ʻia ka utrophin i loko o ka sarcolemma akā ua hoʻopaʻa ʻia i loko o ka ʻiʻo ʻiʻo striated postnatal, kahi i pani ʻia e dystrophin.Ma hope o ka hānau ʻana, ua kaupalena ʻia ka localization o ka utrophin i nā tendons a me nā neuromuscular junctions o nā ʻiʻo skeletal58,59.
ʻO nā hoa paʻa Utrophin e like like me nā dystrophins, ʻoiai ua wehewehe ʻia kekahi mau ʻokoʻa nui.No ka laʻana, pili ka dystrophin me β-DG ma o kāna kikowaena WW, kahi i hoʻopaʻa ʻia e ka ZZ domain (i kapa ʻia no kona hiki ke hoʻopaʻa i ʻelua mau ion zinc) i loko o kāna wahi CT, kahi i koʻikoʻi nui ai nā koena cysteic acid 3307-3354 no kēia launa. ., 61. Hoʻopili pū ʻo Utrophin i ka β-DG ma o ka WW / ZZ domain, akā ʻokoʻa nā koena kikoʻī e kākoʻo ana i kēia pilina me nā koena dystrophin (3307-3345 i ka dystrophin a me 3064-3102 i ka utrophin) 60,61.ʻO ka mea nui, ʻo ka hoʻopaʻa ʻana o ka utrophin i β-DG ma kahi o 2-fold ka haʻahaʻa ma mua o ka dystrophin 61. Ua hōʻike ʻia ʻo Dystrophin e hoʻopaʻa iā F-actin ma o spectrin repeats 11-17, ʻoiai ʻaʻole hiki i nā pūnaewele like i ka utrophin ke hoʻopaʻa iā F-actin, ʻoiai ma ka nā manaʻo kiʻekiʻe, akā hiki ke launa pū ma o kā lākou CH-domain.Hana 62,63,64.ʻO ka hope, ʻaʻole e like me ka dystrophin, ʻaʻole hiki i ka utrophin ke hoʻopaʻa i nā microtubules51.
Biomechanically, utrophin spectrin repeats loaʻa kahi hiʻohiʻona wehe ʻokoʻa i hoʻohālikelike ʻia me dystrophin65.Hoʻopuka hou ʻo Utrophin-spectrin i ka hoʻolālā ʻana i nā ikaika kiʻekiʻe, e like me titin akā ʻaʻole dystrophin65.Kūlike kēia me kona wahi a me kāna kuleana i ka hoʻoili ʻana i ka ikaika elastic elastic ma nā hui tendon, akā hiki ke hoʻolilo i ka utrophin i mea kūpono ʻole e hana ma ke ʻano he pūnāwai molekula i nā pūʻali pale i hoʻoulu ʻia e ka ʻoki ʻana 65.Hoʻohui pū ʻia, hōʻike kēia mau ʻikepili e hiki ke hoʻololi ʻia nā mana mechanotransduction a me ka mechanobuffering i mua o ka overexpression utrophin, ʻoi aku ka hāʻawi ʻana i nā hoa paʻa like ʻole / mechanisms, akā naʻe pono kēia i kahi noiʻi hoʻokolohua hou.
Mai kahi hiʻohiʻona o ka hana, ʻo ka manaʻo o ka utrophin e loaʻa nā hopena like me ka dystrophin e lilo ia i mea lapaʻau kūpono no DMD66,67.ʻO kaʻoiaʻiʻo, ua hōʻike ʻia kekahi mau maʻi DMD i ka overexpress utrophin, ma ke ʻano he hana hoʻopiʻi, a ua hoʻihoʻi maikaʻi ʻia ka phenotype i kahi kiʻi kiʻi me ka utrophin overexpression 68.ʻOiai ʻo ka upregulation o ka utrophin he hoʻolālā lapaʻau paha, ʻo ka noʻonoʻo ʻana i ka ʻokoʻa maʻamau a me ka hana ma waena o ka utrophin a me ka dystrophin a me ka pono o ka hoʻoulu ʻana i kēia overexpression me ka localization kūpono ma ka sarcolemma ʻaʻole maopopo ka hoʻolālā lōʻihi o ka utrophin.ʻO ka mea nui, hōʻike nā mea lawe wahine i kahi ʻano mosaic o ka hōʻike utrophin, a ʻo ka ratio ma waena o ka dystrophin a me ka utrophin hiki ke hoʻololi i ka degere o ka cardiomyopathy dilated i kēia mau maʻi, 69 ʻoiai ua hōʻike ʻia nā hiʻohiʻona murine o nā mea lawe..
ʻO ka subcomplex dystroglycan he ʻelua mau protein, α- a me β-dystroglycan (α-, β-DG), i unuhi ʻia mai ka gene DAG1 a laila hoʻokaʻawale ʻia ma hope o ka unuhi ʻana i ʻelua mau protein 71.ʻO ka α-DG ka glycosylated nui i kaʻaoʻao extracellular o DGCs a pili pono me nā koena proline i ka laminin α2 a me ka agrin72 a me ka picaculin73 a me ka CT / CR māhele o dystrophin73,74,75,76.ʻO ka glycosylation i hoʻopili ʻia, ʻoi aku ka nui o nā koena serine, koi ʻia no kāna pilina me ka ECM.Aia i loko o ke ala glycosylation ka nui o nā enzyme nona nā hoʻololi e alakaʻi ai i ka muscular dystrophy (e nānā pū i ka Papa 1).Hoʻopili kēia i ka O-mannosyltransferase POMT2, fucutin a me fucutin-related protein (FKRP), ʻelua ribitol phosphotransferases e hoʻohui i nā tandem ribitol phosphates i ka glycan kumu, a me ka protein LARGE1 e hoʻohui i ka xylose a me ka glucose.Linear uronic acid polysaccharide, i ʻike ʻia ʻo ka matrix glycan ma ka hope o ka glycan77.Hoʻokomo pū ʻia ʻo FKRP i ka hoʻomohala ʻana a me ka mālama ʻana i ka ECM, a ʻo ka hoʻololi ʻana i loko e alakaʻi i ka hōʻemi ʻana o ka laminin α2 a me α-DG77,78,79.Eia hou, hiki i ka FKRP ke alakaʻi i ka hoʻokumu ʻana o ka lamina basal a me ka matrix extracellular cardiac ma o ka glycosylated fibronectin 80.
Loaʻa i ka β-DG kahi kumu hoʻopaʻa PPxY e hoʻopaʻa pono a hoʻopaʻa iā YAP12.He ʻike hoihoi kēia no ka mea e hōʻike ana ʻo DGC e hoʻoponopono i ka pōʻai cell cardiomyocyte.Hoʻopili ka α-DH i nā cardiomyocytes neonatal me ka agrin, ka mea e hoʻolalelale i ka naʻau hou a me ka DGC76 lysis ma muli o ka maturation cell.I ka oʻo ʻana o nā cardiomyocytes, hoʻemi ʻia ka ʻōlelo aggrin i makemake ʻia i ka laminin, i manaʻo ʻia e kōkua i ka hopu ʻana i ka pōʻai cell76.Ua hōʻike ʻo Morikawa12 i ka hoʻokuʻi pālua ʻana o dystrophin a me salvador, kahi mea hoʻoponopono maikaʻi ʻole o YAP, alakaʻi i ka hyperproliferation o nā cardiomyocytes i loko o ka rumen kumu infarct.Ua alakaʻi kēia i ka manaʻo hoihoi e hiki i ka manipulation YAP ke lilo i waiwai lapaʻau i ka pale ʻana i ka nalo ʻana o ka ʻiʻo ma hope o ka myocardial infarction.No laila, hiki i ka agrin-induced DGC lysis ke hōʻike i kahi axis e ʻae ai i ka hoʻōla ʻana o YAP a he ala kūpono no ka hoʻōla hou ʻana o ka naʻau.
Mechanically, α- a me β-DG pono e mālama i ka pilina ma waena o ka sarcolemma a me ka papa basal 81.Hāʻawi ka α-DG a me ka α7 integrins i ka hoʻoulu ʻana i ka ganglion costal, a ʻo ka nalowale o ka α-DG ke kumu o ka hoʻokaʻawale ʻana o ka sarcolemma mai ka basal lamina, e waiho ana i ka ʻiʻo ʻiʻo iwi i hiki ke hoʻopilikia ʻia.E like me ka mea i hōʻike mua ʻia, hoʻoponopono ka paʻakikī dystroglycan i ka huli ʻana o nā DGC, kahi e hoʻopaʻa ai i ka cognate ligand laminin e hopena i ka tyrosine phosphorylation o ka PPPY-binding motif o β-DG892.Hoʻolaha ʻo Tyrosine phosphorylation ma aneʻi i ka dystrophin disassembly, ka mea e hoʻohuli i ka paʻakikī DGC.ʻO ka physiologically, ua hoʻoponopono nui ʻia kēia kaʻina hana, ʻaʻole i ʻike ʻia i ka muscular dystrophy82, ʻoiai ʻaʻole maopopo loa nā ʻano kumu e hoʻokele ai i kēia kaʻina hana.
Ua hōʻike ʻia ka cyclic stretch e hoʻāla i nā ala ERK1/2 a me AMPK ma o ka dystrophin complex a me ka plectin83 protein pili.ʻO ka hui pū, koi ʻia ka plectin a me ka dystroglycan ʻaʻole wale e hana ma ke ʻano he scaffold, akā e komo pū i ka mechanotransduction, a me ka knockdown o plectin alakaʻi i ka emi ʻana o ka hana o ERK1 / 2 a me AMPK83.Hoʻopili pū ʻia ʻo Plectin i ka cytoskeletal intermediate filament desmin, a ua hōʻike ʻia ka overexpression desmin e hoʻomaikaʻi i ka phenotype maʻi ma mdx: desmin a me mdx mice, kahi DMD84 pālua knockout kiʻi kiʻi.Ma ka launa pū ʻana me β-DG, hoʻopaʻa pololei ʻo plectin iā DGC i kēia ʻāpana o ka cytoskeleton.Eia kekahi, pili ka dystroglycan me ka ulu ʻana o ka mea hoʻokipa receptor-binding protein 2 (Grb2), i ʻike ʻia e pili ana i ka cytoskeletal rearrangements85.Ua hōʻike ʻia ka hoʻōla ʻana o Ras e ka integrin ma o Grb2, hiki ke hāʻawi i kahi ala kūpono no ka crosstalk ma waena o nā integrins a me DGC86.
ʻO ka hoʻololi ʻana i nā genes i komo i ka α-DH glycosylation e alakaʻi i ka mea i kapa ʻia ʻo muscular dystrophy.Hōʻike nā Dystroglycanopathies i ka heterogeneity maʻi akā ke kumu nui ʻia e ka haunaele i ka pilina ma waena o α-DG a me laminin α277.ʻO nā dystrophiglicanoses i hoʻokumu ʻia e nā hoʻololi mua ma DAG1 he mea maʻamau loa, no ka mea he embryonic lethal87 lākou, no laila e hōʻoiaʻiʻo ana i ka pono o ka hui kelepona me ECM.ʻO ia ke kumu o ka hapa nui o nā maʻi dystrophic glycan i kumu ʻia e nā hoʻololi protein lua e pili ana me ka glycosylation.No ka laʻana, ʻo ka hoʻololi ʻana i ka POMT1 ke kumu o ka Walker-Warburg syndrome koʻikoʻi loa, kahi i hōʻike ʻia e ka anencephaly a me ka hoʻopōkole ʻia o ka manaʻolana o ke ola (emi ma lalo o 3 mau makahiki)88.Eia nō naʻe, ʻike nui ʻia nā hoʻololi ʻana o FKRP ma ke ʻano he limb-girdle muscular dystrophy (LGMD), ʻo ia ka mea maʻamau (akā ʻaʻole mau) maʻalahi.Eia naʻe, ua hōʻike ʻia nā hoʻololi ʻana ma FKRP he kumu laha loa o WWS89.Nui nā hoʻololi i ʻike ʻia ma FKRP, kahi o ka hoʻololi ʻana o ka mea hoʻokumu (c.826>A) ke kumu maʻamau i LGMD2I90.
ʻO LGMD2I kahi maʻi muscular dystrophy maʻalahi nona ka pathogenesis i hoʻokumu ʻia ma ka hoʻopau ʻana i ka pilina ma waena o ka matrix extracellular a me ka cytoskeleton intracellular.ʻAʻole maopopo ka pilina ma waena o ka genotype a me ka phenotype i nā poʻe maʻi me ka hoʻololi ʻana i kēia mau genes, a ʻoiaʻiʻo, pili kēia manaʻo i nā protein DSC ʻē aʻe.No ke aha i hōʻike ai kekahi poʻe maʻi me nā hoʻololi FKRP i kahi maʻi phenotype i kūlike me WWS aʻo nā mea ʻē aʻe he LGMD2I?Aia paha ka pane i kēia nīnau ma i) ʻo ka ʻanuʻu o ke ala glycosylation i hoʻopili ʻia e ka mutation, a i ʻole ii) ke degere o ka hypoglycosylation i kēlā me kēia pae.Hiki i ka Hypoglycosylation o α-DG ke ʻae i kekahi pae o ka launa pū ʻana me ka ECM e hopena i kahi phenotype holoʻokoʻa haʻahaʻa, ʻoiai ka dissociation mai ka membrane basement e hoʻonui i ka paʻakikī o ka phenotype maʻi.Hoʻokumu pū ka poʻe maʻi me LGMD2I i ka DCM, ʻoiai ʻaʻole i kākau ʻia kēia ma mua o DMD, e hoʻoikaika ana i ka wikiwiki o ka hoʻomaopopo ʻana i kēia mau hoʻololi i ka pōʻaiapili o nā cardiomyocytes.
Hoʻoikaika ka subcomplex sarcospan-sarcoglycan i ka hoʻokumu ʻana o DHA a pili pono me β-DH.Aia ʻehā mau sarcoglycans unidirectional i loko o ka ʻiʻo cardiac: α, β, γ, a me δ91.Ua hōʻike ʻia i kēia manawa he c.218C>T missense mutation i exon 3 o ka SGCA gene a me kahi hemozygous ʻāpana i nā exons 7-8 ke kumu LGMD2D92.Eia naʻe, i kēia hihia, ʻaʻole i loiloi nā mea kākau i ka phenotype cardiac.
Ua ʻike nā hui ʻē aʻe ʻo SGCD i loko o ka porcine93 a me nā hiʻohiʻona mouse94 e hōʻemi i ka hōʻike protein i loko o ka subcomplex sarcoglycan, e hoʻopau ana i ke ʻano holoʻokoʻa o DGCs a alakaʻi i DCM.Eia hou, ua hōʻike ʻia he 19% o nā mea maʻi āpau me SGCA, SGCB, a i ʻole SGCG nā hoʻololi ʻana i ka maʻi cardiomyopathy, a ʻo 25% o nā maʻi āpau e koi pū i ke kākoʻo hanu95.
ʻO ka hoʻololi hou ʻana i ka sarcoglycan (SG) δ ka hopena i ka hōʻemi ʻana a i ʻole ka pau ʻole o nā paʻakikī sarcoglycan a no laila ʻo DGC i loko o ka ʻiʻo cardiac a nona ke kuleana no LGMD a me kāna DCM96 pili.ʻO ka mea e mahalo ai, ʻo ka hoʻololi ʻana i ka mana-ʻino ma SG-δ he kikoʻī i ka ʻōnaehana cardiovascular a ʻo ia ke kumu o ka cardiomyopathy dilated ʻohana97.SG-δ R97Q a me R71T dominant-negative mutations ua hōʻike paʻa ʻia i loko o nā cardiomyocytes ʻiole me ka ʻole o ka hōʻino nui o ka DGC98 a pau.Eia naʻe, ʻoi aku ka maʻalahi o nā puʻuwai puʻuwai e lawe nei i kēia mau hoʻololi ʻana i ka sarcolemma pōʻino, permeability, a me ka hana ʻino mechanical ma lalo o ke koʻikoʻi mechanical, e kūlike me ka phenotype DCM98.
ʻO Sarcospan (SSPN) he 25 kDa tetraspanin i hoʻopaʻa ʻia i loko o ka subcomplex sarcoglycan a ua manaʻo ʻia he scaffold protein99,100.Ma ke ʻano he scaffold protein, hoʻopaʻa ʻo SSPN i ka localization a me glycosylation o α-DG99,101.Ua ʻike ʻia ka overexpression o SSPN i nā kiʻi kiʻi e hoʻonui i ka paʻa ma waena o ka ʻiʻo a me ka laminin 102.Eia kekahi, ua hōʻike ʻia ʻo SSPN e launa pū me nā integrins, e hōʻike ana i ke ʻano o ka crosstalk ma waena o nā commissures ʻelua, DGC, a me ka integrin-talin-vinculin glycoprotein structure100,101,102.Ua hoʻonui ʻia ka α7β1 i ka ʻiʻo iwi iwi ʻiole i ke kīkē ʻana o SSPN.
Ua hōʻike ʻia kahi haʻawina hou e hoʻonui ai ka overexpression sarcospan i ka maturation a me ka glycosylation o α-DG i loko o ka ʻiʻo cardiac me ke kūʻokoʻa o ka galactosylaminotransferase 2 (Galgt2) knockdown i kahi mdx mouse model o DMD, a laila e hoʻēmi ana i ka maʻi phenotype 101. ka ECM, a laila e hoʻēmi i ka maʻi.Eia kekahi, ua hōʻike lākou i ka overexpression sarcospan e hōʻemi i ka pilina o β1D integrin me DGCs, e hōʻike ana i kahi kuleana kūpono no ka sarcospan i ka hoʻoponopono ʻana i nā complexes integrin101.
He ʻohana ʻo Syntrophins i nā protein liʻiliʻi (58 kDa) e pili ana i nā DGC, ʻaʻohe hana enzymatic intrinsic, a lawelawe ma ke ʻano molecular adapters103,104.ʻElima isoforms (α-1, β-1, β-2, γ-1 a me γ-2) ua ʻike ʻia e hōʻike ana i ka ʻōlelo kikoʻī kikoʻī, me ka isoform α-1 i hōʻike nui ʻia i loko o ka ʻiʻo muscle striated 105.ʻO nā syntrophins nā protein adapter koʻikoʻi e hoʻomaʻamaʻa i ka kamaʻilio ʻana ma waena o ka dystrophin a me nā molekala hōʻailona, ​​me ka neuronal nitric oxide synthase (nNOS) i loko o ka ʻiʻo iwi106.Hoʻopili pololei ʻo α-syntrophin me ka dystrophin 16-17 spectrin repeat domain, kahi e hoʻopili ai i ka nNOS106,107 PDZ-binding motif.
Hoʻopili pū nā Syntrophins me dystrobrevin ma o ka PH2 a me nā kāʻei hoʻopaʻa SU, a pili pū lākou me ka actin cytoskeleton 108.ʻOiaʻiʻo, he hana koʻikoʻi ka syntrophins i ka hoʻoponopono ʻana i ka cytoskeletal dynamics, a hiki i ka α a me β isoforms ke launa pū me F-actin 108 a no laila ke pāʻani nei i ka hoʻoponopono o ka tensegrity a me nā biomechanics o ka cellular. hopena.Eia kekahi, ua hōʻike ʻia nā syntrophins e hoʻoponopono i ka cytoskeleton ma o Rac1109.
Hiki i ka modulating syntrophin pae ke hoʻihoʻi i ka hana, a me kahi noiʻi hou e hoʻohana ana i ka mini-dystrophin i hōʻike i ka ΔR4-R23 / ΔCT kūkulu i hiki ke hoʻihoʻi i ka α-syntrophin a me nā protein DGC ʻē aʻe i nā pae e like me WT mdx cardiomyocytes.
Ma waho aʻe o kā lākou kuleana i ka hoʻoponopono ʻana i ka cytoskeleton, ua kākau maikaʻi ʻia nā syntrophins i ka hoʻoponopono ʻana i nā kahawai ion 111,112,113.Hoʻoponopono ka PDZ-binding motif o nā syntrophins i ke kahawai ʻo Nav1.5111 e hilinaʻi ana i ka puʻuwai puʻuwai, kahi mea nui i ka hoʻokumu ʻana i ka excitability a me ka conduction cardiac.ʻO ka mea e mahalo ai, i ka mdx mouse model, ua ʻike ʻia nā kahawai Nav1.5 i hoʻohaʻahaʻa ʻia a loaʻa nā arrhythmias cardiac i nā holoholona 111.Eia kekahi, ua hōʻike ʻia kahi ʻohana o nā kaila ion mechanosensitive, ka transient receptor potential channel (TRPC), i hoʻoponopono ʻia e α1-syntrophin i loko o ka cardiac tissue 113 a me TRPC6 inhibition ua hōʻike ʻia e hoʻomaikaʻi i nā arrhythmias i ka DMD112 kiʻi kiʻi.Ua hōʻike ʻia ka hoʻonui ʻana i ka hana TRPC6 ma DMD e hopena i ka arrhythmias cardiac, i hoʻomaha ʻia ke hui pū ʻia me PKG 112.Mechanically, dystrophin depletion paipai i ka kikoo-influx o [Ca2+]i e hana i ka upstream o TRPC6 e ho'ā 'ia, e like me ia i hōʻike 'ia ma cardiomyocytes a me vascular smooth muscle cells112,114.ʻO ka Hyperactivation o TRPC6 e hoʻolōʻihi e lilo ia i mea mechanosensor nui a me ka pahuhopu therapeutic kūpono i DMD112,114.
ʻO ka nalowale o ka dystrophin ke alakaʻi i ka lysis a i ʻole ka hoʻopaʻa ʻia ʻana o ka paʻakikī DGC holoʻokoʻa, me ka nalowale o ka nui o nā hana mechanoprotective a me ka mechanotransduction, ka hopena i ka phenotype catastrophic i ʻike ʻia i ka ʻiʻo muscle striated i DMD.No laila, kūpono paha ke noʻonoʻo ʻana e hana pū ana nā RSK a ua hilinaʻi kēlā me kēia ʻāpana i ke alo a me ka hana ʻana o nā mea ʻē aʻe.He ʻoiaʻiʻo loa kēia no ka dystrophin, ka mea i ʻike ʻia no ka hui ʻana a me ka localization o ka sarcolemma complex i ka cardiomyocytes.He kuleana ko kēlā me kēia ʻāpana i ka hāʻawi ʻana i ka stabilization holoʻokoʻa o ka sarcolemma, ka localization o nā protein accessory kī, ka hoʻoponopono ʻana i nā kahawai ion a me ka hōʻike gene, a me ka nalo ʻana o kahi protein hoʻokahi i ka DGC alakaʻi i ka dysregulation o ka myocardium holoʻokoʻa.
E like me ka mea i hōʻike ʻia ma luna nei, nui nā protein DGC i komo i ka mechanotransduction a me ka hōʻailona, ​​​​a ua kūpono loa ka dystrophin i kēia hana.Inā aia ka DGC i loko o nā iwi ʻaoʻao, hōʻoia kēia i ka manaʻo e komo i ka mechanotransduction me nā integrins.No laila, hoʻololi kino nā DGC i ka hoʻoili ikaika anisotropic a komo i ka mechanosensory a me ka cytoskeletal rearrangement o ka microenvironment intracellular, e like me ke kumu hoʻohālike tensegrity.Eia kekahi, hoʻopaʻa ʻo Dp427m i nā pūʻali biomechanical e hiki mai ana ma o ka hoʻonui ʻana i ka spectrin i loko o kāna kikowaena kikowaena kikowaena, a laila e hana ana ma ke ʻano he mechanoprotector ma o ka mālama ʻana i kahi mana unwinding 25 pN ma kahi ākea 800 nm lōʻihi.Ma ka hoʻokaʻawale ʻana, hiki i ka dystrophin ke "hoʻopaʻa" i ka ikaika o ka contraction-relaxation i hana ʻia e ka cardiomyocytes10.Hāʻawi ʻia i ka ʻokoʻa o nā protein a me nā phospholipids e launa pū me nā spectrin repeat domains, he mea hoihoi e noʻonoʻo inā hoʻololi hou ʻia ka spectrin unwinding i nā kinetics paʻa o nā protein mechanosensitive i ke ʻano like me ka talin116,117,118.Akā naʻe, ʻaʻole i hoʻoholo ʻia kēia a pono e noiʻi hou ʻia.