{"id":15347,"date":"2026-05-21T12:46:59","date_gmt":"2026-05-21T12:46:59","guid":{"rendered":"https:\/\/www.proefschriftmaken.nl\/portfolio\/zhe-zhou\/"},"modified":"2026-05-21T12:47:18","modified_gmt":"2026-05-21T12:47:18","slug":"zhe-zhou","status":"publish","type":"us_portfolio","link":"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/zhe-zhou\/","title":{"rendered":"Zhe Zhou"},"content":{"rendered":"","protected":true},"excerpt":{"rendered":"","protected":true},"author":7,"featured_media":15348,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":""},"us_portfolio_category":[45],"class_list":["post-15347","us_portfolio","type-us_portfolio","status-publish","post-password-required","hentry","us_portfolio_category-new-template"],"acf":{"naam_van_het_proefschift":"The UNC45A\u2013MYO5B Axis in Enterohepatic Disorders","samenvatting":"Defecten in MYO5B veroorzaken microvillus insluitingsziekte (MVID) en familiaire intrahepatische cholestase met een laag GGT-gehalte (FIC\/PFIC). Het onderliggende mechanisme omvat voornamelijk de verstoring van Rab11A-afhankelijke apicale recyclingpaden, wat leidt tot de mislokalisatie van essenti\u00eble apicale membraantransporteurs zoals BSEP en NHE3. Recent klinisch bewijs benadrukt dat UNC45A-mutaties die het Osteo-Oto-Hepato-Enterisch (O2HE) syndroom en het Aagenaes-syndroom veroorzaken, resulteren in enterohepatische fenotypes die aanzienlijk overlappen met MYO5B-gerelateerde aandoeningen. UNC45A functioneert als een evolutionair geconserveerde co-chaperonne die essentieel is voor de juiste vouwing, assemblage en stabiliteit van myosinemotoren. Gezien deze fenotypische convergentie hypothetiseren we dat UNC45A fungeert als een kritische stroomopwaartse regulator van MYO5B, waarbij het de eiwithomeostase handhaaft om apicale transportprocessen te ondersteunen.\n\nDit proefschrift beoogt de moleculaire mechanismen te onderzoeken waarmee UNC45A-defici\u00ebntie MVID- en PFIC-achtige fenotypes aanstuurt, specifiek door de functionele link tussen UNC45A en de door MYO5B gemedieerde transportmachinerie te verkennen, en zo nieuwe inzichten te verschaffen in de regulerende netwerken die de epitheliale polariteit binnen het enterohepatische systeem bepalen.\n\nIn Hoofdstuk 2 onderzochten we of er een functionele link bestaat tussen UNC45A en MYO5B, en of verlies van UNC45A invloed heeft op twee MYO5B-afhankelijke processen die ten grondslag liggen aan de pathogenese van MVID: de positionering van RAB11A-positieve recycling endosomen en de ontwikkeling van microvilli. In Hoofdstuk 3 hebben we onderzocht of cholestase bij een UNC45A-defici\u00ebnte pati\u00ebnt zou reageren op een behandeling met de ileale galzuurtransportremmer odevixibat. In Hoofdstuk 4 onderzochten we of een defecte UNC45A-HSP70-interactie de MYO5B-afhankelijke trafficking verstoort en of het verhogen van de beschikbaarheid van chaperonnes de normale lokalisatie herstelt. Hoofdstuk 5 biedt een systematische narratieve review van gevallen van ge\u00efsoleerde FIC geassocieerd met MYO5B-varianten en beoordeelt de klinische waarde van BSEP-afwijkingen.","summary":"Defects in MYO5B cause microvillus inclusion disease (MVID) and low-GGT familial intrahepatic cholestasis (FIC\/PFIC). The underlying mechanism primarily involves the disruption of Rab11A-dependent apical recycling pathways, leading to the mislocalization of essential apical membrane transporters such as BSEP and NHE3. Recent clinical evidence highlights that UNC45A mutations causing Osteo-Oto-Hepato-Enteric (O2HE) syndrome and Aagenaes syndrome result in enterohepatic phenotypes that significantly overlap with MYO5B-related disorders. UNC45A functions as an evolutionarily conserved co-chaperone essential for the proper folding, assembly, and stability of myosin motors. Given this phenotypic convergence, we hypothesize that UNC45A acts as a critical upstream regulator of MYO5B, maintaining its protein homeostasis to support apical trafficking.\n\nThis thesis aims to investigate the molecular mechanisms by which UNC45A deficiency drives MVID- and PFIC-like phenotypes, specifically exploring the functional link between UNC45A and the MYO5B-mediated transport machinery, thereby providing new insights into the regulatory networks governing epithelial polarity within the enterohepatic system.\n\nIn Chapter 2, we investigated whether a functional link exists between UNC45A and MYO5B, and whether loss of UNC45A affects two MYO5B-dependent processes that underlie MVID pathogenesis, RAB11A-positive recycling endosome positioning and microvilli development. In Chapter 3, we addressed whether cholestasis in an UNC45A-deficient patient would respond to treatment with the ileal bile acid transporter inhibitor odevixibat. In Chapter 4, we examined whether defective UNC45A-HSP70 interaction perturbs MYO5B-dependent trafficking and whether increasing chaperone availability restores normal localization. Chapter 5 provides a systematic narrative review of MYO5B variant-associated isolated FIC cases and assessed the clinical value of BSEP abnormalities.","auteur":"Zhe Zhou","auteur_slug":"zhe-zhou","publicatiedatum":"4 juni 2026","taal":"EN","url_flipbook":"https:\/\/ebook.proefschriftmaken.nl\/ebook\/zhezhou?iframe=true","url_download_pdf":"https:\/\/ebook.proefschriftmaken.nl\/download\/d2212589-6ea8-4fd9-893c-3fdad9f13d71\/optimized","url_epub":"","ordernummer":"18848","isbn":"978-94-6534-431-7","doi_nummer":"","naam_universiteit":"Rijksuniversiteit Groningen","afbeeldingen":15349,"naam_student:":"","binnenwerk":"","universiteit":"Rijksuniversiteit Groningen","cover":"","afwerking":"","cover_afwerking":"","design":""},"_links":{"self":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/15347","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio"}],"about":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/types\/us_portfolio"}],"author":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/users\/7"}],"replies":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/comments?post=15347"}],"version-history":[{"count":1,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/15347\/revisions"}],"predecessor-version":[{"id":15350,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/15347\/revisions\/15350"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media\/15348"}],"wp:attachment":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media?parent=15347"}],"wp:term":[{"taxonomy":"us_portfolio_category","embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio_category?post=15347"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}