{"id":8179,"date":"2026-04-03T12:14:12","date_gmt":"2026-04-03T12:14:12","guid":{"rendered":"https:\/\/www.proefschriftmaken.nl\/portfolio\/julie-labau\/"},"modified":"2026-04-23T08:58:58","modified_gmt":"2026-04-23T08:58:58","slug":"julie-labau","status":"publish","type":"us_portfolio","link":"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/julie-labau\/","title":{"rendered":"Julie Labau"},"content":{"rendered":"","protected":false},"excerpt":{"rendered":"","protected":false},"author":8,"featured_media":14062,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":""},"us_portfolio_category":[45],"class_list":["post-8179","us_portfolio","type-us_portfolio","status-publish","has-post-thumbnail","hentry","us_portfolio_category-new-template"],"acf":{"naam_van_het_proefschift":"PATIENT-DERIVED NEURONAL MODELS FOR PHARMACOGENETIC PAIN TREATMENT OF SODIUM CHANNELOPATHIES","samenvatting":"Er is geen Nederlandse samenvatting beschikbaar. De Engelse samenvatting vind je hier<\/a>.","summary":"Of both fast and slow inactivation and enhancement of use-dependent inhibition: contrast the effects of lacosamide on slow inactivation and use dependence in NaV1.7 variants from non-responsive patients were less robust. Importantly, we found that lacosamide selectively enhances fast inactivation only in variants from responders. Taken together these findings begin to unravel biophysical underpinnings that contribute to responsiveness to lacosamide in patients with small fiber neuropathy carrying select NaV1.7 variants.\n\nBuilding on our findings that the NaV1.7 mutation completely abolishes inhibition by clinically-achievable concentrations of lacosamide using molecular docking, we showed in Chapter that NaV1.7 and pore residues are high affinity binding sites for lacosamide. We also used voltage-clamp recordings to demonstrate that lacosamide requires an intact local anesthetic binding site to inhibit NaV channels. Additionally, we demonstrated that the NaV1.7 mutation does not abrogate local anesthetic lidocaine-induced blockade but it does confer sensitivity to the NaV1.7 selective aryl-sulfonamide blocker. Furthermore, we demonstrated that the naturally occurring arginine in NaV1.5 which corresponds to NaV1.7 is not sufficient to explain the resistance of NaV1.5 to clinically-relevant concentrations of lacosamide, suggesting that the contribution of NaV1.7 to lacosamide inhibitory effects is isoform specific. We concluded that both the NaV1.7 residue and an intact local anesthetic site are required for lacosamide\u2019s block of NaV1.7 at a clinically-achievable concentration.\n\nThe translation of our findings is however hindered by using an overexpression heterologous system as transient expression of NaV channel variants in cells only provide a partial view of the underlying pathology. Described in patients, patient-derived iPSCs offer the opportunity to study patient-specific pathophysiological mechanisms and treatment response. Nevertheless, reprogramming and differentiation protocols to obtain nociceptors have mostly yielded immature homogeneous cell populations. In Chapter we developed an in vitro model based on the influence of physicochemical microenvironmental interactions to induce cellular differentiation and provide cells with the full spatiotemporal context and nutrients needed for acquiring a mature phenotype. Specifically, we grafted undifferentiated iPSCs and pre-differentiated iPSCs into neural precursor cells into adult rat and into the excavated ganglions of neonatal rats for differentiation. We reported poor cell survival and differentiation in both models, which lacked immunoreactivity to canonical neuronal markers indicative of their unsuccessful differentiation and maturation. Last, we showed that xeno-transplanted undifferentiated iPSCs maintain an elevated proliferative potential and induce tumorigenesis. Ultimately, further differentiation is necessary to improve their surrogacy as human neurons.\n\nAn alternative way to bridge the gap between human NaVs and iPSC-derived sensory neurons (iPSN) lacking NaV1.7 and NaV1.8 expression is to artificially induce it. In Chapter we utilized dynamic-clamp electrophysiology to precisely tune in varying levels of NaV1.7 and NaV1.8.","auteur":"Julie Labau","auteur_slug":"julie-labau","publicatiedatum":"21 april 2022","taal":"EN","url_flipbook":"https:\/\/ebook.proefschriftmaken.nl\/ebook\/julielabau?iframe=true","url_download_pdf":"","url_epub":"","ordernummer":"FTP-202604031208","isbn":"9789464237559","doi_nummer":"","naam_universiteit":"Universiteit Maastricht","afbeeldingen":14062,"naam_student:":"","binnenwerk":"","universiteit":"Universiteit Maastricht","cover":"","afwerking":"","cover_afwerking":"","design":""},"_links":{"self":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/8179","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\/8"}],"replies":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/comments?post=8179"}],"version-history":[{"count":1,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/8179\/revisions"}],"predecessor-version":[{"id":8180,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/8179\/revisions\/8180"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media\/14062"}],"wp:attachment":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media?parent=8179"}],"wp:term":[{"taxonomy":"us_portfolio_category","embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio_category?post=8179"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}