High-Content Screen for Small-Molecule Modulators of Hedgehog Signalling and the Primary Cilium

Diplôme Thèse High-Content Screen for Small-Molecule Modulators of Hedgehog Signalling and the Primary Cilium eng 2024 2024 author Rossion Charlotte 931419 director Hoogendoorn Sascha 0000-0002-1155-8697 917221 Département de chimie organique (CHIOR) 184 10.13097/archive-ouverte/unige:181060 urn:nbn:ch:unige-1810603 Sc. Vie 308 <p>The Hedgehog (HH) signalling pathway, a conserved means of cell-cell communication, is required for human development and for the maintenance and regeneration of many tissues. Dysfunctional HH signalling is associated with congenital malformations and with the growth of several cancer types. Most of the known pathway inhibitors target Smoothened (SMO), a GPCR-like protein and the main upstream activator of the HH pathway. Although targeting SMO has proven very promising, acquired resistance has compromised this therapeutic strategy. Therefore, there is a critical need to find and develop molecules that target different proteins in the HH pathway. In mammals, HH signaling relies on the primary cilium, a microtubule-based organelle important for many cellular signaling pathways. Therefore, we used NIH-3T3 mouse fibroblasts expressing Hh pathway-responsive GFP reporter and ARL13B, a cilium protein. This experimental design takes into account compounds acting on HH signaling and/or ciliogenesis by assessing transcriptional activation (GFP) levels and cilium morphology (mCherry), respectively. Our microscopy-based screen determined potential hits from a highly chemical diverse library of compounds. After confirmation and selection, we decided to investigate 30 compounds regarding their biological properties. Downstream assays are aimed at identifying the mechanism of action and the target. Ultimately, these small-molecules could open up new ways to interfere with HH signaling in disease.</p> Hedgehog signalling ARL13B Primary cilium High-content screen Small-molecules Dewey 540 36 Département de chimie organique 141 false 1380 Groupe Hoogendoorn 503a93e2-2a6b-45db-a5d3-1243725059c2 Thesis Public Thesis_report_CR_final.pdf 11757853 application/pdf Private 2028-01-01 abf408de20022cffc9cf22ee2188f3e41ce6426305dcd28f61d5393a4c0e3408 9addc2b5-dcd8-449f-9eaa-30192d743015 Imprimatur Public These_approuvée_signée.pdf 182100 application/pdf 0e8d5434187a0c21c50c1fadb74cec440747ef6d457a42c24b937a8d8525aaec 0bcf33e4-9cd8-4c2c-b03c-de3e1db1309b Summary Public Thesis_Résumé_Abstract.pdf 375801 application/pdf 7f86a3ca47346663836f9cf4419effebd07bd7e7e24fdf9af1c976ef52bf7872 openAccess Faculté des sciences / Section de chimie et biochimie / Département de chimie organique

Title	Published in	Access level	OA Policy	Year	Views	Downloads

High-Content Screen for Small-Molecule Modulators of Hedgehog Signalling and the Primary Cilium				2024	87	0

Archive ouverte UNIGE

Rossion, Charlotte

account_balance Affiliation entities

Research groups

Affiliation entities