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Elucidating the role of G-Protein Coupled Receptors (GPCRs) via multi-omics analyses in Bardet-Biedl Syndrome

Mendes Martins, Tiago Filipe; (2023) Elucidating the role of G-Protein Coupled Receptors (GPCRs) via multi-omics analyses in Bardet-Biedl Syndrome. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Bardet-Biedl syndrome (BBS) is a monogenic cause of obesity and has provided intriguing links to ciliary dysfunction and the development of obesity. It has been established, in the last decade, that the aetiology of BBS lies in dysfunction of the primary cilium. Primary cilia are found on most eukaryotic cells including neurons and have a crucial role acting as signalling antennae. The most common phenotypic features developed by most BBS patients is recapitulated in almost all Bbs mouse models. Key to the function of the primary cilium is its capacity to integrate into its membrane a high concentration of specialised receptors, including G-protein coupled receptors (GPCRs). To date, several GPCRs known to regulate energy homeostasis and food behaviour have been localised to neuronal primary cilia including MCHR1, SSTR3, NPY2R, GALR2, and dopamine receptors D1. Within this thesis I propose to set up a clear pipeline for GPCR screening with high-throughput technology, enabling any lab to have a clear view of the disrupted receptors or future drug candidate targets. The proposed project generated a substantial amount of proteomics data for cells lacking the Bbs1 gene and most importantly specific cilia proteomics data which has been shared with other researchers in order to continue the investigation of cilia pathologies and as a tool to discover new drug targets. NPY and KISS receptors were identified as being disrupted in cells lacking cilia formation. Its association with Bbs1, represents compelling evidence in support of lack of recruitment of GPCRs upon Bbs1 KO in IMCD3 cells. Therefore, understanding the defects of the downstream signalling of GPCRs in BBS will not only increase the likelihood of improved and novel therapies for this debilitating disorder, but in doing so may also pave the way for therapeutic interventions for common related disorders.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Elucidating the role of G-Protein Coupled Receptors (GPCRs) via multi-omics analyses in Bardet-Biedl Syndrome
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10162914
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