Full Text Available
Note: Clicking the button above will open the full text document at the original institutional repository in a new window.
Identification of pharmacological chaperones for follicle-stimulating hormone receptor variants
Thesis (PhD (Physiology))--University of Pretoria, 2022.
Saved in:
| Other Authors: | |
|---|---|
| Format: | Thesis |
| Language: | English |
| Published: |
University of Pretoria
2023
|
| Subjects: | |
| Tags: |
No Tags, Be the first to tag this record!
|
| _version_ | 1867613544482078720 |
|---|---|
| access_status_str | Open Access |
| author2 | Newton, Claire |
| author_browse | Newton, Claire |
| author_facet | Newton, Claire |
| collection | Thesis |
| dc_rights_str_mv | © 2022 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Thesis (PhD (Physiology))--University of Pretoria, 2022. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/89738 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:37:50.174Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2023 |
| publishDateRange | 2023 |
| publishDateSort | 2023 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/89738 Identification of pharmacological chaperones for follicle-stimulating hormone receptor variants Newton, Claire sharika.hanyroup@gmail.com Anderson, Ross Hanyroup, Sharika UCTD G protein-coupled receptors Follicle-stimulation hormone receptors Reproductive dysfunction Pharmacological chaperones FSHR-selective small molecules Thesis (PhD (Physiology))--University of Pretoria, 2022. Mutations in G protein-coupled receptors (GPCRs) underlie numerous diseases. Many cause receptor misfolding and failure to reach the cell surface. Pharmacological chaperones are cell-permeant small molecules that engage nascent mutant GPCRs in the endoplasmic reticulum, stabilizing folding and “rescuing” cell surface expression. We previously demonstrated rescue of cell surface expression of luteinizing hormone receptor mutants by an allosteric agonist. In order to achieve this, a mammalian expression vector encoding epitope-tagged wild-type WT) FSHR was modified to introduce nineteen identified FSHR variants described in patients with reproductive dysfunction. These vectors were transiently transfected into HEK 293-T cells and functionality of the variant receptors in response to FSH was examined by receptor signalling assays, while cell surface and total cellular expression/localisation of the variants was examined by receptor enzyme-linked immunosorbent assay (ELISA) and confocal microscopy, before and after treatment with LHR-Chap and the selection of FSHR small molecule agonists. In all cases, results for the variant receptors were compared to the WT receptor. In summary, this study demonstrated a cohort of FSHR-selective small-molecules to act as PCs, and gives rise to the idea that employing such substances therapeutically can aid in treating reproductive dysfunction and infertility in patients who harbour class II (and also potentially class II and class IV) variant FSHRs (and also provides further proof-of-principle to support the identification of other therapeutically useful PCs targeting other GPCRs). As a prelude to further therapeutic development, it would also be interesting to see if findings from this in vitro study can be replicated in vivo, using transgenic mouse models harbouring variant FSHRs. NRF and University of Pretoria (RESCOM grant) Physiology PhD Unrestricted 2023-02-22T06:51:18Z 2023-02-22T06:51:18Z 2023-04-24 2022 Dissertation * A2023 https://repository.up.ac.za/handle/2263/89738 en © 2022 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf University of Pretoria |
| spellingShingle | UCTD G protein-coupled receptors Follicle-stimulation hormone receptors Reproductive dysfunction Pharmacological chaperones FSHR-selective small molecules Identification of pharmacological chaperones for follicle-stimulating hormone receptor variants |
| title | Identification of pharmacological chaperones for follicle-stimulating hormone receptor variants |
| title_full | Identification of pharmacological chaperones for follicle-stimulating hormone receptor variants |
| title_fullStr | Identification of pharmacological chaperones for follicle-stimulating hormone receptor variants |
| title_full_unstemmed | Identification of pharmacological chaperones for follicle-stimulating hormone receptor variants |
| title_short | Identification of pharmacological chaperones for follicle-stimulating hormone receptor variants |
| title_sort | identification of pharmacological chaperones for follicle stimulating hormone receptor variants |
| topic | UCTD G protein-coupled receptors Follicle-stimulation hormone receptors Reproductive dysfunction Pharmacological chaperones FSHR-selective small molecules |
| url | https://repository.up.ac.za/handle/2263/89738 |