|
RAinRARE - Multilevel analyses of retinoic acid signaling to understand and treat a rare form of progressive
Third-party funded project |
Project title |
RAinRARE - Multilevel analyses of retinoic acid signaling to understand and treat a rare form of progressive |
Principal Investigator(s) |
Taylor, Verdon
|
Project Members |
Kaciulis, Marius
|
Organisation / Research unit |
Departement Biomedizin / Embryology and Stem Cell Biology (Taylor) |
Project start |
01.05.2019 |
Probable end |
30.04.2022 |
Status |
Completed |
Abstract |
De novo mutations in the RARb gene, which codes for the retinoic acid receptor beta (RARb), cause a severe and progressive form of early-onset dystonia. RARb functions as a transcription factor that is activated upon binding to retinoic acid (RA). Transfection studies indicate that these de novo mutations confer a gain-of-function (GOF) effect. Movement disorders such as dystonia are typically explained by some dysfunction of the striatum. Interestingly, loss of RARb function in mice induces motor impairment and disrupts the prenatal development and post-natal survival of subsets of striatal neurons. We hypothesize that GOF mutations in RARb cause dystonia by increasing RA signaling in the striatum. Alternatively, these mutations could paradoxically reduce RA signaling by affecting retinoid metabolism through feedback loops. We have used Crispr-Cas9 technology to generate mice carrying one of the GOF mutations identified in patients. These RarbR394C/+ mice show a motor behavior that is reminiscent of that of other mouse models of dystonia. We propose to characterize the development and post-natal integrity of the striatum in these mice by marker analyses (WP1). We will dissect the transcriptional and molecular mechanisms by which this mutation affects neural development or function in these mice (WP2) and in human iPSC-derived neural stem cells (NSCs) and neurons from patients carrying the p.R394C mutation (WP3). To achieve an integrated overview of the RARb signaling networks, we will combine in a FAIR knowledgebase (RAR-kb) the human-mouse phenotypical data and omics data we generate with the curated public datasets (WP4). We will also test RARb selective antagonist to establish new pharmacological models to rescue/prevent RARb GOF pathology (WP2). Finally, normalization of the expression of the top transcriptional/proteomic changes common to mouse and human models will be tested for validation of multi-omics data as potential strategies for therapy or diagnostics (WP2). This work might also shed light on common neurodegenerative disorders of the basal ganglia including Huntington’s and Parkinson’s disease, in which RA and RARb signaling appear to be compromised. |
Financed by |
Swiss National Science Foundation (SNSF)
|
|
|
|
MCSS v5.8 PRO. 0.429 sec, queries - 0.000 sec
©Universität Basel | Impressum
| |
07/05/2024
Research Database / FORSCHUNGSDATENBANK
|