The rarest of the rare – exploring non-coding RNA in the disease pathogenesis of Hutchinson-Gilford progeria syndrome
Description: Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder, caused by a de novo point mutation in the LMNA gene, leading to mis-splicing and a truncated lamin A protein, named progerin. Children show typical symptoms of accelerated aging and die in their teens due to accelerated atherosclerosis and cardiovascular disease. The underlying patho-mechanisms remain unclear, and several clinical trials have shown only limited success. Based on recent work of consortium members we hypothesize that non-coding RNAs (ncRNAs) are causally linked to pathological features in HGPS. State-of-the-art genome-wide sequencing technologies at the single cell level in cardiovascular tissue will be employed to identify ncRNAs HGPS mouse models, and validated in HGPS patient cells. Identified ncRNAs will be functionally tested for their involvement in DNA damage, and mis-splicing in cellular HGPS disease models. Finally, we will use oligonucleotide-based drugs to the most potent ncRNAs in HGPS mouse models to confirm their causal involvement in disease pathology and test their feasibility as novel therapeutic reagents. The transnational and interdisciplinary project involves principal investigators from Sweden, Italy, Austria and Germany, including experts in HGPS mouse models and in molecular biological analyses of cell phenotypes, a clinical researcher and the world-wide largest progeria patient advocacy organization (PRF https://www.progeriaresearch.org). Project duration is 3 years.
Funder: Vetenskapsrådet
Amount: SEK 4,769,000
Funding type: research
Funder scheme: Project grant
Start date: 2019-12-01
End date: 2021-12-31
Investigator: Maria Eriksson
Institution: Karolinska Institutet
Funded outputs count: 5
Funder award ID: 2019-00269
OpenAlex ID: G2208533903