Projektbeschreibung
Lange nicht-kodierende RNS als mögliche therapeutische Ziele bei Gefäßerkrankungen
Therapien auf der Basis von Nukleinsäuren kommen als mögliche Behandlung für viele Krankheiten auf. Der Großteil des menschlichen Genoms wird in nicht-kodierende RNS transkribiert, darunter mehr als 15 000 lange nicht-kodierende RNS. Durch die gezielte Beeinflussung dieser RNS mittels RNS-Interferenz können zelluläre Prozesse moduliert werden. Ziel des vom Europäischen Forschungsrat finanzierten Projekts LongTx ist es, diese RNS, die an der Entstehung von Gefäßerkrankungen beteiligt sind, als potenzielle therapeutische Ziele zu identifizieren. Die Charakterisierung des erkrankten menschlichen Gewebes von Menschen mit Carotisstenose, Schlaganfall und abdominalen Aortenaneurysmen führte zur Bestimmung von zwei geeigneten langen nicht-kodierenden RNS. Das Projektziel besteht darin, diese RNS in einem präklinischen Arterien-auf-dem-Chip-Modell und in vivo in genetisch veränderten Tiermodellen zu untersuchen, wobei der Schwerpunkt auf der effizienten Verabreichung von Antisense-Oligonukleotiden liegt, die auf diese Transkripte abzielen.
Ziel
The perception that RNAs are passive carriers of genetic information has been overturned. Due to the diverse targeting abilities and extensive research in RNA modification and delivery systems, nucleic acid-based therapies have emerged as suitable treatment options for many diseases. Targeting RNAs offers opportunities to modulate numerous cellular processes, including those linked to the large portion of ‘undruggable’ proteins. Currently approved protein-targeted therapies interact with <700 gene products, meaning that only 0.05% of the human genome is presently utilized for treatment. On the contrary, a large fraction of the human genome (>70%) is transcribed into non-coding RNAs. Humans produce more than 15.000 long non-coding RNAs (lncRNA), with a substantial subset of these likely being ‘druggable’ via RNA interference strategies, such as antisense oligonucleotides and siRNAs. In my current LongTx proposal, we aim at identifying suitable lncRNAs with relevance to vascular disease development and progression. To be successful, we made sure that we have identified suitable lncRNAs by profiling diseased human tissue from patients with carotid artery disease and stroke, as well as abdominal aortic aneurysms. Both diseases are currently being treated with suboptimal surgical interventions, and the growing affected patient population would tremendously benefit from novel treatment strategies that enable stabilization of advanced vulnerable atherosclerotic lesions, and also limit the risk for acute aortic ruptures and dissections. The two lncRNAs we have identified in preliminary studies using single-cell, bulk, and spatial transcriptomics are called CRNDE and NKILA. We propose to study these lncRNAs in disease-relevant preclinical in vitro (arteries-on-chips) and in vivo (genetically mutated mice and mini-pigs) models, with a strong focus on novel local delivery concepts for antisense oligonucleotide inhibitors that site-specifically target both transcripts.
Wissenschaftliches Gebiet
- medical and health sciencesclinical medicineangiologyvascular diseases
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesclinical medicinesurgerysurgical procedures
- medical and health sciencesbasic medicineneurologystroke
- natural sciencesbiological sciencesgeneticsRNA
Schlüsselbegriffe
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-ERC - HORIZON ERC GrantsGastgebende Einrichtung
81675 Muenchen
Deutschland