Pathogenesis driven by RNAs with expansion of trinucleotide repeats: mechanisms and therapeutic strategies (Q84328)
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Project Q84328 in Poland
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | Pathogenesis driven by RNAs with expansion of trinucleotide repeats: mechanisms and therapeutic strategies |
Project Q84328 in Poland |
Statements
3,499,222.0 zloty
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3,499,222.0 zloty
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100.0 percent
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1 October 2018
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30 September 2021
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UNIWERSYTET IM. ADAMA MICKIEWICZA W POZNANIU
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Q2513981 (Deleted Item)
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Myotonic Dystrophy (DM) and Fragile X-associated tremor-Ataxia Syndrome (FXTAS) are dominant disorders caused by RNA gain of function of expanded CUG or CGG repeats. Both RNAs may sequester nuclear proteins, and their repeat sequences undergo untypical translation into toxic mono-amino acid peptides. Since the causative molecular target is well defined, DM and FXTAS are highly amenable to the development of RNA targeting therapy. We and others demonstrated that reduction of protein sequestration on toxic CUG repeats using various oligonucleotide-based approaches or small compounds led to promising results in animal models of DM; therefore, now we want to develop similar tools to reduce the effect of FXTAS mutation by targeting RNA with CGG expansion, to reduce its translation rate. We also aim to achieve the gene therapy tool to overexpress the therapeutic proteins which may rescue nuclear proteins from pathogenic sequestration in DM. We are going to study mechanisms of both diseases. (Polish)
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Myotonic Dystrophy (DM) and Fragile X-associated tremor-Ataxia Syndrome (FXTAS) are dominant disorders caused by RNA gain of function of expanded CUG or CGG repeats. Both RNAs may sequester nuclear proteins, and their repeat sequences Undergo untypical translation into toxic mono-amino acid peptides. Since the causative molecular target is well defined, DM and FXTAS are highly amenable to the development of RNA targeting therapy. We and others demonstrated that reduction of protein sequestration on toxic CUG repeats using various oligonucleotide-based approaches or small compounds led to promising results in animal models of DM; therefore, now we want to develop similar tools to reduce the effect of FXTAS mutation by targeting RNA with CGG expansion, to reduce its translation rate. We also aim to achieve the gene therapy tool to overexpress the therapeutic proteins which may rescue nuclear proteins from pathogenic sequestration in DM. We are going to study mechanisms of both diseases. (English)
14 October 2020
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La dystrophie myotonique (DM) et le syndrome de Trémor-Ataxie Fragile associé aux X (FXTAS) sont des troubles dominants causés par le gain d’ARN de la fonction des répétitions CUG ou CGG élargies. Les deux ARN peuvent séquestrer les protéines nucléaires, et leurs séquences répétées subissent une traduction atypique en peptides acides mono-amino toxiques. Étant donné que la cible moléculaire causale est bien définie, les DM et les FXTAS sont très propices au développement d’un traitement de ciblage de l’ARN. Nous et d’autres avons démontré que la réduction de la séquestration des protéines sur les répétitions de CUG toxiques à l’aide de diverses approches à base d’oligonucléotides ou de petits composés a conduit à des résultats prometteurs dans les modèles animaux de DM; par conséquent, nous voulons maintenant développer des outils similaires pour réduire l’effet de la mutation FXTAS en ciblant l’ARN avec l’expansion CGG, afin de réduire son taux de traduction. Nous visons également à réaliser l’outil de thérapie génique pour surexprimer les protéines thérapeutiques qui peuvent sauver les protéines nucléaires de la séquestration pathogène dans le DM. Nous allons étudier les mécanismes des deux maladies. (French)
30 November 2021
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Myotonic Dystrophie (DM) und Fragile X-assoziiertes Tremor-Ataxia-Syndrom (FXTAS) sind dominante Störungen, die durch RNA-Zunahme der Funktion von erweiterten CUG- oder CGG-Wiederholungen verursacht werden. Beide RNAs können Kernproteine Sequester, und ihre Wiederholungssequenzen werden untypisch in toxische Monoaminosäurepeptide umgesetzt. Da das kausative molekulare Ziel gut definiert ist, sind DM und FXTAS für die Entwicklung der RNA Targeting Therapie sehr gut geeignet. Wir und andere haben gezeigt, dass die Reduktion der Proteinsequestrierung bei toxischen CUG-Wiederholungen mit verschiedenen Oligonukleotid-basierten Ansätzen oder kleinen Verbindungen zu vielversprechenden Ergebnissen bei Tiermodellen von DM geführt hat; deshalb wollen wir jetzt ähnliche Tools entwickeln, um die Wirkung der FXTAS-Mutation zu reduzieren, indem wir RNA mit CGG-Erweiterung gezielt ansprechen, um die Übersetzungsrate zu reduzieren. Wir wollen auch das Gentherapie-Tool erreichen, um die therapeutischen Proteine zu überdrücken, die Kernproteine aus der pathogenen Sequestration in DM retten können. Wir werden die Mechanismen beider Krankheiten untersuchen. (German)
7 December 2021
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Myotonic Dystrofie (DM) en Fragile X-geassocieerd Tremor-Ataxie Syndroom (FXTAS) zijn dominante stoornissen veroorzaakt door RNA-toename van functie van uitgebreide CUG of CGG-herhalingen. Beide RNA’s kunnen kerneiwitten Sequesteren, en hun herhalingssequenties ondergaan atypische vertaling in toxische mono-aminozuurpeptiden. Aangezien het veroorzakende moleculaire doel goed gedefinieerd is, zijn DM en FXTAS hoogst vatbaar voor de ontwikkeling van RNA gericht therapie. Wij en anderen hebben aangetoond dat de vermindering van eiwitvastlegging op toxische CUG zich herhaalt met behulp van verschillende op oligonucleotide gebaseerde benaderingen of kleine verbindingen die hebben geleid tot veelbelovende resultaten in diermodellen van DM; daarom willen we nu vergelijkbare tools ontwikkelen om het effect van FXTAS-mutatie te verminderen door RNA te richten op CGG-uitbreiding, om de vertaalsnelheid te verlagen. We streven er ook naar het gentherapie-instrument te bereiken om de therapeutische eiwitten te overexpresseren die nucleaire eiwitten kunnen redden van pathogene vastlegging in DM. We gaan de mechanismen van beide ziekten bestuderen. (Dutch)
16 December 2021
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La distrofia miotonica (DM) e la sindrome da tremore-atassia associata a X Fragile (FXTAS) sono disturbi dominanti causati da RNA guadagno di funzione di CUG espanso o CGG ripetizioni. Entrambi gli RNA possono Sequester proteine nucleari, e le loro sequenze ripetute subiscono una traduzione atipica in peptidi tossici mono-amminoacidi. Poiché l'obiettivo molecolare causale è ben definito, DM e FXTAS sono altamente suscettibili allo sviluppo della terapia di targeting RNA. Noi e altri abbiamo dimostrato che la riduzione del sequestro proteico sulle ripetizioni tossiche del CUG utilizzando vari approcci basati su oligonucleotidi o piccoli composti ha portato a risultati promettenti in modelli animali di DM; pertanto, ora vogliamo sviluppare strumenti simili per ridurre l'effetto della mutazione FXTAS puntando l'RNA con l'espansione del CGG, per ridurre il suo tasso di traduzione. Abbiamo anche lo scopo di ottenere lo strumento di terapia genica per sovraesprimere le proteine terapeutiche che possono salvare le proteine nucleari dal sequestro patogeno in DM. Studieremo i meccanismi di entrambe le malattie. (Italian)
16 January 2022
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Identifiers
POIR.04.04.00-00-5C0C/17
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