Objective
Huntington´s disease (HD) is an incurable and fatal neurodegenerative disease, manifested by a progressive loss of neurons, causing neuronal motor dysfunction, cognitive decline and death. The disease is caused by a CAG repeat expansion in the Huntingtin (HTT) gene. The CAG expansion induces a neurotoxic effect, mainly thought to be caused by the expanded protein. However, also expanded RNA transcripts can cause toxicity by generation of small CAG-repeated RNAs. Generation of these small RNAs depends on Dicer ribonuclease activity and their toxic effects are modulated by Ago proteins. This links RNA toxicity with the RNA interference (RNAi) pathway, suggesting abnormal induction of gene silencing through small-repeated RNAs.
The DNA damage response (DDR) plays a role in HD pathogenesis as well. Recently, it was shown that small RNAs derived from Dicer and Drosha processing can induce and control this response. The goal of this project is to address the possible link between small CAG-repeated RNA toxicity and the DDR pathway in HD.
We hypothesize that small RNAs activate a DDR response and thereby induce neurotoxicity. We will address this by the following objectives: 1) Establish whether CAG-repeated RNAs activate the DDR pathway, 2) Establish whether DDR inhibition can modulate small RNA toxicity and whether DDR activation is RNAi pathway dependent, 3) Validation of our results using in vivo and ex vivo samples. We will use in vitro cell models combined with ex vivo brain samples from HD affected mice and humans. The effect of small CAG-repeated RNAs on activation of the DDR response will be analyzed by western blot, immuno-fluorescence and immuno-histochemistry. Small RNA pool analysis, knockdown studies and lentiviral transfection approaches will be used to reveal the specificity of the effect and the RNAi pathway dependence.
This project will contribute to a better understanding of HD pathogenesis, RNA biology, small RNA toxicity and the DDR pathway.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics DNA
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics RNA
You need to log in or register to use this function
We are sorry... an unexpected error occurred during execution.
You need to be authenticated. Your session might have expired.
Thank you for your feedback. You will soon receive an email to confirm the submission. If you have selected to be notified about the reporting status, you will also be contacted when the reporting status will change.
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP7-PEOPLE-2012-IEF
See other projects for this call
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
08003 Barcelona
Spain
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.