Obiettivo Neuropsychiatric disorders such as dementia and depression are among the leading causes of disability and exert a dramatic burden on Europe’s healthcare systems. In order to devise more effective therapies it is essential to elucidate their genetic basis. However, to date genetic association studies have only identified a small fraction of the genetic determinants, possibly due to neglect of some important genomic variations, especially DNA repeat expansions. Expanded DNA repeats above a certain threshold are associated with various neurological disorders, the most common of which are polyglutamine diseases caused by exonic triplet (cytosine-adenine-guanine (CAG)) repeat expansions leading to a range of cognitive and psychiatric abnormalities. Emerging findings indicate that even CAG repeat length variations in the normal range in polyglutamine disease-associated genes (PDAGs) can affect mental health and cognition. Nevertheless, virtually nothing is known about the biological mechanisms through which these genetic variations affect brain structure and function. Therefore, the key objective of this proposal is to evaluate the effects of CAG repeat polymorphisms in PDAGs on brain structure and function, both in healthy controls and carriers of the mutation for Huntington disease (HD), the most common polyglutamine disease. To this end I will: 1) Systematically assess the association between these genetic polymorphisms and mental health, cognition and brain morphometric and functional MRI imaging in a large cohort of well-characterized control subjects and HD mutation carriers, and 2) Perform pathway analysis using gene expression data already available from these participants in order to elucidate the underlying molecular pathways. This proposal is unique as it translates novel insights into the pathophysiology of polyglutamine diseases to those of more common, complex disorders, thereby accelerating development of effective therapies for all patient groups. Campo scientifico natural sciencesbiological sciencesgeneticsDNAmedical and health sciencesbasic medicinephysiologypathophysiologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesbasic medicineneurologydementianatural sciencesbiological sciencesgeneticsmutation Programma(i) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Argomento(i) MSCA-IF-2015-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Invito a presentare proposte H2020-MSCA-IF-2015 Vedi altri progetti per questo bando Meccanismo di finanziamento MSCA-IF-EF-ST - Standard EF Coordinatore UNIVERSITY COLLEGE LONDON Contribution nette de l'UE € 97 727,40 Indirizzo GOWER STREET WC1E 6BT London Regno Unito Mostra sulla mappa Regione London Inner London — West Camden and City of London Tipo di attività Higher or Secondary Education Establishments Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Partecipazione a programmi di R&I dell'UE Opens in new window Rete di collaborazione HORIZON Opens in new window Costo totale € 97 727,40
