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Triplet repeat polymorphisms as modifiers of health and disease

Projectomschrijving

Lange stukjes DNA herhalingen zijn de oorzaak van bepaalde erfelijke neurologische stoornissen gekenmerkt door cognitieve, psychiatrische en metabole afwijkingen. In dit onderzoeksproject vonden wij dat ook kortere stukjes DNA herhalingen, die veel voorkomen in de algemene bevolking, als genetische risicofactoren een rol kunnen spelen bij het ontstaan van veelvoorkomende ziekten zoals dementie, depressie en overgewicht, die gezamenlijk wereldwijd honderden miljoenen mensen treffen. Door het identificeren van nieuwe genetische risicofactoren, zullen de bevindingen uit dit onderzoeksproject niet alleen leiden tot een beter inzicht in de ontstaanswijze van deze ziekten maar hopelijk ook de weg bakenen voor het ontwikkelen van effectievere, oorzakelijke behandelingen in de toekomst.

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Samenvatting van de aanvraag

Diseases such as dementia, depression and diabetes are among the leading causes of disability and exert a dramatic burden on society’s social, economic and health care systems. In order to understand their pathophysiology and 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 because of the focus on single-nucleotide polymorphisms and consequently neglect of other important genomic variations, especially DNA repeat expansions. Expanded DNA repeats above a certain threshold are associated with many hereditary neurological disorders, the most common of which are polyglutamine diseases caused by intronic triplet (cytosine-adenine-guanine (CAG)) repeat expansions leading to a range of cognitive, psychiatric, motor and metabolic abnormalities. Emerging findings, including our own pilot data, suggest that even CAG repeat length variations in the normal range in polyglutamine disease-associated genes (PDAGs) could affect mental health, cognition and metabolism. As CAG repeat polymorphisms in PDAGs are highly prevalent in the general population, we postulate that these genomic variations could be common modifiers of age-associated neuropsychiatric, cognitive and metabolic disturbances. To test this hypothesis we aim to systematically evaluate the association between CAG repeat polymorphisms in PDAGs and: 1) mental health, cognition, metabolism and brain volumetric MRI imaging in large cohorts of well-characterized healthy subjects and patients with dementia and depression, 2) disease severity in patients with Huntington disease, the most common polyglutamine disease, and 3) intracellular processes in patient-derived cell lines (combining transcriptome profiling, gene overexpression and exon-skipping methods) in order to unravel the underlying molecular pathways. This project is unique as it translates novel insights into the pathophysiology of polyglutamine diseases to those of more common, complex disorders, thereby uniting divergent domains of academic and biopharmaceutical research and accelerating development of effective therapies for all patient groups.

Onderwerpen

Kenmerken

Projectnummer:
91615080
Looptijd: 100%
Looptijd: 100 %
2015
2018
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Dr. N.A. Aziz
Verantwoordelijke organisatie:
Leiden University Medical Center