H2020Индивидуална стипендия2016–2017

BRAIN REPEATS · Repeat polymorphisms as genetic modifiers of brain function in healthy subjects and Huntington disease mutation carriers

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2016-10-01 → 2017-09-30
Финансиране от ЕС: 97 727 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Повторенията в ДНК, като например специфичните CAG последователности, се анализират като фактори, влияещи върху структурата и работата на мозъка. Това помага за по-доброто разбиране на причините за развитие на невропсихиатрични заболявания като деменция и депресия.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Repeat polymorphisms as genetic modifiers of brain function in healthy subjects and Huntington disease mutation carriers

What is the problem/issue being addressed? Many genetic association studies, mainly genome-wide association studies (GWAS), have been performed to identify genetic risk factors for neuropsychiatric diseases. However, the single-nucleotide polymorphisms identified through this approach only account for a small fraction of the genetic determinants, giving rise to the problem of ‘missing heritability’. A main reason is likely that GWAS cannot assess the contribution of other important genetic polymorphisms, especially DNA repeat expansions. Expansions of simple repeat sequences in genomic DNA have been associated with many hereditary brain disorders, but their association with (normal) brain structure and function is largely unknown. Among expanded repeat disorders polyglutamine diseases are the most prevalent. These diseases are characterized by a trinucleotide (cytosine-adenine-guanine (CAG)) repeat expansion in the translated regions of otherwise unrelated genes, resulting in proteins with expanded polyglutamine domains. In this project we strive to elucidate part of this 'missing heritability' problem of complex neuropschiatric disorders by evaluating the role of tandem repeat variations, especially CAG repeat polymorphisms, as modulators of brain structure and function. What is the problem/issue being addressed? Neuropsychiatric disorders such as dementia and depression are among the most common diseases worldwide and belong to the top 10 leading causes of disability in high-income countries. However, current treatments are mainly symptomatic and far from optimal. In order to devise more effective therapeutic and preventive strategies a better understanding of their pathogenesis is essential. A vital step in elucidating the pathogenesis of these disorders is to gain more insight into the genetic determinants of normal as well as perturbed brain function. This project will help to identify novel genetic determinants of brain structure and function and, thereby, help to design and develop new treatments for these devastating diseases in the future. What are the overall objectives? The key objective of this proposal is thus to evaluate the effects of CAG repeat polymorphisms in polyglutamine disease-associated genes (PDAGs) on brain structure and function, both in healthy controls and Huntington disease (HD) mutation carriers.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITY COLLEGE LONDON · LondonКоординаторОбединеното кралство