H2020Индивидуална стипендия2018–2020

DUX4 · Function of DUX4 in skeletal muscle and non-muscle tissues

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

Период: 2018-07-01 → 2020-09-29
Финансиране от ЕС: 177 599 €
Участници: 1
Схема: MSCA-IF-EF-RI

Линиите свързват координатора с партньорите.

Накратко на български

Протеинът DUX4 се изследва в скелетните мускули и други тъкани, за да се разбере как влияе върху гените. Това помага да се установи дали системното блокиране на DUX4 при мускулна дистрофия FSHD засяга негативно останалите органи в тялото.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Function of DUX4 in skeletal muscle and non-muscle tissues

DUX4 expression in skeletal muscle is associated with the development of facioscapulohumeral muscular dystrophy (FSHD). DUX4 encodes a transcription factor that plays an important role in the initiation of gene expression after fertilization in mammals. As FSHD patients mainly present with muscular symptoms, research in the field has focused on unravelling the consequences of DUX4 expression in skeletal muscle. Research on DUX4 expression in non-muscle tissues is limited, but increasing evidence suggests a biological function for DUX4 in these tissues. As systemic DUX4 suppression is a potential therapy for FSHD, it is important to define the consequences of DUX4 suppression in non-muscle tissues. The action entitled “Function of DUX4 in skeletal muscle and non-muscle tissues” addressed the hypothesis that DUX4 has an underappreciated biological function in non-muscle tissues. The following objectives were formulated: * Objective 1: To establish which non-muscle tissues, and what cell types, express DUX4. * Objective 2: To determine the consequences of DUX4 expression in skeletal muscle and non-muscle tissues and to identify which genes and pathways are direct targets of DUX4 in these tissues. * Objective 3: To establish if systemic treatment with DUX4 antisense oligonucleotides (ASOs) negatively impacts somatic tissues in which DUX4 has a biological function. Upon completion of the action, we now know which non-muscle tissues, and what specific cell types, express DUX4. We also know that systemic treatment with DUX4 ASOs does not have a major impact on non-muscle tissues in which DUX4 has a biological function.

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

Цел на проекта

Somatic expression of the retrogene DUX4 in skeletal muscle is associated with the development of the common myopathy facioscapulohumeral muscular dystrophy (FSHD). As FSHD patients mainly present with muscular symptoms, research in the FSHD field has focused on unraveling the functional consequences of DUX4 expression in skeletal muscle. Research on DUX4 expression in non-muscle tissues is limited, but increasing evidence suggests a biological function for DUX4 in somatic tissues. I aim to characterize DUX4 expression in non-muscle tissues, to determine the genome-wide transcriptional consequences of DUX4 expression, to identify DUX4 target genes in these tissues, and to establish whether treatment with DUX4 antisense oligonucleotides negatively impacts somatic tissues in which DUX4 has a biological function. First, I will use a combination of quantitative reverse transcriptase PCR, immunofluorescence staining, and flow cytometry to establish which tissues and what cell types express DUX4 in human and mouse. Next, I will use the innovative technique of single-cell RNA sequencing to determine the autonomous and non-autonomous functional consequences of DUX4 expression in DUX4-positive tissues. In parallel, to establish which genes and pathways are direct targets of DUX4 and whether tissue-specific differences exist, I will employ DUX4-chromatin immunoprecipitation sequencing. Finally, I will determine the effect of DUX4 suppression in vitro and in vivo. The proposed work will provide in depth analysis into the biological function of DUX4 in somatic tissues, contribute to the long-standing enigma in the field why FSHD presents as a muscle-specific disease, and provide guidance to DUX4-targeted therapies that are currently being developed.

Оригинален текст от CORDIS (на английски).

Участници

ACADEMISCH ZIEKENHUIS LEIDEN · LeidenКоординаторНидерландия