Current Research Grants

The FSHD Global Research Foundation puts all its effort into finding a cure or treatment for FSHD.

The Foundation is currently funding a number of groundbreaking research projects around the world (with a particular encouragement of Australian based research) aimed at achieving this goal.

Research Institution: MonashUniversity

Location: Melbourne, Australia

Principal Investigator: Professor Christina Mitchell

Primary Focus: FHL1

Status: Project Underway

The Monash team wants to find out whether stimulation of the calcineurin/NFAT pathway may reduce muscle wasting in FSHD sufferers. Calcineurin works with the protein NFAT to stimulate muscle growth and repair - which is essential for healthy bodies.  Levels of NFAT are reduced in muscle from FSHD patients.

The team from Monash have shown the protein FHL1 is an important activator of calcineurin/NFAT. Professor Mitchell and her team have made mice with elevated levels of FHL1. Amazingly, these mice have demonstrated increased muscle growth and strength, reduced muscle fatigue and are protected from age-related muscle weakness. Of course, what is possible in mice might also be possible in humans. FHL1 is therefore a potential therapeutic target to reduce muscle wasting and promote muscle repair in FSHD sufferers through its ability to stimulate calcineurin/NFAT.

To examine this hypothesis the Monash team will increase levels of FHL1, first in a muscle cell culture model of FSHD and secondly in a FRG1 mouse model of FSHD. Collectively, the results from these studies will give scientists an idea as to whether FHL1 and the calcineurin/NFAT pathway can play key roles in the treatment of FSHD and other diseases.

Research Institution: Sydney IVF

Location: Sydney, Australia

Principal Investigator: Dr Tomas Stojanov

Primary Focus: Derivation of FSHD-specific human embryonic stem cell (hESC) lines

Status: Project Underway

Disease specific hES cells are sought to be a powerful tool for research into specific disease mechanisms and as in vitro model systems for drug development in a number of pharmaceutically underserved diseases. The current Sydney IVF project involves the derivation of up to 6 hESC lines from embryos identified by Preimplantation Genetic Diagnosis (PGD) containing the chromosomal rearrangements associated with the FSHD condition. Derivations will be performed under standardised and fully defined culture conditions. Successfully derived stem cell lines will be fully characterised, cryo-banked and expanded to supply the demand for FSHD research worldwide using high content and high throughput systems. Genetic and developmental modifications of these lines by the Sydney IVF lab will further tailor the FSHD-specific cell lines to future applications in drug development and testing assays.

Only eggs that are unusable for IVF because they carry the FSHD mutation will be used. In addition, in all instances donors would have to provide their consent for use of the otherwise discarded eggs.

Research Institution: ToulaneMedicalSchool 

Location: Louisiana, USA

Principal Investigator: Professor Melanie Ehrlich

Primary Focus: Comparing the DNasel-Hypersensitive Chromatin Landscape at 4q35 of FSHD and Control Cells

Status: Project Underway

One of the major genetic questions about FSHD is the identity of the gene or genes that are immediately affected by short D4Z4 arrays and reside at the end of the long arm of chromosome 4 (4q35.2). Previous studies of FSHD-related gene expression at 4q35.2 were mostly confined to known genes. The team is the US hypothesized that an unannotated gene or gene regulatory sequence somewhere in the 4 million base-pairs at 4q35.2 plays a critical role by interacting with an FSHD-determining, short D4Z4 tandem repeat. The 4q35.2 DNA sequence that the research team seeks might be one of the new types of genes that codes for a biologically active RNA, but no protein. Alternatively, it might be a standard protein-encoding gene that is not annotated in the current DNA databases. Another possibility is that the special 4q35.2 sequence which we propose interacts with D4Z4 is not a gene, but only a site that controls gene activity from afar. It might regulate disease-linked expression of a weak gene inside D4Z4, perhaps at the beginning of a short repeat array.

To find this D4Z4-interacting sequence, we will map nucleosome-free chromatin sites at 4q35.2. Nucleosome-free sites typically regulate gene expression. Myoblasts, fibroblasts, and lymphoblastoid cell lines will be analyzed for nucleosome-free sites using high-resolution tiling microarrays to map DNA sequences from the DNaseI-hypersensitive fraction (DNase-chip). The myoblasts and fibroblasts will be from FSHD patients and from controls. The experiments on these types of cells will address questions of FSHD-specificity and tissue-specificity of nucleosome-free sites. The lymphoblastoid cell lines are being used to further examine the cell-type specificity of nucleosome-free sites at 4q35.2 and to allow us to study cells from patients with the ICF syndrome (immunodeficiency, centromeric region instability, and facial anomalies). ICF is a very rare disease in which D4Z4 arrays are unusually deficient in DNA methylation. In FSHD patients there is also a deficiency of methylation at the disease-linked D4Z4, but it is less pronounced. DNA methylation is important to study because it is interrelated with chromatin structure. The research should provide roadmaps for the chromatin landscape at 4q35.2 and so help us to discover what makes the short D4Z4 arrays in this region linked to FSHD while those at 10q26.3 have no effect on human health.

Research Institution: RadboudUniversityNijmegen

Location: The Netherlands

Principal Investigator: Prof. dr. Baziel van Engelen & Prof. dr. George W Padberg  

Primary Focus: Biomarkers in FSHD, a metabolome study in blood, urine and muscle

Status: Project Underway

Taking advantage of an already approved grant proposal on exercise training and cognitive behavioural therapy, and using new muscle magnetic resonance (MR) imaging methods in combination with a metabolome approach on human body fluids, the team in the Netherlands aim at establishing biomarkers for disease progression and a better understanding of the pathobiology underlying FSHD.

The results of this research should pave the way to further, and better designed future treatment interventions for FSHD, which is a disease for which there is currently no treatment except for symptomatic management. Most notably, the identification of biomarkers will allow objective monitoring of the efficacy of newly tested drugs or other intervention strategies.

Research Institution: University of Massachusetts Medical School

Location: Massachusetts, USA

Principal Investigator: Professor Rossella Tupler

Primary Focus: Defining the mechanism controlling muscle-specific gene expression in FSHD. 

Status:    Approved/Underway

FSHD is very complex disorder with a unique molecular defect.  While all other genetic disorders depend on mutated genes, FSHD has been associated with the reduction of a string of DNA elements, named D4Z4, located at the tip of chromosome 4 long arm.  We have associated the reduction of the string of D4Z4 elements to the hyper-activity of three genes names ANT1, FRG1, and FRG2.  Here we present a study that aims at understanding how we can control the hyperactivity of these genes in muscle. 

We expect this study: 1) to bring a more precise information to explain the mechanism responsible for the appearance of the disease; 2) to identify factors that can influence FSHD onset; and 3) to generate tools that can facilitate the development of the therapeutic strategies.

Research Institution: Faculte de Medecine de la Timone

Location: Timone, France

Principal Investigator: Dr Frederique Magdinier PhD

Primary Focus: Deciphering the long distance interactions of the D4Z4 array in control and FSHD cells. 

Status:  Approved/Underway

An investigation of the molecular and epigenetic mechanisms associated with FSHD and more specifically, the functional activities of the 3.3kb D4Z4 repeat.  Therefore we created a large collection of constructs carrying 1 to > 11 D4Z4 repeats in the presence or absence of 4qA or 4qB specific sequences.  These constructs were stably integrated into human cells and the influence of D4Z4 on gene expression, chromatin organisation and sub nuclear positioning is analysed.

The aim of this proposal is to investigate the long-range chromatin interactions depending on the number of D4Z4 elements and identify distant sequences that might be regulated by D4Z4 in control myoblasts and cells from FSHD patients.  We hope that this project will help to understand the function of D4Z4 in organising the chromatin architecture in normal cells and understand how the reduction of this array to a certain threshold of repeats leads to FSHD through the identification of new candidate sequences.

Research Institution:  Fondazione Centro San Rafaele del Monte Tabor

Location:  Milan, Italy

Principal Investigator:  Dr Davide Gabellini

Primary Focus:  Study of the Molecular Genetic Basis of FSHD 

Status:  Approved

FSHD usually displays its first symptoms in young adults through the progressive loss of muscle strength in the face, shoulders and upper arms.  Unlike most genetic diseases, the mutation that causes FSHD does not alter the function of a specific protein. Instead, FSHD is caused by a deletion of a region on chromosome 4 (called D4Z4) that is required to ensure that proteins coded by the chromosome 4q35 region are expressed at low level in muscle.

Indeed, we have previously shown that increased expression of one of these proteins (FRG1) in mouse muscle can replicate symptoms of FSHD.  However, how D4Z4 controls expression of the proteins coded by 4q35 genes and how increased expression of FRG1 in muscle cells leads to muscle wasting is not understood. 

In this proposal, we plan to define the molecular mechanism of D4Z4 regulatory action in muscle cells and to determine how its alteration causes muscle wasting.  Completion of the proposed studies will allow us to identify new targets for drug development in the hopes of finding an effective therapy for FSHD. 

Please email research@fshdglobal.org now if you would like us to notify you directly when further information becomes available for this section.