research

muscular dystrophy

summary

Our research aims to understand the causes of inherited muscle and bone diseases and explore potential therapies. Through better understanding of the molecular pathology of muscular dystrophies and skeletal disorders we will improve the genetic counselling available for individuals and families, better treat patients and most importantly find and develop new treatments.

group leader(s)

Shireen Lamande

Dr Shireen Lamandé
Muscular Dystrophy
Murdoch Childrens Research Institute
Royal Children's Hospital
Flemington Road
Parkville Victoria 3052

T +61 3 8341 6465
F +61 3 9345 7997
E shireen.lamande@mcri.edu.au

group leader biography

current research projects

Project 1: Molecular pathology of the collagen VI muscular dystrophies.

Mutations in collagen VI underlie two muscular dystrophies, Bethlem myopathy and Ullrich congenital muscular dystrophy. We have focused on identifying collagen VI mutations in these patients and understanding how and why the mutations cause muscle disease. Most structural mutations are in the collagen VI triple helix and alter protein assembly and secretion, so we can be sure they are pathogenic. We have also identified amino acid changes within the globular A-domains. The A-domains are very polymorphic and we are often unable to provide a diagnosis for patients because we can't distinguish rare non-pathogenic changes from disease causing mutations. We are using protein structural studies to determine how amino acid substitutions affect protein folding, stability and interactions. This will improve diagnosis for patients and families and increase our understanding of collagen VI biology and pathology. Around 30% of Bethlem and Ullrich patients do not have collagen VI mutations and our research program is identifying the genes that underlie muscular dystrophy in these patients.

Project 2:TRPV4 in skeletal development and arthritis

Our recent work on a novel form of inherited arthritis called Familial Digital Arthropathy-Brachydactyly (FDAB) identified mutations in the cation channel TRPV4. FDAB patients have severe early osteoarthritis in the hands and feet thus implicating TRPV4 as an important new candidate gene in arthritis. This project focuses on how the TRPV4 mutations disrupt channel function using biochemical and pharmacological approaches. We are using proteomic approaches to identify proteins that interact with TRPV4 and influence down-stream signaling pathways, and are developing a knockin mouse with an FDAB mutation to allow us to study pathogenic mechanisms in more detail.

Project 3: Matrix remodeling in the pathophysiology of muscular dystrophy

Increased fibrosis impairs muscle regeneration and exacerbates the susceptibility of dystrophic muscle to damage. This degradation of muscle structure and function is not yet adequately addressed by current gene, cell or pharmacological therapeutic strategies. Extracellular matrix remodelling enzymes, such as ADAMTS5, have a dynamic expression pattern throughout mammalian skeletal muscle development and significant upregulation in the regenerative phase of skeletal muscle growth in a muscular dystrophy (mdx) mouse model suggesting that it could be an ameliorating factor in muscular dystrophy. We are investigating whether ADAMTS5 is important for muscle regeneration and growth, in dystrophic models.

Project 4: Cytokine mediated enhancement of cell based therapies for muscular dystrophy

The potential benefits of using cytokines such LIF in the therapeutic regime for Duchenne muscular dystrophy may be in protection of skeletal muscle from damage, increasing the survival of precursor cells after transplantation or increasing the proliferation and fusion of donor injected cells. Factors which reduce the loss of skeletal muscle mass after traumatic injury, reconstructive surgery, neuromuscular disease characterized by skeletal muscle wasting and normal ageing process is an important area of study and may have significant societal implications.

Project 5: ENU mutagenesis as a tool to identify modifier loci in muscular dystrophy

Traditionally, understanding gene function requires baseline knowledge of the expression and localisation of a particular gene of interest. However, this approach is limited to known genes, and restricts the identification of novel genes and their roles in the tissue/s being studied. In this approach project, male mice are treated with ENU and then bred and their offspring screened for phenotypic abnormalities; using serum creatine kinase as a marker of damage.

team members

Stephanie Amico - Honours Student (UoM Paeds)
Sarah Chan - Honours Student (UoM Paeds)
Chantal Coles - Research Officer
Liam Hunt - RESEARCH OFFICER
Chris Kintakas - PhD Student (Deakin/Medicine)
Teodor Mocioaca - Honours Student (UoM Paeds)
Adam Piers - PhD Student (UoM Vet Sci)
Susan Toulson - Visitor
Jason White - Senior Research Fellow
Keryn Woodman - PhD Student (UoM Vet Sci)

publications

Hunt LC., Anthea Coles C., Gorman CM., Tudor EM., Smythe GM., White JD. Alterations in the expression of leukemia inhibitory factor following exercise: comparisons between wild-type and mdx muscles. PLOS Currents (2011) PubMed
Hunt LC., Upadhyay A., Jazayeri JA., Tudor E., White JD. Caspase-3, myogenic transcription factors and cell cycle inhibitors are regulated by leukemia inhibitory factor to mediate inhibition of myogenic differentiation. Skeletal muscle 1 (17) (2011)