Laboratory head: Dr Paul Gregorevic
Scientists in the Muscle Research and Therapeutics Laboratory use gene transfer technology to study muscle diseases.
Skeletal muscle accounts for almost half a person's body mass, yet we easily take for granted its role in our health and lifestyle. The reality is that physical frailty caused by a loss of strength is the primary cause of death among a significant proportion of the elderly population, and patients with a host of medical conditions. Even a moderate decline in muscle strength caused by advancing age, bed rest or inactive lifestyle can dramatically increase the incidence and severity of many serious medical conditions.
The goal of the Laboratory for Muscle Research and Therapeutics is to understand the cellular mechanisms that regulate muscle growth, wasting and metabolism, so that we can develop new methods of preventing or treating the symptoms of muscle-related diseases. Our studies also consider these mechanisms in the context of cardiac muscle adaptation, and heart disease.
The research places a particular emphasis on employing recombinant viral vectors designed and manufactured in-house as a means to selectively alter gene expression in mouse models, and analyses these using a host of established and cutting-edge techniques spanning the disciplines of biological and biomedical science. Employing the advantages of gene delivery technologies this way enables us to interrogate the cellular mechanisms controlling muscle adaptation in vivo with a combination of speed, precision, and efficacy not attained using other approaches.
- Study mouse models of skeletal muscle adaptation and neuromuscular disease.
- Investigate the mechanisms of signalling and gene regulation that control the skeletal muscle phenotype.
- Design and manufacture recombinant viral vectors to examine the physiological impact of manipulating signalling and gene in musculature.
- Develop novel genetic and non-genetic therapies to prevent or reverse the loss of muscle mass, function and metabolism associated with disease and the aging process.
How does manipulation of the TGFβ network affect muscle adaptation in health and disease
The transforming growth factor-β (TGFβ) signaling network is one of the most important regulators of muscle development and post-natal adaptation. We have shown that individual TGFβ superfamily ligands influence intramuscular signalling differently to promote wasting and growth. Our research is dissecting the specific elements of the system that contribute to growth vs. wasting, and investigating how we can manipulate TGFβ signalling from within to counter muscle wasting.
Molecular regulation of β-adrenergic signaling as a therapy for muscle wasting
Stimulation of the β-adrenergic signalling pathway promotes protein synthesis and inhibits protein degradation in muscle, but administering drugs to activate this pathway may prove challenging in the clinic because of the risks of adverse effects in other tissues. We have found that we can use gene therapy tools to activate this pathway and promote muscle growth in the absence of administering drugs. We are testing strategies that manipulate this pathway as prospective muscle therapeutics.
The cellular mechanisms controlling gene expression associated with muscle growth and wasting
Different modes of skeletal muscle growth and wasting uniquely alter gene expression. We are seeking to define distinct and common programs of gene expression associated with muscle growth and wasting states, to identify key mechanisms that govern muscle mass, functional capacity and metabolism. We are using viral vectors to manipulate the expression of specific genes, and dissect the key processes that control muscle adaption.
The role of non-coding RNAs in skeletal muscle adaptation and disease
The discovery of non-coding RNAs has revised our understanding of cell biology. Families of non-coding RNAs are differentially expressed in skeletal muscle during development, adaptation and muscle disease, but their biological functions are poorly understood. We are investigating the expression and roles of non-coding RNAs in skeletal muscle, and evaluating the therapeutic potential of manipulating non-coding RNA activity in skeletal muscle.
Novel gene therapies for neuromuscular disorders, non-degenerative wasting and muscle trauma
Interventions for muscle-related diseases can correct the primary defect, or counter the development of pathology via other mechanisms. We have used viral-vector interventions to increase muscle mass and function in mice modelling a variety of muscle diseases. We are now exploring how to enhance the therapeutic potential of our most promising interventions.
Using gene therapies to treat diabetes and diabetic complications
Type 2 diabetes is one of the world's fastest growing health problems. Using a gene therapy-based strategy to express specific proteins from skeletal muscles, we have found we can improve many of the most important features of diabetic pathology in mice. We are now investigating how to enhance and develop the therapeutic potential of this approach.
Student research opportunities
Justin Chen, PhD (postdoctoral research fellow)
Jonathan Davey, PhD (postdoctoral research fellow)
Kevin Watt, PhD (postdoctoral research fellow)
Hongwei Qian, PhD (research scientist)
Adam Hagg, MSc (research assistant)
Rachel Thomson, PhD (research assistant)
Timothy Colgan (PhD student)
Queenie Lee (BSc Hons student)