Research
Department of Pharmacology
The Burkin Lab is currently working on understanding the role the α7β1 integrin plays in muscle development and disease. We are also working on developing therapeutics for Duchenne muscular dystrophy (DMD) and Merosin deficient congenital muscular dystrophy (MDC1A).
The α7β1 integrin
The α7β1 integrin is the predominant laminin-binding integrin in cardiac and skeletal muscle. The α7β1 integrin is important receptor during muscle development and repair. Mutations in the α7 integrin gene cause α7-related congenital muscular dystrophy. Several studies have demonstrated the α7β1 integrin is a major modifier of disease progression in DMD and MDC1A:
- Enhanced transgenic expression of the α7 integrin in the skeletal muscle of mouse models of DMD and MDC1A improves muscle pathology and increases life expectancy.
- Loss of α7 integrin in the dystrophin deficient mdx mouse model of DMD accelerates muscle disease progression.
- AAV-mediated gene transfer of α7 or β1D integrin alleviates muscle disease in mouse models of DMD.
Together these studies support the idea the α7β1 integrin is target for drug-based therapies for muscle disease.
Duchenne Muscular Dystrophy (DMD)
DMD is a common neuromuscular disease dystrophy that affects 1 in 5,000 male births. DMD patients have mutations in the gene encoding dystrophin located on the X-chromosome. These mutations result in the absence of dystrophin, a 427 kDa cytoskeletal protein in muscle which nucleates a transmembrane complete and serves as a molecular glue binding muscle cells to the extracellular matrix. In DMD patients, loss of dystrophin results in contraction induced muscle damage leading to progressive loss of muscle integrity and function. DMD patients suffer from severe, progressive muscle degeneration with clinical symptoms first detected between 2 to 5 years of age. As the disease progresses patients are confined to a wheelchair in their teens and die in their second or third decade of life from cardiopulmonary failure. There are currently no cure and limited treatment options for DMD.
LAMA2-related congenital muscular dystrophy (LAMA2-CMD)
LAMA2-CMD also known as Merosin Deficient Congenital Muscular Dystrophy type 1A (MDC1A) is caused by mutations in the LAMA2 gene located on human chromosome 6q22-23 resulting in loss of laminin-α2 protein. Laminin-α2 is required for the formation of Laminin-211/221 (merosin), a major component of the basal lamina, that surrounds skeletal and cardiac muscle. LAMA2-CMD patients exhibit severe muscle weakness from birth ("floppy baby" syndrome), dysmyelinating neuropathy and muscle atrophy. Patients exhibit feeding problems and/or respiratory difficulties and often require the placement of a feeding tube and/or ventilator assistance. Most LAMA2-CMD patients are unable to walk without assistance and are confined to a wheelchair. LAMA2-CMD patients exhibit changes in brain white matter which is associated with an increased likelihood of seizures. There is currently no cure or treatment for LAMA2-CMD and patients can die as early as the first decade of life.