Information for Researchers
The fundamental goals of the Beggs Laboratory are to understand the molecular biology of skeletal muscle and to use this information to study inherited disorders of muscle function. To achieve this, our laboratory is taking four complementary approaches.
The first approach is to identify and characterize new muscle-specific genes and proteins and learn as much as possible about their basic biology. The underlying assumption is that these new genes are likely to include ones that are defective in patients with various congenital myopathies. Much previous work has concentrated on the α-actinins which are essential Z-line proteins. Current studies include several new sarcomeric proteins identified through interactions with α-actinin.
After learning about the cell biology and biochemistry of normal genes and proteins, we are then in a position to look for abnormalities of these genes in patients with muscle weakness. Thus, the second approach is to ascertain and enroll patients and families with various congenital myopathies and then study their DNA and muscle to find and understand the causes of their disorders. In the past few years, we have made much progress in understanding the basis of nemaline myopathy, including the identification of three thin filament proteins involved in this disorder. Current studies are also focusing on myotubular/centronucluclear myopathy, multi/minicore myopathies and other forms of congenital myopathy, including undefined cases without firm diagnoses. Knowing the genetic basis for each disorder will be critical to designing specific and effective treatments for some of these diseases.
The third approach is to learn as much as possible about the physiologic state of diseased muscle from patients with congenital myopathy. One frustrating aspect of medical genetics today is that knowing the exact genetic defect has often not allowed us to fully understand how the disease is caused and, more importantly, how we can treat it. Utilizing microarray technology, we are studying global gene expression patterns to determine the "downstream" or secondary consequences of particular genetic mutations and to identify novel muscle genes for further study. These genomic and proteomic approaches are yielding important new insights into basic muscle biology as well as the pathophysiology of inherited muscle diseases.
The fourth approach is to employ cellular and animal models of the congenital myopathies in order to better understand the disease process. In order to find a cure for a genetic disease, it is crucial to study the function of the normal gene to understand how its deficiency can cause the disease. Cellular and animal models have been proven to be indispensable tools for this purpose. In the case of muscular disease, C2C12 cells which are derived from a muscle cell line are an excellent choice since they can form myotubes (muscle cells) in vitro. These myotubes can twitch (contract) and to some extent mimic the muscle function. Furthermore, we now have the technology to easily inactivate ("turn off") a specific gene of interest in these cells in order to study the consequences of its deficiency. Using a mouse model of x-linked myotubular myopathy, we are learning more about various treatment options.
For a partially annotated list of categorized Beggs Lab publications, click here.