STRUCTURE AND FUNCTION OF NATIVE AND EDITED DYSTROPHIN RODS

The purpose of this study is to examine the biophysical properties of the rod region of the dystrophin protein. This is important due to the severity of the disease Duchenne Muscular Dystrophy, (DMD), which is associated with the malfunction of this protein. DMD is one of the most serious single gene genetic defects of man. This rod region consists of a number of repeat motifs called spectrin type repeats or STRs. The thermodynamical and biochemical stability analysis shows, which single motifs are unstable on their own and which ones become more stable when linked to their appropriate tandem neighbors. This knowledge will impact strategies to produce modified mini dystrophins for gene therapy. Exon skipping therapy is an emerging approach to treat such genetic diseases. This is done by the administration of modified antisense oligonucleotides, AONs, which can interfere with exon splicing process and eliminate certain exons from the mature transcript. Furthermore, the rod region has a number of ancillary functions, such as providing secondary binding sites for actin, neuronal NO synthetase and phospholipids, which may be adversely perturbed by the edits.Ph.D. in Biological, Chemical, and Physical Sciences, May 201