The muscular dystrophies are a group of progressive muscle wasting disorders that currently have limited treatment options. The only indications are glucocorticoids, which are a class of hormones over 70 years old. Glucocorticoids provide strength to many dystrophic patients, although they also exert significant side effects upon chronic use. While there is a need for improved drugs, the molecular mechanism of action behind the beneficial effects of glucocorticoids has remained elusive. However, accumulating evidence has implicated the NF-κB pathway as a potential driving factor behind their positive effects.
Traditional NF-κB inhibitors have only been shown to be effective at blocking the pathway in non-muscle cells, and therefore may not be the ideal candidates. We proposed that muscle specific NF-κB inhibitors could have the best therapeutic potential. In order to test this hypothesis, we developed an in vitro NF-κB inhibition assay in myoblasts and myotubes. Upon its utilization we identified several potent inhibitors that are analogues of glucocorticoids. These analogues (VBP drugs) are structurally distinct due to an inclusion of a delta-9,11 double bond in their steroid C cyclohexane ring.
Our next goal was to evaluate VBP drugs in vivo, but a significant challenge in pre-clinical drug testing is the ability to sensitively and comprehensively assess disease pathology. New technologies emerging in live imaging are attempting to improve these aspects of drug testing, but none have yet been successful at reliably detecting muscle pathology. Herein, we describe the development of a novel live imaging method based on cathepsin enzymatic activity to quantitatively determine muscle inflammation and pathology.
Upon further investigation of VBP drugs, we found that although they do not compete for the glucocorticoid receptor active site, they retain important downstream glucocorticoid signaling effects. We utilized our novel imaging method to assess VBP drugs for the treatment of the mdx mouse model of Duchenne muscular dystrophy, and demonstrate drug efficacy without any apparent side effects. In summary, we found that VBP drugs exhibit specific therapeutic benefits, and could serve as a potential replacement for glucocorticoids in the future.
|Advisor:||Nagaraju, Kanneboyina, Hoffman, Eric|
|Commitee:||Constant, Stephanie, Hamad, Abdu, Perry, David, Van Den Anker, John|
|School:||The George Washington University|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 71/09, Dissertation Abstracts International|
|Subjects:||Molecular biology, Pharmacology, Medical imaging|
|Keywords:||Cathepsin b, Duchenne muscular dystrophy, Glucocorticoids, Inflammation, Live optical imaging, NF-kappa b|
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