Pharmacological glucocorticoids have been the standard of care for most inflammatory disorders since the 1950's, and remain among the most prescribed drugs worldwide. They are used off-label to treat Duchenne (DMD) and a subset of limb-girdle (LGMD) muscular dystrophies. Despite impressive efficacy and widespread use, their complex mechanism of action has not been dissected, and harsh side effects are a large problem that limits their utility and negatively impacts patient quality of life. A new compound, VBP15, separates efficacy from side effects in the mdx mouse model of DMD, and is now moving towards DMD clinical trials. This, along with key mouse mutations in receptor pathways, will help to address an important, long-standing question: What is the mechanism of action of pharmacological glucocorticoids, and how can this be improved? The aims of this proposal are: 1) to determine ligand-specific effects on GR- phosphorylation, degradation and DNA interactions; 2) to determine if GR has a role in dystrophin-deficiency disease etiology, and in efficacy of steroids; and 3) to find if membrane-stabilizing mechanisms of action (VBP15, poloxamer-188) produce benefits to dystrophic heart health that are not found for current treatments. The PI, Dr. Christopher Heier, is a PhD molecular geneticist whose background in pediatric neuromuscular disorders and translational molecular medicine is uniquely suited to advance the aims in this proposal. During the K99 phase, Dr. Heier will obtain new training in: 1) next-generation sequencing technologies (ChIP-seq), ii) live-cell imaging (FRAP, or Fluorescence Recovery After Photobleaching), and iii) live-animal imaging (echocardiography). Dr. Heier has assembled a strong mentoring team with expertise in genetics, animal models, live-cell imaging, and -omics approaches to both whole organisms and single cells (Primary Mentor: Eric Hoffman, PhD, Co-mentors: Kanneboyina Nagaraju, PhD, DVM, Jyoti Jaiswal, PhD). The proposed K99/R00 application is the ideal vehicle to promote Dr. Heier's ultimate goal of transitioning to an independent career focused upon developing next- generation therapeutics for neuromuscular Orphan diseases, in a manner that benefits larger patient populations through shared molecular biology pathways.
Glucocorticoids are among the most prescribed drugs in the world and are used for a wide variety of inflammatory disorders, however they have harsh side effects and an unclear mechanism of action. VBP15 is a new drug which reproduces the efficacy of glucocorticoids in the absence of side effects in the mdx model of Duchenne muscular dystrophy (DMD). This work will dissect glucocorticoid mechanisms of action using VBP15 and novel strains of mutant mice, to produce knowledge that leads to next-generation therapies and new standards of care for DMD and other disorders featuring inflammation or disruptions of membrane integrity.
| Fiorillo, Alyson A; Tully, Christopher B; Damsker, Jesse M et al. (2018) Muscle miRNAome shows suppression of chronic inflammatory miRNAs with both prednisone and vamorolone. Physiol Genomics 50:735-745 |
