Mechanisms of anti-inflammation and membrane stabilization in muscular dystrophy

Children'S Research Institute, Washington DC

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Project Summary/Abstract: 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.