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Mechanisms of corticosteroids in dystrophic cardiomyopathy

皮质类固醇治疗营养不良性心肌病的机制

基本信息

批准号：
10669137
负责人：
Christopher Ryan Heier
金额：
$ 7.6万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-11-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10669137
关键词：
Ablation Address Adrenal Cortex Hormones Affect Agonist Animal Model Animals Anti-Inflammatory Agents Asparagine Becker Muscular Dystrophy Binding Biological Models Cardiomyopathies Cell Culture Techniques Cells Childhood Chronic Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Corticosteroid Receptors Data Disease Dissociation Drug Prescriptions Drug Targeting Duchenne muscular dystrophy Dystrophin Etiology Fibrosis Functional disorder Gene Expression Genes Genotype Glucocorticoid Receptor Goals Grant Heart Heart Diseases Heart failure Human Hydroxysteroids Immune Inflammation Inflammatory Knock-out Knockout Mice Knowledge Ligands LoxP-flanked allele Mediating Methodology MicroRNAs Mineralocorticoid Receptor Modeling Molecular Mus Muscle Muscular Dystrophies Mutation Myocardium Myopathy Outcome Pathology Patients Persons Pharmaceutical Preparations Pharmacodynamics Phase Phenotype Physiological Point Mutation Positioning Attribute Prednisone Receptor Activation Role Safety Serum Signal Transduction Skeletal Muscle Steroid Receptors Steroids Structure System Testing Tissues Transactivation Work antagonist cardioprotection clinically relevant drug development drug discovery dystrophic cardiomyopathy effective therapy exon skipping therapy gene therapy improved improved outcome mdx mouse micro-dystrophin mortality mouse model novel novel therapeutics pharmacologic receptor restoration side effect standard of care tool

项目摘要

Corticosteroids provide an important drug class for treatment of numerous forms of heart failure and chronic inflammation, together affecting over 432 million people. In Duchenne muscular dystrophy (DMD), drugs that target corticosteroid receptors are used to treat heart and skeletal muscle. Our lab developed a first-in-class dissociative steroid that shows efficacy as both a heart-protective and anti-inflammatory drug. Our work in the mdx mouse model of DMD was critical for moving this drug, vamorolone, into DMD clinical trials (now in Phase 2b). In early cell and animal studies, vamorolone showed anti-inflammatory efficacy while avoiding key side effects. Subsequently, we discovered new readouts of drug activity and important impacts of corticosteroids on dystrophic hearts. Cardiomyopathy is a feature of both the severe muscle disease DMD (caused by loss of dystrophin) and the milder muscle disease Becker muscular dystrophy (dystrophin in-frame deletions). As promising new therapies are being developed that seek to convert severe DMD genotypes into milder Becker- like phenotypes, importance of treating dystrophic hearts should grow because cardiomyopathy is the leading cause of Becker mortality. Moving forward, it will be important to address knowledge gaps regarding the mechanisms of selective steroids, roles of specific steroid receptors in the heart, and impacts of steroids on Becker-like hearts. This knowledge is important because cardiomyopathy is a leading cause of DMD mortality and current corticosteroids have problematic safety profiles. Our long-term goal is to dissect mechanisms of steroid signaling that can be selectively targeted to improve treatment of chronic pediatric diseases. This can greatly improve outcomes for DMD in a way that also impacts much larger groups of heart, muscle and inflammatory diseases. The objective of this grant is to dissect mechanisms of corticosteroid receptors that impact dystrophic cardiomyopathy. The advanced expertise and tools developed by our lab place us in a unique position to accomplish this using a combination of cell culture, receptor mutation, tissue-specific knockout, micro-dystrophin gene therapy, and animal model systems. We propose the central hypothesis that 11β-hydroxysteroid agonists activate receptor transactivation to drive progression of dystrophic heart pathology. Our rationale is that identifying corticosteroid mechanisms which can be selectively targeted will provide a basis for the improved treatment of DMD and other diseases with heart failure or chronic inflammation.

皮质类固醇是治疗多种形式的心力衰竭和慢性心力衰竭的重要药物