Mechanisms of anti-inflammation and membrane stabilization in muscular dystrophy

肌营养不良症的抗炎和膜稳定机制

• 批准号: 9513799
• 负责人: Christopher Ryan Heier
• 金额: $ 24.9万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-11 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9513799
• 关键词: Ablation; Address; Adverse effects; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Arrhythmia; Basic Science; Binding Sites; Biological Assay; Canis familiaris; Cardiac; Cardiac health; Cardiomyopathies; Caring; Cell membrane; Cells; ChIP-seq; Childhood; Clinical Trials; Complex; DNA; DNA Binding; Data; Deficiency Diseases; Disease; Doctor of Philosophy; Drug Design; Drug effect disorder; Duchenne muscular dystrophy; Dystrophin; Echocardiography; Electrocardiogram; Elements; Etiology; Event; Fluorescence Recovery After Photobleaching; Genetic; Glucocorticoid Receptor; Glucocorticoids; Goals; Heart; Image; Inflammation; Inflammatory; Injury; Knockout Mice; Knowledge; Label; Laser injury; Ligands; Limb structure; Membrane; Membrane Fluidity; Mentors; Modeling; Modification; Molecular; Molecular Biology; Molecular Medicine; Mus; Muscle; Muscular Atrophy; Muscular Dystrophies; Mutant Strains Mice; Mutation; Myopathy; Myositis; NR3C1 gene; Nerve; Neuromuscular Diseases; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacologic Actions; Pharmacology; Phase; Phenotype; Phosphorylation; Physical Chemistry; Physiological; Point Mutation; Poloxamer 188; Positioning Attribute; Primary Myocardial Diseases; Proteins; Quality of life; Rare Diseases; Research; Role; Steroids; Technology; Testing; Training; Transactivation; Ubiquitination; Vertebral column; Whole Organism; Work; animal imaging; career; delta Sarcoglycan; experience; experimental study; improved; kinase inhibitor; live cell imaging; mdx mouse; mouse model; muscle strength; mutant; neuromuscular; next generation; next generation sequencing; novel; novel strategies; novel therapeutics; patient population; pi bond; prednisolone; receptor; repaired; response; standard of care; therapeutic development; validation studies

 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.

 描述（由申请人提供）：项目概要/摘要：自20世纪50年代以来，药理学糖皮质激素一直是大多数炎性疾病的标准治疗药物，并且仍然是全世界最常用的处方药之一。它们被用于标签外治疗杜氏（DMD）和肢带（LGMD）肌营养不良症的子集。尽管令人印象深刻的疗效和广泛的使用，其复杂的作用机制尚未被解剖，和苛刻的副作用是一个大问题，限制了他们的效用和负面影响患者的生活质量。一种新的化合物VBP 15在DMD的mdx小鼠模型中将疗效与副作用分开，现在正在进行DMD临床试验。这一发现，沿着小鼠受体通路的关键突变，将有助于解决一个重要的、长期存在的问题：药理学糖皮质激素的作用机制是什么，如何改善？该提案的目的是：1）确定配体对GR磷酸化、降解和DNA相互作用的特异性作用; 2）确定GR是否在肌营养不良蛋白缺乏症病因学和类固醇的功效中起作用; 3）发现膜稳定作用机制（VBP 15，泊洛沙姆-188）是否对营养不良心脏健康产生当前治疗方法未发现的益处。主要研究者Christopher Heier博士是一名分子遗传学博士，他在儿科神经肌肉疾病和转化分子医学方面的背景非常适合推进本提案中的目标。在K99阶段，Heier博士将获得以下方面的新培训：1）下一代测序技术（ChIP-seq），ii）活细胞成像（FRAP，或光漂白后荧光恢复），iii）活动物成像（超声心动图）。Heier博士组建了一个强大的指导团队，拥有遗传学、动物模型、活细胞成像和整个生物体和单细胞的组学方法方面的专业知识（主要导师：Eric霍夫曼，PhD，共同导师：Kanneboyina Nagaraju，PhD，DVM，Jyoti Jaiswal，PhD）。拟议的K99/R 00应用程序是促进Heier博士过渡到独立职业生涯的最终目标的理想工具，该职业生涯专注于开发神经肌肉孤儿疾病的下一代治疗方法，通过共享的分子生物学途径使更多患者群体受益。