Genetic repair of muscular degeneration associated with Duchenne muscular dystrophy

杜氏肌营养不良症相关肌肉变性的基因修复

基本信息

批准号：
10439290
负责人：
Martin F. Engelke
金额：
$ 37.54万
依托单位：
ILLINOIS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10439290
关键词：
Acute Address Affect Afferent Neurons Animal Model Animals Area Award Behavior Behavioral Biological Assay Biological Models Brain Caenorhabditis elegans Calcium Calmodulin Canis familiaris Cell Line Cell membrane Cell physiology Cessation of life Chemicals Complement Coupling DNA Sequence Alteration Defect Degenerative Disorder Development Disease Disease Progression Duchenne muscular dystrophy Dystrophin Embryonic Development Exertion Extracellular Matrix Failure Fishes Functional disorder Genes Genetic Grant Growth Homeostasis Human Immunohistochemistry Impairment Individual Intervention Larva Lesion Link Longevity Mediating Mitochondria Modeling Molecular Target Mus Muscle Muscle Cells Muscle Development Muscular Dystrophies Mutation Myoblasts Myopathy Necrosis Nematoda Nerve Degeneration Nervous system structure Neurologic Neurons Nociceptors Orthologous Gene Outcome Pathogenesis Pathology Pathway interactions Patients Phenotype Physical activity Play Preclinical Testing Prevention Process Proteins Public Health RNA Interference RNA interference screen Regimen Reporter Role Sensory Severity of illness Signal Pathway Signal Transduction Structure System Testing Therapeutic Titrations United States National Institutes of Health Validation Work advanced system base behavioral phenotyping burden of illness fly high throughput screening improved insight link protein loss of function mutation male muscle degeneration mutant myogenesis nervous system development patient response pre-clinical therapy relating to nervous system repaired screening side effect therapeutic candidate therapeutic target treatment response

项目摘要

Project Summary/Abstract: Duchenne Muscular dystrophy (Dmd) is a lethal degenerative disease affecting 1 in 5,000 males. Dmd is caused by mutations in the gene encoding dystrophin, a highly conserved protein linking muscle cell membranes with the extracellular matrix and the contractile machinery within them. Dystrophin has structural and signaling functions. Loss of dystrophin is linked to muscular and neural degeneration. While traditional analyses of mice, worms and other animals modeling Dmd genetically, through loss-of-function mutations in the dystrophin gene, resulted in great advances, these systems have only produced relatively mild muscular and behavioral phenotypes. To date there is no cure for Dmd. To model the acute muscle degeneration observed in Dmd patients in a model system amenable to genetics we developed a fast and inexpensive nematode assay. Our assay elicits strong behavioral and cellular phenotypes in dystrophic (dys-1) nematodes to a degree not previously attained in other systems. During our previous award cycle, we improved our assay to allow automatization and medium to high throughput screening of candidate treatments. We went on to characterize many dystrophic phenotypes and found that they first arise during embryogenesis. We also identified the first neurological impairments in dystrophic worms, where the sensory function of ASH neurons is impaired. A suppressor mutant, and an RNA-interference screen both pointed to calmodulin as a therapeutic target. The first specific aim of this project is to characterize the onset of dystrophic phenotypes during myogenesis, and to separate the contribution of dystrophin’s signaling and structural roles to these deficits. This will identify the mechanism by which muscles become impaired during development. The second aim is to characterize the role dystrophin plays in the structure and function of the ASH neurons. These well-studied neurons will provide an amenable springboard to study the neuropathophysiology of Dmd. In the third aim, we will use our assay to identify downstream effectors of calmodulin responsible for the prevention of dystrophic phenotypes observed following reduction of calmodulin function in dys-1 animals. Identifying these effectors will be key to finding safe treatment avenues, sparing additional processes mediated by calmodulin. To validate our findings and bridge the gap to humans, we will use humanized dystrophic nematodes and human myogenic cell lines. Completion of these aims will provide key insights into Dmd pathophysiology and identify new molecular targets and pathways that can be used to treat this disease.

项目摘要/摘要： Duchenne肌肉营养不良症（DMD）是一种致命的退化性疾病，影响了5,000名男性中有1个。 DMD 是由编码肌营养不良蛋白的基因中的突变引起的，这是一种高度保守的蛋白，连接肌肉细胞带有细胞外矩阵和收缩机械的膜。肌营养不良蛋白具有结构和信号功能。肌营养不良蛋白的丧失与肌肉和神经变性有关。尽管通过功能丧失对小鼠，蠕虫和其他动物进行基因建模DMD的传统分析肌营养不良蛋白基因的突变导致了很大的进步，这些系统仅产生了相对的轻度肌肉和行为表型。迄今为止，尚无法治愈DMD。建模在模型系统中观察到的DMD患者中观察到的急性肌肉变性遗传学我们开发了一种快速且廉价的线虫测定法。我们的测定引起了强烈的行为和营养不良（DYS-1）线虫中的细胞表型以前在其他系统中未附着的程度。在以前的奖励周期中，我们改进了评估，以允许自动化和中等至高候选治疗的吞吐量筛查。我们继续描述了许多营养不良的表型并发现它们在胚胎发生期间首先出现。我们还确定了第一个神经系统障碍在营养不良的蠕虫中，灰神经元的感觉功能受损。抑制突变体， RNA干扰屏幕都指向Calmoulin是一种治疗靶标。第一个具体目的项目是为了表征肌发生过程中营养不良表型的发作，并将其分开肌营养不良的信号传导和结构作用对这些缺陷的贡献。这将确定肌肉在发育过程中受到损害的机制。第二个目的是表征肌营养不良蛋白在灰神经元的结构和功能中发挥作用。这些良好的神经元将提供一个可正常的跳板来研究DMD的神经病理生理学。在第三个目标中，我们将使用我们的评估以确定负责预防营养不良的钙调蛋白的下游影响 DYS-1动物中钙调蛋白功能降低后观察到的表型。识别这些效果将是寻找安全治疗途径的关键，保留由钙调蛋白。为了验证我们的发现并弥合了与人类的差距，我们将使用人性化营养不良线虫和人类肌生成细胞系。这些目标的完成将为DMD提供关键的见解病理生理学并确定可用于治疗该疾病的新分子靶标和途径。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Factors that influence magnetic orientation in Caenorhabditis elegans

DOI：
10.1007/s00359-019-01364-y
发表时间：
2020-05-01
期刊：
JOURNAL OF COMPARATIVE PHYSIOLOGY A-NEUROETHOLOGY SENSORY NEURAL AND BEHAVIORAL PHYSIOLOGY
影响因子：
2.1
作者：
Bainbridge, C.;Clites, B. L.;Vidal-Gadea, A. G.
通讯作者：
Vidal-Gadea, A. G.

Response to comment on "Magnetosensitive neurons mediate geomagnetic orientation in Caenorhabditis elegans".

对“磁敏神经元介导秀丽隐杆线虫地磁定向”评论的回应。

DOI：
10.7554/elife.31414
发表时间：
2018
期刊：
eLife
影响因子：
7.7
作者：
Vidal-Gadea,Andres;Bainbridge,Chance;Clites,Ben;Palacios,BridgitteE;Bakhtiari,Layla;Gordon,Vernita;Pierce-Shimomura,Jonathan
通讯作者：
Pierce-Shimomura,Jonathan