Molecular Characterization of Extraocular Muscle (EOM)

眼外肌 (EOM) 的分子表征

基本信息

批准号：
7649177
负责人：
TEJVIR S KHURANA
金额：
$ 39.75万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7649177
关键词：
Biochemical Biological Assay Biomechanics Calcium Cell Nucleus Characteristics Databases Disease Disease susceptibility Duchenne muscular dystrophy Ensure Fiber Frequencies Functional disorder Funding Fura-2 Gene Expression Gene Expression Profile Goals Graves&apos Disease Health Homeostasis Human Image Immunohistochemistry Limb structure Messenger RNA Methods MicroRNAs Mitochondrial Myopathies Molecular Molecular Profiling Motion Muscle Muscle Fibers Muscle function Muscular Dystrophies Myasthenia Myasthenia Gravis Myopathy Neuromuscular Junction Pathogenesis Pathway interactions Pattern Physiological Play Preparation Property Proteome Public Domains Reflex action Reporter Role Science Skeletal Muscle Strabismus Synapses Testing Tissue-Specific Gene Expression Tissues Untranslated Regions Vision Western Blotting base insight laser capture microdissection mRNA Expression orbit muscle public health relevance ratiometric therapeutic development visual deprivation

项目摘要

DESCRIPTION (provided by applicant): The long-term goals are to comprehensively characterize extraocular muscles (EOMs) at the molecular level. Precise functioning of EOMs is an absolute requirement for optimal vision in humans. EOMs are highly specialized and undergo a wide range of reflexes/motions and the detailed properties of EOMs are different from those of other muscles. Enigmatically, EOMs have differential sensitivity to certain diseases. EOMs have prominent involvement in myasthenia gravis, Grave's disease and mitochondrial myopathies; they are spared, however, in Duchenne muscular dystrophy (DMD), despite the widespread involvement of all other skeletal muscle groups. Our central thesis is that EOMs are fundamentally different from other skeletal muscles; and that we can trace their unique properties and disease susceptibilities to unique patterns of their molecular constituents; a 'molecular barcode'. During the past funding period we have comprehensively defined the EOM 'transcriptome' and 'proteome'. These studies provide us with many insights into EOM function and provide us with a global picture of the unique molecular signature of EOM. While supporting our central thesis, the molecular characterization is as yet incomplete. A number of hypotheses remain unaddressed regarding differential expression in EOMs of newly discovered classes of regulatory molecules (e.g. microRNAs), expression differences at the subcellular level (e.g. sub-synaptic or NMJ regional expression) or indeed functional consequences of differential gene expression (e.g. altered calcium handling) in EOMs vs limb muscles. To test these hypotheses we propose: a) to define the EOM 'miRNAome', validate miRNA expression differences and create an EOM mRNA-miRNA interactome database; b) to define the transcriptome at the sub-synaptic (NMJ) regions of EOM and identify alterations to the sub-synaptic transcriptome due to visual deprivation, and, c) characterize expression of calcium regulatory molecules and calcium homeostatic mechanisms in EOM. The health relatedness of this project is that by completion of these aims we will ensure clearer understanding of the molecular and functional diversity of EOMs, their biomechanical properties, insights into pathophysiology of these unique muscles and therapeutic development for disease. PUBLIC HEALTH RELEVANCE: The health relatedness of this project is that by completion of our aims we will ensure clearer understanding of the molecular and functional diversity of EOMs as well as their biomechanical properties as well as insights into of these unique muscles.

描述（由申请人提供）：长期目标是在分子水平上全面表征眼外肌（EOM）。 EOM 的精确运行是人类最佳视力的绝对要求。 EOM 高度专业化，经历广泛的反射/运动，并且 EOM 的详细属性与其他肌肉不同。神秘的是，EOM 对某些疾病具有不同的敏感性。 EOM 与重症肌无力、格雷夫氏病和线粒体肌病密切相关；然而，尽管所有其他骨骼肌群都广泛受累，但他们却幸免于杜氏肌营养不良症（DMD）。我们的中心论点是 EOM 与其他骨骼肌有根本的不同。我们可以根据其分子成分的独特模式追踪其独特的特性和疾病易感性； “分子条形码”。在过去的资助期间，我们全面定义了 EOM“转录组”和“蛋白质组”。这些研究为我们提供了对 EOM 功能的许多见解，并为我们提供了 EOM 独特分子特征的全局图景。虽然支持我们的中心论点，但分子表征尚不完整。关于新发现的调节分子（例如 microRNA）类别的 EOM 中的差异表达、亚细胞水平的表达差异（例如突触下或 NMJ 区域表达）或差异基因表达的实际功能后果（例如改变的改变），许多假设仍未得到解决。 EOM 与肢体肌肉中的钙处理）。为了测试这些假设，我们建议：a) 定义 EOM“miRNAome”，验证 miRNA 表达差异并创建 EOM mRNA-miRNA 相互作用数据库； b) 定义 EOM 亚突触 (NMJ) 区域的转录组，并识别由于视觉剥夺导致的亚突触转录组的改变，以及 c) 表征 EOM 中钙调节分子和钙稳态机制的表达。该项目与健康的相关性在于，通过完成这些目标，我们将确保更清楚地了解 EOM 的分子和功能多样性、其生物力学特性、对这些独特肌肉的病理生理学的见解以及疾病的治疗开发。公共健康相关性：该项目与健康的相关性在于，通过完成我们的目标，我们将确保更清楚地了解 EOM 的分子和功能多样性及其生物力学特性以及对这些独特肌肉的见解。