Molecular Characterization of Extraocular Muscle (EOM)

眼外肌 (EOM) 的分子表征

• 批准号: 7896547
• 负责人: TEJVIR S KHURANA
• 金额: $ 41.2万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/7896547
• 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' 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; relational database; therapeutic development; visual deprivation

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描述眼外肌(EOMS)。EOMS的精确功能是人类最佳视力的绝对要求。EOMS是高度专业化的，经历了广泛的反射/运动，并且EOMS的详细特性不同于其他肌肉。令人费解的是，EOMS对某些疾病具有不同的敏感性。EOMS在重症肌无力、Grave‘s病和线粒体肌病中有显著的参与；然而，它们在Duchenne肌营养不良症(DMD)中幸免于难，尽管所有其他骨骼肌群都广泛参与其中。我们的中心论点是，EOMS从根本上不同于其他骨骼肌；我们可以将它们的独特属性和疾病易感性追溯到其分子组成的独特模式；分子条形码。在过去的资助期间，我们全面定义了EOM‘转录组学’和‘蛋白质组学’。这些研究为我们提供了许多关于EOM功能的见解，并为我们提供了EOM独特的分子特征的全球图景。虽然支持了我们的中心论点，但分子表征至今仍不完整。关于新发现的调控分子(如microRNAs)在EOMS中的差异表达，在亚细胞水平的表达差异(例如，亚突触或NMJ区域表达)，或者实际上EOMS与肢体肌肉中差异基因表达的功能后果(例如，钙处理的改变)，许多假说仍未解决。为了验证这些假说，我们建议：a)定义EOM‘miRNAome’，验证miRNA表达差异，并创建EOM mRNA-miRNA交互作用组数据库；b)定义EOM突触亚区(NMJ)的转录组，并确定由于视觉剥夺对突触亚区转录组的改变；以及c)表征EOM中钙调节分子的表达和钙稳态机制。这个项目与健康相关的是，通过完成这些目标，我们将确保更清楚地了解EOMS的分子和功能多样性、它们的生物力学特性、对这些独特肌肉的病理生理学的洞察以及疾病治疗的发展。与公共健康相关：这个项目与健康相关的是，通过完成我们的目标，我们将确保更清楚地了解EOMS的分子和功能多样性，以及它们的生物力学特性，以及对这些独特肌肉的洞察。

项目成果

Distinctive patterns of microRNA expression in extraocular muscles.

• DOI: 10.1152/physiolgenomics.00169.2009
• 发表时间: 2010-05
• 期刊: Physiological genomics
• 影响因子: 4.6
• 作者: U. Zeiger;T. Khurana

Gene profiling in experimental models of eye growth: clues to myopia pathogenesis.

• DOI: 10.1016/j.visres.2010.03.021
• 发表时间: 2010-11-23
• 期刊: VISION RESEARCH
• 影响因子: 1.8
• 作者: Stone, Richard A.;Khurana, Tejvir S.
• 通讯作者: Khurana, Tejvir S.

Identification and characterization of layer-specific differences in extraocular muscle m-bands.

眼外肌 m 带层特异性差异的识别和表征。

• DOI: 10.1167/iovs.06-0701
• 发表时间: 2007
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: Wiesen,MartinHJ;Bogdanovich,Sasha;Agarkova,Irina;Perriard,Jean-Claude;Khurana,TejvirS
• 通讯作者: Khurana,TejvirS