The functional role of sarcomeric nonmuscle myosin IIB in extraocular muscles

肌节非肌肉肌球蛋白 IIB 在眼外肌中的功能作用

• 批准号: 8303207
• 负责人: Carole L. Moncman
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303207
• 关键词: Adult; Appearance; Biochemical; Biological Assay; Birth; Development; Disease; Embryo; Extracellular Matrix Proteins; Eye; Eye Movements; Eyelid structure; Fiber; Genetically Engineered Mouse; Imaging Techniques; In Vitro; Life; Longevity; Mesoderm; Microfilaments; Mus; Muscle; Muscle Development; Muscle Fibers; Myocardium; Myofibrillogenesis; Myosin ATPase; Myosin Heavy Chains; Neural Crest; Neuromuscular Junction; Nonmuscle Myosin Type IIB; Pathway interactions; Pattern; Perinatal; Peripheral; Phenotype; Positioning Attribute; Protein Isoforms; Proteins; Rattus; Research Personnel; Rodent; Role; Sarcomeres; Sensory; Skeletal Muscle; Skin; Slide; Striated Muscles; Structural Protein; Structure; Testing; Thick Filament; Thin Filament; Time; Tissues; Vision; Visual; cell motility; early experience; experience; fetal; in vivo; insight; interest; member; muscular structure; non-muscle myosin; orbit muscle; postnatal; programs; research study; vision development

DESCRIPTION (provided by applicant): The extraocular muscles (EOMs) are categorized as skeletal muscles; however, emerging evidence indicates that they deviate significantly from the prototypical members of this muscle class. For example, many myofilament, cytoskeletal and extracellular matrix proteins have unique expression patterns in developing and adult EOMs, including the sustained expression of embryonic and fetal myosin isoforms (MyHC), the presence of a unique EOM-specific MyHC, and co-expression of cardiac and skeletal muscle isoforms of thick and thin filament accessory proteins. We demonstrated that a nonmuscle myosin (nmMyH IIB) is present in the sarcomeric A band of putative tonic EOM fibers. Although small amounts of nmMyH IIB are found in the Z-line of cardiac and skeletal muscles, its unique distribution within the A band in EOM tonic fibers is further evidence of the complexity and unconventional developmental program of the eye muscles. We will use genetically engineered mice to delete nmMyH IIB in a tissue and time-specific manner in order to test the following central hypothesis: the sarcomeric distribution of nmMyH IIB in EOM fibers depends on normal visual experience postnatally and is necessary for normal EOM contractile function in the adult. Thus we have defined the following specific aims: 1) determine whether normal visual experience early in life is necessary for the expression and sarcomeric localization of nmMyH IIB in rodent EOMs, 2) define the role of nmMyH IIB on sarcomeric structure in rodent EOMs and 3) determine the influence of nmMyH IIB on the contractile function of rodent EOMs. These results will establish the role of nmMyH IIB in EOM fibers during early postnatal development and in the adult and should provide valuable insights into our understanding of the normal EOM phenotype and how it might change with disease.)

描述(申请人提供)：眼外肌(EOMS)被归类为骨骼肌；然而，越来越多的证据表明，它们明显偏离了这一肌肉类别的典型成员。例如，许多肌丝、细胞骨架和细胞外基质蛋白在发育和成人EOMS中具有独特的表达模式，包括胚胎和胎儿肌球蛋白亚型(MyHC)的持续表达，独特的EOM特异性MyHC的存在，以及心肌和骨骼肌粗丝和细丝附属蛋白的共同表达。我们证明了肌球蛋白(NmMyH IIB)存在于肌节A带的强直性EOM纤维中。虽然在心肌和骨骼肌的Z线上发现了少量的nmMyH IIB，但它在EOM紧张性纤维的A带中的独特分布进一步证明了眼肌的复杂性和非常规的发育程序。我们将使用基因工程小鼠以组织和时间特定的方式删除nmMyH IIB，以检验以下中心假设：nmMyH IIB在EOM纤维中的肌节分布取决于出生后正常的视觉体验，并且是成人正常EOM收缩功能所必需的。因此，我们确定了以下具体目标：1)确定nmMyH IIB在啮齿动物EOMS中的表达和肌瘤定位是否需要早期正常的视觉体验；2)确定nmMyH IIB在啮齿动物EOMS中对肌节结构的作用；3)确定nmMyH IIB对啮齿动物EOMS收缩功能的影响。这些结果将确定nmMyH IIB在EOM纤维在出生后早期发育和成人中的作用，并将为我们理解正常的EOM表型以及它可能随着疾病而变化提供有价值的见解。)