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: 8512730
• 负责人: Carole L. Moncman
• 金额: $ 31.74万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512730
• 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（由申请人提供）：眼外肌（EOM）被归类为骨骼肌;然而，新出现的证据表明，它们显著偏离了该肌肉类别的原型成员。例如，许多肌丝、细胞骨架和细胞外基质蛋白在发育和成年EOM中具有独特的表达模式，包括胚胎和胎儿肌球蛋白同种型（MyHC）的持续表达、独特EOM特异性MyHC的存在以及心脏和骨骼肌同种型的粗丝和细丝辅助蛋白的共表达。我们证明了一个非肌肉肌球蛋白（nmMyH IIB）是存在于肌节A带推定的紧张性眼外肌纤维。虽然在心肌和骨骼肌的Z线中发现了少量的nmMyH IIB，但其在EOM紧张性纤维中A带内的独特分布进一步证明了眼肌的复杂性和非常规发育程序。我们将使用基因工程小鼠删除nmMyH IIB在组织和时间特异性的方式，以测试以下中心假设：nmMyH IIB在眼外肌纤维的肌节分布取决于正常的视觉经验出生后，是必要的正常眼外肌收缩功能在成人。因此，我们确定了以下具体目标：1）确定生命早期的正常视觉体验是否是啮齿动物眼外肌中nmMyH IIB的表达和肌节定位所必需的，2）确定nmMyH IIB对啮齿动物眼外肌中肌节结构的作用，3）确定nmMyH IIB对啮齿动物眼外肌收缩功能的影响。这些结果将确立nmMyH IIB在出生后早期发育和成人眼外肌纤维中的作用，并为我们理解正常眼外肌表型及其如何随疾病变化提供有价值的见解。