The long-term goal of the proposed studies is to understand the cell and molecular diversity of extraocular muscle (EOM) in health and disease and establish the mechanisms that contribute toward eye muscle sparing or targeting in neuromuscular disorders.
Specific Aims 1 and 2 address the origins of the EOM phenotype through manipulations of potential regulatory mechanisms at key times in development. The hypothesis that expression of the EOM-specific myosin is extrinsically regulated requiring signaling mechanisms unique to oculomotor motoneurons will be tested using conventional microscopy and sophisticated cell and molecular biology techniques. Tissue-specific regulatory mechanisms are highly pertinent since mutations may contribute toward EOM-specific disorders. The strategy of disrupting or uncoupling sensory-motor interactions during development also is used to examine modulation of the EOM phenotype by the developing visual and vestibular sensory systems that drive eye movements.
Specific Aims 3 and 4 represent an important new step toward linking features of this unique phenotype to disease mechanisms. Much of our knowledge of the responsiveness of skeletal muscle to neurogenic or myogenic disease is based upon information from a limb muscle prototype. Disease states interact with well-characterized muscle fiber types to produce patterned pathological changes that are reliably used in diagnosis. Fundamental differences in the EOM phenotype provide a basis for differential response in disease.
Specific Aim 3 analyzes (a) morphopathologic changes to better understand the mechanisms responsible for and adaptive changes subsequent to human congenital fibrosis of EOM and (b) a transgenic mouse model with maldevelopment of some oculomotor motoneuron pools to better understand the etiology of and muscle consequences in Duane's retraction syndrome. Preliminary studies have shown that EOM exhibits constitutively high antioxidant capacity.
Specific Aim 4 tests the hypothesis that high antioxidant enzyme activity is an important factor in the resistance of EOM to dystrophinopathies. Free radicals are a final common pathway for neuron and muscle pathology in a variety of diseases and insults. Consequently, the relative protection of EOM seen in a variety of insults may be, at least in part, the result of efficient free radical scavenging mechanisms. Taken together, knowledge of EOM properties and adaptive/maladaptive responses in disease will provide a mechanistic understanding of ocular motility disorders that occur in isolation from or in conjunction with those of other skeletal muscles.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
7R01EY009834-06
Application #
2711076
Study Section
Special Emphasis Panel (ZRG1-VISB (01))
Project Start
1993-07-01
Project End
2000-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Porter, John D; Israel, Sheri; Gong, Bendi et al. (2006) Distinctive morphological and gene/protein expression signatures during myogenesis in novel cell lines from extraocular and hindlimb muscle. Physiol Genomics 24:264-75
Spencer, Robert F; Porter, John D (2006) Biological organization of the extraocular muscles. Prog Brain Res 151:43-80
Zhou, Lan; Porter, John D; Cheng, Georgiana et al. (2006) Temporal and spatial mRNA expression patterns of TGF-beta1, 2, 3 and TbetaRI, II, III in skeletal muscles of mdx mice. Neuromuscul Disord 16:32-8
Khanna, Sangeeta; Cheng, Georgiana; Gong, Bendi et al. (2004) Genome-wide transcriptional profiles are consistent with functional specialization of the extraocular muscle layers. Invest Ophthalmol Vis Sci 45:3055-66
Porter, John D; Merriam, Anita P; Leahy, Patrick et al. (2004) Temporal gene expression profiling of dystrophin-deficient (mdx) mouse diaphragm identifies conserved and muscle group-specific mechanisms in the pathogenesis of muscular dystrophy. Hum Mol Genet 13:257-69
Cheng, Georgiana; Merriam, Anita P; Gong, Bendi et al. (2004) Conserved and muscle-group-specific gene expression patterns shape postnatal development of the novel extraocular muscle phenotype. Physiol Genomics 18:184-95
Cheng, Georgiana; Mustari, Michael J; Khanna, Sangeeta et al. (2003) Comprehensive evaluation of the extraocular muscle critical period by expression profiling in the dark-reared rat and monocularly deprived monkey. Invest Ophthalmol Vis Sci 44:3842-55
Andrade, Francisco H; Merriam, Anita P; Guo, Wei et al. (2003) Paradoxical absence of M lines and downregulation of creatine kinase in mouse extraocular muscle. J Appl Physiol 95:692-9
Porter, John D; Merriam, Anita P; Gong, Bendi et al. (2003) Postnatal suppression of myomesin, muscle creatine kinase and the M-line in rat extraocular muscle. J Exp Biol 206:3101-12

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