Alterations in visual experience during a well-defined postnatal window, the critical period, produce irreversible damage to vision. Knowledge of this critical period concept has dramatically improved how the pediatric ophthalmologist manages disorders of vision, eye alignment, and ocular motility. Taking a page from the visual critical period literature, the properties of the developing visuomotor system may be determinants of the cell and molecular diversity of extraocular muscle. The correlate of this hypothesis is that alterations in visuomotor development produce irreversible changes in extraocular muscle biology. Compelling evidence has emerged demonstrating that there is a critical period in the course of extraocular muscle development. Perturbations in visual development alter the expression of a myosin heavy chain gene that is uniquely expressed in extraocular muscle, while similar perturbations in the adult have no effect. Muscle is an elegant structure-function model, with coordinate regulation of traits that determine fiber type. The major tenet evolving from previous studies is that the developing visuomotor system exerts global effects on eye muscle development in the same way that visual experience globally influences visual function. Studies for the next project period are designed to develop an integrated concept of the extraocular muscle critical period.
Specific Aim 1 characterizes myosin gene regulation in relationship to the extraocular muscle critical period, using competitive PCR and mRNA cellular localization techniques.
Specific Aim 2 assesses the role that visuomotor development and the extraocular muscle critical period play in the maturation of mechanisms for calcium homeostasis and energy metabolism, by means of a battery of biochemical assays for rate-limiting enzymes.
Specific Aim 3 evaluates the nascent concept of an extraocular muscle critical period in subhuman primates. Extraocular muscle biology will be assessed in order to determine the consequences that altered visual development and congenital strabismus have for extraocular muscle of a foveate organism. Ultimately, the management of strabismus, not yet a perfect science, likely will be improved, as the relationship between the visual critical period and EOM development is better understood.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009834-09
Application #
6384353
Study Section
Special Emphasis Panel (ZRG1-VISB (03))
Program Officer
Hunter, Chyren
Project Start
1993-07-01
Project End
2004-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
9
Fiscal Year
2001
Total Cost
$226,500
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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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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