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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013862-07
Application #
7896547
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Araj, Houmam H
Project Start
2001-12-01
Project End
2011-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
7
Fiscal Year
2010
Total Cost
$412,002
Indirect Cost
Name
University of Pennsylvania
Department
Physiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Stone, Richard A; Pardue, Machelle T; Iuvone, P Michael et al. (2013) Pharmacology of myopia and potential role for intrinsic retinal circadian rhythms. Exp Eye Res 114:35-47
Amenta, Alison R; Yilmaz, Atilgan; Bogdanovich, Sasha et al. (2011) Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice. Proc Natl Acad Sci U S A 108:762-7
Stone, Richard A; McGlinn, Alice M; Baldwin, Donald A et al. (2011) Image defocus and altered retinal gene expression in chick: clues to the pathogenesis of ametropia. Invest Ophthalmol Vis Sci 52:5765-77
Pistilli, Emidio E; Bogdanovich, Sasha; Garton, Fleur et al. (2011) Loss of IL-15 receptor ýý alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles. J Clin Invest 121:3120-32
Ketterer, Caroline; Zeiger, Ulrike; Budak, Murat T et al. (2010) Identification of the neuromuscular junction transcriptome of extraocular muscle by laser capture microdissection. Invest Ophthalmol Vis Sci 51:4589-99
Zeiger, Ulrike; Mitchell, Claire H; Khurana, Tejvir S (2010) Superior calcium homeostasis of extraocular muscles. Exp Eye Res 91:613-22
Baby, Santhosh M; Bogdanovich, Sasha; Willmann, Gabriel et al. (2010) Differential expression of utrophin-A and -B promoters in the central nervous system (CNS) of normal and dystrophic mdx mice. Brain Pathol 20:323-42
Zeiger, Ulrike; Khurana, Tejvir S (2010) Distinctive patterns of microRNA expression in extraocular muscles. Physiol Genomics 41:289-96
Stone, Richard A; Khurana, Tejvir S (2010) Gene profiling in experimental models of eye growth: clues to myopia pathogenesis. Vision Res 50:2322-33
Pacheco-Pinedo, Eugenia C; Budak, Murat T; Zeiger, Ulrike et al. (2009) Transcriptional and functional differences in stem cell populations isolated from extraocular and limb muscles. Physiol Genomics 37:35-42

Showing the most recent 10 out of 20 publications