Strabismus is a misalignment of the visual axis, which can lead to severe deficiencies such as loss of central vision from one eye, known as amblyopia. Strabismus is relatively common in the general population with estimates of 5-6 percent. The etiology of strabismus is multifactorial. Current therapies for restoration of visual alignment include muscle weakening by surgical recession or pharmacological denervation with botulinum toxin and muscle tightening by surgical resection. In the proposed research project, the trophic regulation between eye muscles an innervating oculomotor neurons will be explored with the long-term goal to supplement surgical treatment of strabismus with a pharmacological treatment targeted at trophic interactions. Injections of trophic factors or trophic antagonists into selected eye muscles may restore balanced eye movements by mimicking intrinsic trophic mechanisms. The proposed studies will test in an animal model how trophic manipulations of oculomotor neurons and eye muscles can adjust the strength of these muscles, increase the survival of oculomotor neurons during development, increase numbers of collateral axonal branches of oculomotor neurons, and maintain axon collaterals and endplates. Studies will determine which trophic factors are produced in the eye muscles, which functions they have on muscle mass, muscle strength, nerve sprouting, and maintenance of axons or endplates. Additional studies will determine whether the muscle-derived factors are transported retrogradely to the oculomotor neurons and support the survival of these neurons. The time course of trophic interactions between eye muscles and their nerves will be explored with the goal to understand and manipulate the trophic responses which are induced by denervation with botulinum toxin or in chronically paralyzed muscle such as the avian genetic mutant, crooked neck dwarf (cn/cn). These studies will focus on four trophic factors, brain-derived neurotrophic factor (BDNF), glial cell-line-derived neurotrophic factor (GDNF), and the insulin-like growth factors (IGF I, II), and, added in the resubmission, cardiotrophin-1 (CT-1). Additional trophic factors will be screened for their potential to modify the strength of eye muscles. A combined pharmacological, molecular, physiological and morphological approach including the ultrastructural level will provide a meaningful assessment of the prospects for a trophic, pharmacological treatment of strabismus and other eye muscle disorders as a supplement to current resection and denervation procedures.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY012841-01A1
Application #
6193033
Study Section
Visual Sciences B Study Section (VISB)
Program Officer
Hunter, Chyren
Project Start
2000-09-01
Project End
2005-07-31
Budget Start
2000-09-01
Budget End
2001-07-31
Support Year
1
Fiscal Year
2000
Total Cost
$190,872
Indirect Cost
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
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Feng, Cheng-Yuan; Hennig, Grant W; Corrigan, Robert D et al. (2012) Analysis of spontaneous and nerve-evoked calcium transients in intact extraocular muscles in vitro. Exp Eye Res 100:73-85
von Bartheld, Christopher S (2012) Distribution of Particles in the Z-axis of Tissue Sections: Relevance for Counting Methods. Neuroquantology 10:66-75
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Feng, Cheng-Yuan; von Bartheld, Christopher S (2011) Expression of insulin-like growth factor 1 isoforms in the rabbit oculomotor system. Growth Horm IGF Res 21:228-32
Li, Tian; Feng, Cheng-Yuan; von Bartheld, Christopher S (2011) How to make rapid eye movements ""rapid"": the role of growth factors for muscle contractile properties. Pflugers Arch 461:373-86
Feng, Cheng-Yuan; Wiggins, Larisa M; von Bartheld, Christopher S (2011) The locus ceruleus responds to signaling molecules obtained from the CSF by transfer through tanycytes. J Neurosci 31:9147-58
Von Bartheld, Christopher S; Altick, Amy L (2011) Multivesicular bodies in neurons: distribution, protein content, and trafficking functions. Prog Neurobiol 93:313-40
Li, Tian; Wiggins, Larisa M; von Bartheld, Christopher S (2010) Insulin-like growth factor-1 and cardiotrophin 1 increase strength and mass of extraocular muscle in juvenile chicken. Invest Ophthalmol Vis Sci 51:2479-86
Feng, Chengyuan; Von Bartheld, Christopher S (2010) Schwann cells as a source of insulin-like growth factor-1 for extraocular muscles. Muscle Nerve 41:478-86

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