Strabismus is a misalignment of the visual axes which is relatively common in the general population with estimates of 5-6%. When this disorder occurs in infants, it can lead to severe deficiencies such as loss of central vision from one eye, known as amblyopia. Current therapies for restoration of visual alignment are based on weakening the relatively too strong antagonistic eye muscle, either by surgical recession or pharmacological denervation with botulinum toxin and muscle tightening by surgical resection. There is currently no therapeutic approach that strengthens the weaker muscle. The proposed research is based on recent evidence showing that the strength of muscles is regulated by trophic factors. Experiments were designed to identify trophic factors that either directly affect muscle fibers or provide feedback signals between eye muscles and innervating motor neurons. In the long-term, this project seeks to supplement surgical treatment of strabismus with a pharmacological treatment targeted at trophic interactions. Using an advantageous chicken animal model, we will test the hypothesis that an experimentally weakened developing eye muscle can be strengthened with trophic factors. Injections of trophic factors into selected eye muscles during a critical period of development may restore balanced eye movements by mimicking intrinsic trophic mechanisms. The effectiveness and duration of acute and chronic application of trophic factors will be explored. Additional studies will characterize adaptive responses (molecular, physiological and morphological) that are induced by denervation with botulinum toxin, mechanical denervation, or muscle lesion. Trafficking of trophic factors in mutant mouse models with motor neuron degeneration will be analyzed to identify underlying causes of motor degeneration. Weak and strong human eye muscles of different ages will be examined to compare expression of trophic factors and their receptors. Our studies will focus on trophic factors with established effects in the oculomotor system: glial cell line-derived neurotrophic factor (GDNF), insulin-like growth factors (IGFs), and cardiotrophin-1 (CT-1). A combined pharmacological, molecular, physiological and morphological approach, including the ultra-structural level, will provide a meaningful assessment of the prospects for a trophic, pharmacological treatment of strabismus and other eye muscle disorders as an alternative or supplement to current surgical and denervation procedures.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012841-09
Application #
7645702
Study Section
Central Visual Processing Study Section (CVP)
Program Officer
Araj, Houmam H
Project Start
2000-01-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
9
Fiscal Year
2009
Total Cost
$211,193
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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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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