Our studies are directed at advancing treatments to cure infantile and acquired strabismus. At least 3% of the children born in the U.S. are diagnosed with strabismus each year. Early treatment of strabismus can prevent loss of visual function, but strabismus management remains challenging. This is partly because we lack a definitive understanding of its etiology. Our studies will fill this gap in knowledge and lead to improved therapies for strabismus. Eye misalignment in some cases is likely due to improper calibration of the tonic innervation of individual extraocular muscles (EOM) or specific muscle compartments. Acquired strabismus may follow injury of EOM or their innervation. Ultimately, eye alignment, gaze-holding and eye movements all depend on the quality of ocular motor innervation supplied to the EOM. Our studies will determine how current surgical methods and novel application of growth factors alter oculomotor neuronal properties associated with eye alignment. Our long term goal is to develop pharmacologic therapies to modulate force in an "underacting" or "overacting" EOM by changing intrinsic neuronal firing properties and innervational density and modulating perineuronal nets on the motor neurons that innervate the EOM to allow for synaptic plasticity and motor fusion. We will test these strategies in a non-human primate model of sensory-induced strabismus. We also hope to prevent maladaptations that occur after normal human strabismus surgery in order to reduce surgical failure rate. We have 5 specific aims: I. What are the molecular signals that influence the growth of axons and maintain the innervational pattern of the extraocular muscles? We will analyze patterns of growth factor and receptor expression in rabbit EOM, followed by use of exogenously added growth factors or antibodies to modulate the innervational pattern and density. II. Can EOM innervation be manipulated so that maladaptations at the muscle level that occur after surgical recession and/or resection are prevented? We will manipulate nerve growth in EOM by either promoting or preventing proliferation of satellite cells and/or nerve sprouting and neuromuscular junction formation. III. Can we modulate the perineuronal nets around mature motor neurons, and does this result in altered synaptic connections after sustained growth factor treatments? We will define perineuronal net structure and determine efficacy of sustained release BDNF, IGF1, and BMP4 to modulate perineuronal nets, and determine if it will restore motor neuron synaptic plasticity. IV. How do our proven growth factors alter oculomotor neuronal firing properties in the ocular motor system of normal non- human primates? We will analyze neuronal firing rates after treatments we pioneered, IGF-1 and BMP4, which increase or decrease force generation and muscle size. V. We hypothesize that growth factors can effectively treat strabismus. We will use our established methods to produce sensory-induced strabismus in infant monkeys, and then evaluate novel treatments employing growth factor treatments to correct eye misalignment.

Public Health Relevance

At least 3% of the children born in the United States are diagnosed with strabismus every year. Early treatment of strabismus can prevent loss of visual function, but strabismus management remains challenging. Our long term goal is to develop pharmacologic therapies to modulate force in an underacting or overacting EOM by changing intrinsic neuronal firing properties and innervational density and modulating perineuronal nets on the motor neurons that innervate the EOM to allow for synaptic plasticity and motor fusion.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015313-10
Application #
8511649
Study Section
Special Emphasis Panel (ZRG1-IFCN-T (02))
Program Officer
Araj, Houmam H
Project Start
2004-01-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$530,421
Indirect Cost
$114,733
Name
University of Minnesota Twin Cities
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Walton, Mark M G; Mustari, Michael J; Willoughby, Christy L et al. (2015) Abnormal activity of neurons in abducens nucleus of strabismic monkeys. Invest Ophthalmol Vis Sci 56:9-Oct
Hebert, Sadie L; Daniel, Mark L; McLoon, Linda K (2013) The role of Pitx2 in maintaining the phenotype of myogenic precursor cells in the extraocular muscles. PLoS One 8:e58405
Willoughby, Christy L; Christiansen, Stephen P; Mustari, Michael J et al. (2012) Effects of the sustained release of IGF-1 on extraocular muscle of the infant non-human primate: adaptations at the effector organ level. Invest Ophthalmol Vis Sci 53:68-75
Berg, Kathleen T; Hunter, David G; Bothun, Erick D et al. (2012) Extraocular muscles in patients with infantile nystagmus: adaptations at the effector level. Arch Ophthalmol 130:343-9
Anderson, Brian C; Daniel, Mark L; Kendall, Jeffrey D et al. (2011) Sustained release of bone morphogenetic protein-4 in adult rabbit extraocular muscle results in decreased force and muscle size: potential for strabismus treatment. Invest Ophthalmol Vis Sci 52:4021-9
Christiansen, Stephen P; Antunes-Foschini, Rosalia S; McLoon, Linda K (2010) Effects of recession versus tenotomy surgery without recession in adult rabbit extraocular muscle. Invest Ophthalmol Vis Sci 51:5646-56
Harrison, Andrew R; Lee, Michael S; McLoon, Linda K (2010) Effects of elevated thyroid hormone on adult rabbit extraocular muscles. Invest Ophthalmol Vis Sci 51:183-91
Christiansen, Stephen P; Anderson, Brian C; McLoon, Linda K (2008) Botulinum toxin pretreatment augments the weakening effect of injection with ricin-mAb35 in rabbit extraocular muscle. J AAPOS 12:122-7
Anderson, Brian C; Christiansen, Stephen P; McLoon, Linda K (2008) Myogenic growth factors can decrease extraocular muscle force generation: a potential biological approach to the treatment of strabismus. Invest Ophthalmol Vis Sci 49:221-9
Antunes-Foschini, Rosalia S; Miyashita, Denise; Bicas, Harley E A et al. (2008) Activated satellite cells in medial rectus muscles of patients with strabismus. Invest Ophthalmol Vis Sci 49:215-20

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