Thyroid-related eye disease (TED) is an important public health burden that causes loss of productivity and reduces quality of life. TED can lead to chronic debilitating pain and headaches, double vision, corneal exposure, dry eyes, secondary glaucoma and compressive optic neuropathy, and carries a significant risk of vision loss. The pathogenesis of TED is incompletely understood, but involves the activation of orbital fibroblasts by an unidentified thyroid-related cell signal. Activated fibroblasts in turn secrete large quantities of hyaluronan, causing significant swelling of orbital tissues and especially extraocular muscles. In addition, orbital fibroblasts mediate a severe inflammatory orbitopathy that leads to orbital fibrosis. Orbital fibroblasts can also proliferate and differentiate into adipocytes, filling the orbit with excess fat. The combination of tissue swelling, scarring and adipogenesis leads to exophthalmos and a compartment syndrome whereby normal orbital tissues are compressed by the abnormal ones, leading to compressive optic neuropathy, secondary glaucoma and chronic orbital headaches. Exophthalmos can lead to chronic dry eyes and corneal exposure. The swelling and fibrosis of muscles can lead to ocular misalignment and diplopia. Orbital fibroblasts are derivatives of the neural crest, a transient population of pluripotent cells that differentiate into a broad range of tissues during embryogenesis. The unique behavior of orbital fibroblasts in TED may be partially caused by their embryologic neural crest origins. The main hypothesis of this project is that embryologic processes that occur during the development of the orbital neural crest are important in the pathogenesis of TED. The biology of the orbital neural crest is unknown and largely unexplored. The goal of this research project is to utilize the genetic and cell biology tools available in zebrafish to shed new light on the genetics and cell biology of orbital neural crest-derived tissues, in order to lead to improved diagnostic and treatment for TED and other orbital diseases. Thyroid-related eye disease is an important public health burden that causes loss of productivity anda reduced quality of life.Thegoal of this research is to utilize the genetic and cell biology tools available in zebrafish (a vertebrate model system) to shed new light on the biology of orbital neural crest-derived tissues, in order to lead to improved diagnosis and treatment for TEDand other orbital diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08EY018689-05
Application #
8204650
Study Section
Special Emphasis Panel (ZEY1-VSN (03))
Program Officer
Araj, Houmam H
Project Start
2008-01-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$216,625
Indirect Cost
$16,046
Name
University of Michigan Ann Arbor
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Bohnsack, Brenda L; Kahana, Alon (2013) Thyroid hormone and retinoic acid interact to regulate zebrafish craniofacial neural crest development. Dev Biol 373:300-9
Bohnsack, Brenda L; Kasprick, Daniel S; Kish, Phillip E et al. (2012) A zebrafish model of axenfeld-rieger syndrome reveals that pitx2 regulation by retinoic acid is essential for ocular and craniofacial development. Invest Ophthalmol Vis Sci 53:7-22
Kish, Phillip E; Bohnsack, Brenda L; Gallina, Donika et al. (2011) The eye as an organizer of craniofacial development. Genesis 49:222-30
Bohnsack, Brenda L; Gallina, Donika; Thompson, Hannah et al. (2011) Development of extraocular muscles requires early signals from periocular neural crest and the developing eye. Arch Ophthalmol 129:1030-41
Kasprick, Daniel S; Kish, Phillip E; Junttila, Tyler L et al. (2011) Microanatomy of adult zebrafish extraocular muscles. PLoS One 6:e27095
Bohnsack, Brenda L; Gallina, Donika; Kahana, Alon (2011) Phenothiourea sensitizes zebrafish cranial neural crest and extraocular muscle development to changes in retinoic acid and IGF signaling. PLoS One 6:e22991