Mutations in microfibril proteins (fibrillins and latent- TGF?-binding proteins) underlie syndromes in which the eye is typically, and often severely, affected. Microfibrils are key force-bearing elements of the extracellular matrix but recent studies have shown that they also serve as important hubs for growth factor signaling. Specifically, microfibrils regulate the bioavailability of both transforming growth factor beta (TGF?) and bone morphogenetic proteins (BMPs), two classes of growth factors with well-documented roles in eye development and disease. Preliminary experiments from our laboratory have determined the distribution and organization of microfibril components in the eye. These studies also demonstrated that mice harboring targeted disruptions in microfibril genes represent promising model systems for studying the signaling role of microfibrils during eye development. Building on our preliminary results we will examine the role of fibrillin-2 (Fbn2; the most abundantly expressed fibrillin in the embryo) in closure of the optic fissure and the contribution of TGF? signaling to this process. The ciliary zonule of the adult eye is composed almost entirely of microfibrils. Preliminary studies suggest that the attachment point of the zonule on the lens surface helps to specify the edge of the lens epithelium and implicated BMP signaling in this process. This hypothesis will be tested using mice in which the fibrillin-1 gene (Fbn1;the major fibrillin isoform in the adult eye) is conditionally deleted in the non-pigmented layer of the ciliary epithelium. Finally, in humans, mutations in LTBP2, a microfibril-associated protein, are associated with early onset glaucoma. Therefore, we will test the role of Ltbp2 in the eye and examine whether deletion of Ltbp2 in mice leads to a glaucomatous phenotype. Together, the experiments will provide insights into the role of microfibrils during eye development and disease. Because the signaling pathways mediated by microfibrils are amenable to pharmacologic manipulation, insights arising from our studies may help guide the development of effective treatment regimens for these currently intractable conditions.

Public Health Relevance

Mutations in microfibril proteins (fibrillins and latent-TGFbeta-binding proteins) underlie syndromes in which the eye is typically and often severely affected. Microfibrils function as both structural elements of the extracellular matrix and hubs for growth factor signaling. Insights into the role of microfibrils in ocular development should help guide th development of treatments for the currently intractable ocular manifestations of these conditions.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY024607-01
Application #
8751961
Study Section
Special Emphasis Panel (BVS)
Program Officer
Araj, Houmam H
Project Start
2014-09-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$422,663
Indirect Cost
$143,803
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130