Project Summary/Abstract
Genomic Loci Modulating Biomechanics and Glaucoma in Recombinant Inbred Mice
Glaucoma is a major cause of blindness and current treatments are insufficient. Here we propose novel studies
to identify genomic loci associated with risk factors for glaucoma; specifically, we search for loci modulating the
biomechanical properties of the sclera, thought to influence how intraocular pressure (IOP) insult is transmitted
to optic nerve head (ONH) cells and tissues. Our central hypothesis is that specific genomic loci and associated
molecular networks determine scleral biomechanical properties (stiffness and viscoelasticity) and are related to
the risk of developing glaucomatous optic neuropathy.
We propose 2 specific aims (SA’s) to test this hypothesis. Both aims use the BXD recombinant inbred (RI) mouse
set, a well-characterized mouse genetic reference panel providing a powerful tool for quantitative trait locus
(QTL) analysis. In SA1, we will measure the biomechanical properties of the sclera in BXD RI substrains and
carry out QTL analysis to identify genomic loci that associate with scleral stiffness and viscoelasticity. In SA2,
we will expose mice to the insult of elevated IOP (both steady and unsteady), and investigate whether extreme
values of scleral stiffness and viscoelasticity predispose these animals to ONH astrocyte activation, thought to
play an important early role in glaucomatous ONH changes.
This project is innovative for several reasons. It represents a novel use of a powerful genetic reference panel
(the BXD RI mouse set) to study and identify risk factors for glaucoma. In so doing, the proposed work is, to our
knowledge, the first attempt to identify genes associated with scleral biomechanical properties in an unbiased
screen, and to investigate whether such properties are associated with early markers of glaucomatous change.
Further, this proposal uses novel technology, first developed to measure outflow facility in mouse eyes, to study
how the sclera and ONH astrocytes respond to both steady and unsteady pressure insults.
We expect, as suggested by our preliminary data, to discover genomic loci that associate with scleral
biomechanical properties. Doing so is the first step towards identifying gene networks that determine scleral
stiffness and viscoelasticity, two properties that indirectly influence the biomechanical insult that ONH cells
experience in glaucoma. The benefits will be twofold. First, these discoveries would provide a powerful tool to
better understand the role of scleral biomechanics in the pathophysiology of retinal ganglion cell loss in
glaucoma. Second, they would motivate studies in humans, potentially identifying novel risk factors for
development of glaucoma in clinical populations.