Project Summary
The underlying pathophysiological mechanisms in glaucomatous ganglion cell degeneration are still not
clear. Because of this, current medications rely on modifying a major risk factor, which is intraocular pressure.
However, lowering intraocular pressure alone is not always sufficient, and many patients continue to slowly
lose vision. Identifying new mechanisms that are either harmful or beneficial for ganglion cell survival will
benefit the development of alternative treatments for glaucoma.
A leading hypothesis in the pathophysiology of glaucoma is that astrocytes within the optic nerve head
(ONH) play an important role in the ganglion cell degeneration, albeit it is not clear what this role is. Astrocytes
are a focus because (1) they populate the ONH, a site where early ganglion cell axon injury occurs, and (2)
astrocytes in the ONH become highly “reactive”, a process that changes their morphology, function and
molecular phenotype, but in the white matter of the CNS is not well understood. Although the field recognizes
their importance, there is a fundamental lack of understanding of the properties of ONH astrocytes (and white
matter astrocytes in general), what makes them different and what they are doing in disease. Studies to date
have typically used whole ONH tissues and/or examined either a single or a small group of genes/pathways to
better understand ONH astrocytes, but this is an incomplete picture.
Here, we have combined whole transcriptome profiling with a novel ribotag strategy that allows us to
isolate mRNAs specifically from astrocytes from different tissue regions. We will compare the astrocyte
transcriptome from the unmyelinated ONH, the myelinated optic nerve proper and corpus callosum, in young
and aged mice, and mice that have undergone chronic elevations in intraocular pressure. We hypothesize that
ONH astrocytes are a molecularly distinct population compared to astrocytes in the more distal myelinated
optic nerve proper, and that they have functional specializations associated with the fact that glaucomatous
pathophysiological changes preferentially occur in the nerve head region. Age and elevations in intraocular
pressure induces a unique transcriptional profile. Our previous morphological characterization and
immunocytochemical labeling patterns strongly suggest that ONH astrocytes are indeed unique from those in
the other regions. Our specific aims to test the hypothesis are: (1) investigate the transcriptional profile of
astrocytes in the ONH, optic nerve proper and corpus callosum in both normal young (3 mths) and aged mice
(12 mths), and (2) investigate the transcriptional profile of astrocytes from the ONH and optic nerve proper in
young (3 mths) and aged mice (12 mths) following a chronic elevation in intraocular pressure.
This exploratory proposal will provide an important knowledge base for future more focused hypothesis
driven studies.
