The astrocyte transcriptome in age and glaucoma: a comparative study of the optic nerve head, optic nerve proper and corpus callosum

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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.