Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma

Gareth R. Howell, Danilo G. Macalinao, Gregory L. Sousa, Michael Walden, Ileana Soto, Stephen C. Kneeland, Jessica M. Barbay, Benjamin L. King, Jeffrey K. Marchant, Matthew Hibbs, Beth Stevens, Ben A. Barres, Abbot F. Clark, Richard T. Libby, Simon W.M. John

Research output: Contribution to journalArticle

212 Citations (Scopus)

Abstract

Glaucoma is one of the most common neurodegenerative diseases. Despite this, the earliest stages of this complex disease are still unclear. This study was specifically designed to identify early stages of glaucoma in DBA/2J mice. To do this, we used genome-wide expression profiling of optic nerve head and retina and a series of computational methods. Eyes with no detectable glaucoma by conventional assays were grouped into molecularly defined stages of disease using unbiased hierarchical clustering. These stages represent a temporally ordered sequence of glaucoma states. We then determined networks and biological processes that were altered at these early stages. Early-stage expression changes included upregulation of both the complement cascade and the endothelin system, and so we tested the therapeutic value of separately inhibiting them. Mice with a mutation in complement component 1a (C1qa) were protected from glaucoma. Similarly, inhibition of the endothelin system with bosentan, an endothelin receptor antagonist, was strongly protective against glaucomatous damage. Since endothelin 2 is potently vasoconstrictive and was produced by microglia/macrophages, our data provide what we believe to be a novel link between these cell types and vascular dysfunction in glaucoma. Targeting early molecular events, such as complement and endothelin induction, may provide effective new treatments for human glaucoma.

Original languageEnglish
Pages (from-to)1429-1444
Number of pages16
JournalJournal of Clinical Investigation
Volume121
Issue number4
DOIs
StatePublished - 1 Apr 2011

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Endothelins
Glaucoma
Cluster Analysis
Endothelin-2
Biological Phenomena
Inbred DBA Mouse
Optic Disk
Microglia
Neurodegenerative Diseases
Blood Vessels
Retina
Up-Regulation
Macrophages
Genome
Mutation

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Howell, G. R., Macalinao, D. G., Sousa, G. L., Walden, M., Soto, I., Kneeland, S. C., ... John, S. W. M. (2011). Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. Journal of Clinical Investigation, 121(4), 1429-1444. https://doi.org/10.1172/JCI44646
Howell, Gareth R. ; Macalinao, Danilo G. ; Sousa, Gregory L. ; Walden, Michael ; Soto, Ileana ; Kneeland, Stephen C. ; Barbay, Jessica M. ; King, Benjamin L. ; Marchant, Jeffrey K. ; Hibbs, Matthew ; Stevens, Beth ; Barres, Ben A. ; Clark, Abbot F. ; Libby, Richard T. ; John, Simon W.M. / Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 4. pp. 1429-1444.
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Howell, GR, Macalinao, DG, Sousa, GL, Walden, M, Soto, I, Kneeland, SC, Barbay, JM, King, BL, Marchant, JK, Hibbs, M, Stevens, B, Barres, BA, Clark, AF, Libby, RT & John, SWM 2011, 'Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma', Journal of Clinical Investigation, vol. 121, no. 4, pp. 1429-1444. https://doi.org/10.1172/JCI44646

Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. / Howell, Gareth R.; Macalinao, Danilo G.; Sousa, Gregory L.; Walden, Michael; Soto, Ileana; Kneeland, Stephen C.; Barbay, Jessica M.; King, Benjamin L.; Marchant, Jeffrey K.; Hibbs, Matthew; Stevens, Beth; Barres, Ben A.; Clark, Abbot F.; Libby, Richard T.; John, Simon W.M.

In: Journal of Clinical Investigation, Vol. 121, No. 4, 01.04.2011, p. 1429-1444.

Research output: Contribution to journalArticle

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AU - Macalinao, Danilo G.

AU - Sousa, Gregory L.

AU - Walden, Michael

AU - Soto, Ileana

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AU - Barbay, Jessica M.

AU - King, Benjamin L.

AU - Marchant, Jeffrey K.

AU - Hibbs, Matthew

AU - Stevens, Beth

AU - Barres, Ben A.

AU - Clark, Abbot F.

AU - Libby, Richard T.

AU - John, Simon W.M.

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