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Abstract #45655 Published in IGR 13-2
Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma
Howell GR; MacAlinao DG; Sousa GL; Walden M; Soto I; Kneeland SC; Barbay JM; King BL; Marchant JK; Hibbs MJournal of Clinical Investigation 2011; 121: 1429-1444
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.
S. W. M. John. Howard Hughes Medical Institute, Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609, United States. Email: simon.john@jax.org
Classification:
3.6 Cellular biology (Part of: 3 Laboratory methods)
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
