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Citations to this article

Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma
Gareth R. Howell, … , Richard T. Libby, Simon W.M. John
Gareth R. Howell, … , Richard T. Libby, Simon W.M. John
Published March 7, 2011
Citation Information: J Clin Invest. 2011;121(4):1429-1444. https://doi.org/10.1172/JCI44646.
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Research Article Ophthalmology Article has an altmetric score of 6

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

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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.

Authors

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

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2009 Total
Citations: 7 13 24 26 28 21 19 14 18 18 20 13 18 18 3 1 261
Citation information
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Citations to this article in year 2016 (18)

Title and authors Publication Year
Targeting the complement system for the management of retinal inflammatory and degenerative diseases
H Xu, M Chen
European Journal of Pharmacology 2016
Mice Homozygous for a Deletion in the Glaucoma Susceptibility Locus INK4 Show Increased Vulnerability of Retinal Ganglion Cells to Elevated Intraocular Pressure
S Gao, TC Jakobs
The American Journal of Pathology 2016
Exercise reverses age-related vulnerability of the retina to injury by preventing complement-mediated synapse elimination via a BDNF-dependent pathway
V Chrysostomou, S Galic, P Wijngaarden, IA Trounce, GR Steinberg, JG Crowston
Aging Cell 2016
Endothelins Inhibit Osmotic Swelling of Rat Retinal Glial and Bipolar Cells by Activation of Growth Factor Signaling
S Vogler, A Grosche, T Pannicke, P Wiedemann, A Reichenbach, A Bringmann
Neurochemical Research 2016
Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes
WS Chung, PB Verghese, C Chakraborty, J Joung, BT Hyman, JD Ulrich, DM Holtzman, BA Barres
Proceedings of the National Academy of Sciences 2016
Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma
PA Williams, JR Tribble, KW Pepper, SD Cross, BP Morgan, JE Morgan, SW John, GR Howell
Molecular Neurodegeneration 2016
Retinal Macroglial Responses in Health and Disease
R Hoz, B Rojas, AI Ramírez, JJ Salazar, BI Gallego, A Triviño, JM Ramírez
BioMed Research International 2016
Glial coverage in the optic nerve expands in proportion to optic axon loss in chronic mouse glaucoma
A Bosco, KT Breen, SR Anderson, MR Steele, DJ Calkins, ML Vetter
Experimental Eye Research 2016
Genetic Networks in Mouse Retinal Ganglion Cells
FL Struebing, RK Lee, RW Williams, EE Geisert
Frontiers in Genetics 2016
C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury
SM Silverman, BJ Kim, GR Howell, J Miller, SW John, RJ Wordinger, AF Clark
Molecular Neurodegeneration 2016
Automated Axon Counting in Rodent Optic Nerve Sections with AxonJ
K Zarei, TE Scheetz, M Christopher, K Miller, A Hedberg-Buenz, A Tandon, MG Anderson, JH Fingert, MD Abràmoff
Scientific Reports 2016
YBR/EiJ mice: a new model of glaucoma caused by genes on chromosomes 4 and 17
KS Nair, M Cosma, N Raghupathy, MA Sellarole, NG Tolman, W Vries, RS Smith, SW John
Disease models & mechanisms 2016
Time-Lapse Retinal Ganglion Cell Dendritic Field Degeneration Imaged in Organotypic Retinal Explant Culture
TV Johnson, EN Oglesby, MR Steinhart, E Cone-Kimball, J Jefferys, HA Quigley
Investigative ophthalmology & visual science 2016
Complement component 3 (C3) expression in the hippocampus after excitotoxic injury: role of C/EBPβ
E Hernandez-Encinas, D Aguilar-Morante, JA Morales-Garcia, E Gine, M Sanz-SanCristobal, A Santos, A Perez-Castillo
Journal of Neuroinflammation 2016
Early Cytoskeletal Protein Modifications Precede Overt Structural Degeneration in the DBA/2J Mouse Model of Glaucoma
GN Wilson, MA Smith, DM Inman, CM Dengler-Crish, SD Crish
Frontiers in neuroscience 2016
Astrocyte Structural and Molecular Response to Elevated Intraocular Pressure Occurs Rapidly and Precedes Axonal Tubulin Rearrangement within the Optic Nerve Head in a Rat Model
S Tehrani, L Davis, WO Cepurna, TE Choe, DC Lozano, A Monfared, L Cooper, J Cheng, EC Johnson, JC Morrison, KS Cho
PloS one 2016
A Period of Controlled Elevation of IOP (CEI) Produces the Specific Gene Expression Responses and Focal Injury Pattern of Experimental Rat Glaucoma
JC Morrison, WO Cepurna, S Tehrani, TE Choe, H Jayaram, DC Lozano, B Fortune, EC Johnson
Investigative ophthalmology & visual science 2016
Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma
A Krishnan, F Fei, A Jones, P Busto, A Marshak-Rothstein, BR Ksander, M Gregory-Ksander
Journal of immunology (Baltimore, Md. : 1950) 2016

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