The DOI matches its Crossref record; 77 of the 77 references it cites were found in a registry or an index.
Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma
Open accessAbstract
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.
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“Indeed, in a mouse model of glaucoma, a neurodegenerative disease associated with RGC loss and gliosis, C1q and C3 are highly upregulated and deposited on retinal synapses and C1q deficiency or microglial ‘inactivation’ with minocycline provide significant neuroprotection (Howell et al., 2011; Steele et al., 2006; Stevens et al., 2007).”
From Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner (2012) · cites this paper as Howell et al., 2011
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Cites
Statistical significance for genomewide studies
Storey, J. D., & Tibshirani, R. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1530509100 · Cited by 9,692
KEGG for linking genomes to life and the environment
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affy—analysis of Affymetrix GeneChip data at the probe level
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The Classical Complement Cascade Mediates CNS Synapse Elimination
Stevens, B., Allen, N. J., Vazquez, L. E., Howell, G. R., Christopherson, K. S., Nouri, N., Micheva, K. D., Mehalow, A. K., Huberman, A. D., Stafford, B., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.036 · Cited by 3,313
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Self-citationNumber of people with glaucoma worldwide.
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Ringnér, M. (2008) · Nature Biotechnology · doi:10.1038/nbt0308-303 · Cited by 2,407
Microglia and inflammation-mediated neurodegeneration: Multiple triggers with a common mechanism
Block, M. L., & Hong, J.-S. (2005) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2005.06.004 · Cited by 1,557
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Cited by
Sorted by citations
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer, D. P., Lehrman, E. K., Kautzman, A. G., Koyama, R., Mardinly, A. R., Yamasaki, R., Ransohoff, R. M., Greenberg, M. E., Barres, B. A., & Stevens, B. (2012) · Neuron · doi:10.1016/j.neuron.2012.03.026 · Cited by 4,089
Self-citationMicroglia emerge as central players in brain disease
Salter, M. W., & Stevens, B. (2017) · Nature Medicine · doi:10.1038/nm.4397 · Cited by 1,767
Self-citationThe Complement System: An Unexpected Role in Synaptic Pruning During Development and Disease
Stephan, A. H., Barres, B. A., & Stevens, B. (2012) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-061010-113810 · Cited by 1,113
Self-citationThe molecular basis of retinal ganglion cell death in glaucoma
Almasieh, M., Wilson, A. M., Morquette, B., Vargas, J. L. C., & Polo, A. D. (2011) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2011.11.002 · Cited by 988
Astrocyte reactivity and reactive astrogliosis: costs and benefits
Pekny, M., & Pekna, M. (2014) · Physiological Reviews · doi:10.1152/physrev.00041.2013 · Cited by 934
Metadata
- Authors
- Howell, G. R., Macalinao, D. G., Sousa, G. L., Walden, M., Soto, I., Kneeland, S. C., Barbay, J. M., King, B. L., Marchant, J. K., Hibbs, M., Stevens, B., Barres, B. A., Clark, A. F., Libby, R. T., & John, S. W. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- Jackson Laboratory (US)
- Mount Desert Island Biological Laboratory (US)
- Tufts University (US)
- Harvard University (US)
- Stanford University (US)
- University of North Texas Health Science Center (US)
- University of Rochester (US)
- Corresponding author
- John, Simon W.M.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2011-04-01
- Volume
- 121
- Issue
- 4
- Pages
- 1429-1444
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3069778
- OpenAlex
- W1983740408
- Cited by
- 473
- References
- 77
- Citations by year
- 2026: 25 · 2025: 28 · 2024: 20 · 2023: 46 · 2022: 43 · 2021: 34 · 2020: 39 · 2019: 26 · 2018: 24 · 2017: 33 · 2016: 29 · 2015: 35 · 2014: 24 · 2013: 28 · 2012: 28
- FWCI
- 26.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- American Health Assistance Foundation
- Research to Prevent Blindness
- National Institutes of Health (NIH T32, EY011721)
- National Eye Institute (EY018606, R29EY011721, R01EY018606, R01EY011721, EY011721, F32EY014515)
- National Institute of Neurological Disorders and Stroke (T32 NS51112-05, T32NS051112)
- Topics
- Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Keywords
- glaucoma, early-stage disease, complement system, endothelin system, endothelin receptor antagonism, bosentan, C1QA, optic nerve head, retina, microglia/macrophages, vascular dysfunction, disease progression, therapeutic target, DBA/2J mice
- MeSH terms
- Bosentan, Animals, Disease Models, Animal, Female, Glaucoma, Humans, Mice, Inbred DBA, Mice, Mutant Strains, Optic Nerve, Retina, Sulfonamides, Signal Transduction, Up-Regulation, Complement C1q, Cluster Analysis, Endothelin-2, Gene Expression Profiling, Mice, Endothelin Receptor Antagonists
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