We have shown that one of the major genes with altered expression in the glaucomatous retina is complement component C1q. Retinal C1q is up-regulated early in the disease process in the DBA/2 mouse model of glaucoma, in laser induced monkey glaucoma and in human glaucoma. We have also made significant progress towards generating a congenic C1q knockout (KO) strain on the DBA/2 background which we will employ in future studies to understand the role of C1q in glaucoma. The changes in expression of C1q and other complement genes, suggest that a neuro-inflammatory process is operational in glaucomatous retinal ganglion cell (RGC) pathology. In fact we present preliminary evidence that an inflammatory reaction is critical for the development of RGC loss in the DBA/2 mouse. Based on the above and the role that complement plays in modulating adaptive immunity we propose the following hypothesis on how complement activation participates in the pathogenesis of glaucoma: Intermediate components of complement activation cause RGC axon and soma damage. [Whether this damage occurs directly or indirectly (through effects on supportive cells, retinal glia or immune cells and extracellular matrix) is beyond the scope of the present project]. To test this hypothesis we must first understand which of the many effector complement molecules are involved in this process. We thus propose the following specific aims: SA1.Test the corollaries that expression levels and/or amounts of intermediate complement components are altered in the retinas from induced and spontaneous (DBA/2) mouse models of glaucoma, as well as in laser induced primate glaucoma and in specimens from patients with glaucoma. SA2. Determine whether complement activation through the classical pathway is involved in the pathophysiology of the disease by characterizing phenotypically the congenic DBA/2 C1q -/- animals we have generated in the previous funding period. SA3. Determine whether the C4 and C3 complement components are required for development of the glaucomatous pathology. This will be achieved by assessing RGC and axonal loss as well as glial activation in congenic DBA/2 C4 -/-and C3-/- animals, as well as in C4 and C3 KO and wild type animals subjected to laser- induced IOP elevation. SA4. Determine whether C5 has a protective role in the pathogenesis of glaucoma. This will be achieved by assessing RGC and axonal loss as well as glial activation in congenic DBA/2 C5 sufficient animals as well as in C5 KOs and wild type mice subjected to laser-induced IOP elevation. SA5. Determine the effect of pressure on Muller cell and RGC complement component expression in vitro. This proposal will dissect the various complement components to allow precise determination of their role in the pathogenesis of glaucoma. Findings will have wider implications for other neurodegenerative disease.

Public Health Relevance

Changes in expression of C1q and other complement genes, suggest that a neuro- inflammatory process is operational in glaucomatous retinal ganglion cell (RGC) pathology. Although it is tempting to try to introduce new therapies once a new pathway involved in neurodegeneration has been identified (in this case anti-complement therapies), it is important to first fully understand all the implications of any intervention in order to avoid wasting valuable resources and potentially even harming patients. This proposal will dissect the various complement components to allow precise determination of the role of each one in the pathogenesis of glaucoma and allow us to rationally design new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015224-10
Application #
8306579
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
Project Start
2003-12-01
Project End
2014-09-29
Budget Start
2012-09-30
Budget End
2014-09-29
Support Year
10
Fiscal Year
2012
Total Cost
$241,287
Indirect Cost
$90,010
Name
Suny Downstate Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
040796328
City
Brooklyn
State
NY
Country
United States
Zip Code
11203
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Kumari, Ruma; Astafurov, Konstantin; Genis, Alina et al. (2015) Differential Effects of C1qa Ablation on Glaucomatous Damage in Two Sexes in DBA/2NNia Mice. PLoS One 10:e0142199
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