Neuroprotection and Retinal Ganglion Cell Death The overarching goal of the studies proposed in this application is to understand the specific apoptosis pathways that are triggered in RGC in glaucoma in order to identify targets for neuroprotection. In this application, we will build on a series of exciting new observations to test our hypothesis that calcineurin acts as a central control point in RGC death in glaucoma. In the aqueous outflow obstruction (Morrison) rat model of experimental glaucoma, we observe an increased lOP-related apoptotic cascade that involves dephosphorylation of proapoptotic Bad,release of cytochrome c (cytc) from the mitochondria, caspase activation and apoptotic retinal ganglion RGC loss. We hypothesize that these events are a consequence of aberrant calcineurin activation. Treatment of rats with surgically induced glaucoma with the calcineurin inhibitor, FK506 (tacrolimus, an FDA-approved immunosuppressant), leads to a dramatic neuroprotective response with blunting of the pBad dephosphorylation, cyt c release, RGC loss and axonal destruction. Moreover, in both rats with elevated IOP and the DBA/2J mouse model of glaucoma, we observe only in eyes with elevated IOP the appearance of a truncated form of calcineurin that lacks a key inhibitory domain, and is therefore constitutively active and proapoptotic. New preliminary data are consistent with calpain causing this abnormal cleavage event. These results suggest that calpain and calcineurin activation are critical early mediators of pressure-induced RGC death and that calcineurin activation is a potential nodal point in the control of RGC death in glaucoma. This hypothesis is tested in 3 aims: We propose to further evaluate the relationship between IOP and calpain and calcineurin activation and apoptosis of RGC to understand early events in IOP induced RGC death (aim 1). We will formally test the hypothesis thta the mechanism of action of FK506 is local inhibition of calcineurin (aim2). We will assess the role of calpain activation of calcineurin and of caspases, and determine whether calpain inhibition is neuroprotective in experimental glaucoma (aim 3). If further confirmed, these findings point towards a novel neuroprotective strategy with clinical applicability.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013399-09
Application #
8002010
Study Section
Special Emphasis Panel (ZRG1-BDCN-F (02))
Program Officer
Agarwal, Neeraj
Project Start
2001-04-01
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
9
Fiscal Year
2011
Total Cost
$322,898
Indirect Cost
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114
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Wu, Hai-Yan; Hudry, Eloise; Hashimoto, Tadafumi et al. (2010) Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci 30:2636-49
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Fan, Bao Jian; Figuieredo Sena, Dayse R; Pasquale, Louis R et al. (2010) Lack of association of polymorphisms in elastin with pseudoexfoliation syndrome and glaucoma. J Glaucoma 19:432-6

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