Endothelin B (ETB) receptors have been shown to be elevated in various ocular tissues in animal models of glaucoma. Our preliminary data suggest that ETA receptors are also increased in retinas of rats with elevated IOP. Previous work from our laboratory showed that many of the deleterious effects of ocular hypertension including optic nerve axonal injury and retinal ganglion cell (RGC) loss are attenuated in ETB receptor-deficient rats. This suggests a causative role of ETB receptors in neurodegeneration. However, the mechanisms underlying endothelin mediated neurodegeneration of the optic nerve and RGCs are not understood. The main hypothesis that antagonism of the endothelin receptors promotes neuroprotection by attenuating the c-Jun N-terminal kinase (JNK) and p38 MAP kinase pathway during ocular hypertension. The current grant application will comprise of the following specific aims: 1) Determine if the endothelin receptors mediate neurodegeneration of RGCs and their axons by activating c-Jun N-terminal kinase (JNK) and p38 MAP kinase signaling pathways in rodents. 2) Elucidate the signaling mechanisms involved in endothelin mediated apoptosis of cultured primary retinal ganglion cells. 3) Investigate if endothelin receptor antagonism is neuroprotective in a rodent model of ocular hypertension. The highlights of this project include a gene therapy intervention using adeno-associated viral knock down of ETA as well as the ETB receptor to determine its neuroprotective effects during ocular hypertension in rats. Another approach proposed in the grant is the use of endothelin receptor antagonists to block endothelin receptors and promote neuroprotection in IOP elevated rats. The project will assess the contribution of endothelin receptors to neurodegeneration and delineate the role of the JNK and p38 MAP kinase pathway in endothelin receptor-mediated neurodegeneration during ocular hypertension in rats. The project will also generate possibilities for molecular as well as pharmacological interventions to block endothelin receptors thereby promote neuroprotection of RGCs and their axons. The basic information gained from these studies would facilitate development of neuroprotective agents for treatment of glaucoma.

Public Health Relevance

Endothelin receptors are proteins that are increased in the eyes with increased pressure as seen in glaucoma. In the current grant application, attempts will be made to block endothelin receptors to protect nerve cells in the eye from dying due to elevated ocular pressure. The protective approaches developed from these studies could help in developing new drugs for glaucoma treatment.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY028179-02
Application #
9559700
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Liberman, Ellen S
Project Start
2017-09-30
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of North Texas
Department
Ophthalmology
Type
Graduate Schools
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107