Determining the importance of Endothelins in glaucoma

Gareth Howell, PhD
The Jackson Laboratory (Bar Harbor, ME)
Year Awarded:
2010
Grant Duration:
April 1, 2010 to September 30, 2012
Disease:
Glaucoma
Award Amount:
$100,000
Grant Reference ID:
G2010023
Award Type:
Standard
Award Region:
US Northeastern

Co-principal Investigators

Simon John, PhD
The Jackson Laboratory (Bar Harbor, ME)
Recipient of the Thomas R. Lee award for National Glaucoma Research

Characterizing the Endothelin System in Glaucoma

Summary

No therapies are available that target neuronal death in glaucoma. Here, we assess an important pathway, the Endothelin System, to better understand the mechanisms of neuronal cell death. Endothelins are normally thought to influence, blood pressure. However, this work could lead to the development of improved therapies for human glaucoma.

Details

Glaucoma affects 70 million people worldwide. It is caused by the death of retinal ganglion cells, the output neurons of the retina. No treatments are available that target neuronal death in glaucoma as the mechanisms involved are unclear. We and others have good evidence for an important role of the Endothelin System in glaucoma but the full importance is not known. We will use a mouse model of heritable glaucoma to fully characterize key members of the Endothelin System at different stages of glaucoma. We will concentrate on very early stages of glaucoma, prior to significant neuronal cell loss. In addition, we will assess glaucoma in mice deficient in a key member of the Endothelin System, Endothelin-2. This work has the potential to lead to improved therapies for human glaucoma.

Research Updates

In this proposal, Dr. Howell’s and Dr. John’s team is assessing the role of the Endothelin system in glaucoma. Components of the Endothelin system are present in glaucoma, but the importance of this is not clear. They assessed the role of the Endothelin system in DBA/2J mice, a widely-used model of glaucoma. DBA/2J show key features of glaucoma including an age-related elevation of intraocular pressure and regional loss of retinal ganglion cells, the output neuron of the retina. In the first year, Dr. Howell’s and Dr. John’s team made exciting progress showing that Endothelin-2 (EDN2), a key molecule in the Endothelin system is expressed in macrophages/microglia very early in glaucoma. Macrophages/microglia are immune cells that survey the environment and respond to signals that may indicate disease processes. The team believes these cells may be harming blood vessels, a potentially early step in glaucoma.

In order to ascertain whether these cells are harming blood vessels, they needed to localize other key components of the Endothelin system, including the receptors EDNRA and EDNRB. In the second year of funding, the team has shown that EDN2 is expressed in macrophages/microglia in the optic nerve head (Howell et al., 2012). They have shown that these cells are likely to infiltrate from the blood vessels very early in glaucoma. In addition, they showed that an FDA-approved drug, called Bosentan, can block the effects of EDN2 and protect mice from developing visible damage to their retina due to glaucoma. This drug is already used to treat pulmonary hypertension and chronic heart failure in humans. If proven effective in further laboratory and human clinical testing, this new Bosentan treatment could potentially prevent eye damage and vision loss due to glaucoma.

Two critical experiments are underway to continue to assess the importance of EDN2 in infiltrating macrophages/microglia. First, they are assessing glaucoma in DBA/2J mice that have an EDN2-deficient bone marrow (no EDN2 in the immune cells). Secondly, they are assessing glaucoma in mice that have been administered another type of Endothelin receptor antagonist drug. Further work is required to fully characterize the potential benefits of blocking the Endothelin system as a viable treatment for glaucoma.

Publications

Howell GR, Macalinao DR, Sousa G, Walden M, Soto I, Kneeland S, Barbay J, King BL, Marchant JK, Hibbs M, Stevens B, Barres BA, Clark AF, Libby RT, and John SWMJ. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J. Clinical Investigation PubMed Icon Google Scholar Icon

Harmon K, Barbay JM, Porciatti V, Anderson MG, Smith RS, Clark AF, Libby RT and John SWM (2012). Radiation treatment inhibits monocyte entry into the optic nerve head and prevents glaucoma in DBA/2J mice. J. Clin. Invest. 122(4):1246-61. PubMed Icon Google Scholar Icon

Howell GR, Soto I, Zhu X, Ryan M, Macalinao DG, Sousa GL, Caddle LB, Harmon K, Barbay JM, Porciatti V, Anderson MG, Smith RS, Clark AF, Libby RT and John SWM (2012). Radiation treatment inhibits monocyte entry into the optic nerve head and prevents glaucoma in DBA/2J mice. J. Clin. Invest.
122(4):1246-61. PubMed Icon Google Scholar Icon

Reinholdt LG*, Howell GR*, Czechanski AM, Macalinao DG, MacNicoll KH, Lin C-S, Donahue LR and John SWMJ (2012). Generating embryonic stem cells from the inbred mouse strain DBA/2J, a model of glaucoma and other complex diseases. Plos One (in press).
*Authors contributed equally