The cornea is the clear part of the eye, of which the endothelium is its innermost layer. This single layer of cells has minimal capacity for self-regeneration and so is very susceptible to blunt trauma and disease onset which can lead to loss of healthy cells. Once healthy endothelial cell numbers falls below the critical value of 1000 cells/mm2, the ability of the endothelium to sustain activities necessary to keep the cornea clear and hence good vision is compromised. Consequently the protection of the endothelium is of public interest. We looked at endothelial protection from the perspective of soluble Adenylate Cyclase (sAC) and adenosine A2b receptors (A2b R). In response to a stimulus, cells use intermediaries known as second messengers to bring about a response. Both sAC and A2b R have cAMP as their common second messengers. For the corneal endothelium, cAMP is a very potent agent to increase endothelium self-preservation. Our studies revealed that: (1) increase in sAC activity by its ligand, bicarbonate (HCO3 -), favors survival; (2) this sAC mediated protection occurs by sAC relaying the HCO3- signal to an increase in cAMP and its immediate effector Protein Kinase A. This signaling pathway produces an increase in the transcription factor pCREB and the mitochondrial tethered protein pBcl2, two events which are pro-survival; (3) Stimulation of A 2b R also protects the endothelium by increasing pCREB and pBcl2. In this thesis, the evidence for sAC and A2b R protection will be presented.
|Advisor:||Bonanno, Joseph A.|
|Commitee:||Srinivas, Sangly P., Watkins, John, Wilson, Graeme|
|School Location:||United States -- Indiana|
|Source:||DAI-B 70/10, Dissertation Abstracts International|
|Keywords:||Adenosine receptors, Apoptosis, Cellular stress protection, Corneal endothelium, Soluble adenylate cyclase, Staurosporine, cAMP|
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