The ocular ciliary epithelium is a bilayer of neuroepithelial cells with a characteristic neuroendocrine phenotype. The expression by the ciliary epithelium of genes encoding neuropeptide processing enzymes, neuropeptides, peptide hormones and receptors restricted to neuroendocrine tissues establishes the molecular basis of our observations that this ocular tissue displays neuroendocrine functions. The PI formulated the hypothesis that, in the anterior segment of the eye, the ciliary epithelium is the primary site of synthesis of neuropeptides and peptide hormones (i.e., neurotensin, atrial natriuretic peptide, angiotensinogen) of known hypertensive/hypotensive actions in the cardiovascular system, and with potential roles in the regulation of eye pressure. He proposes that the ciliary epithelium modulates eye pressure by endocrine mechanisms (autocrine/paracrine) through regulatory peptides acting on the inflow system [nonpigmented (NPE) and pigmented ciliary epithelial cells (PE)], and/or on the outflow system [trabecular meshwork cells (TM)]. The major experimental approach of this research will be: 1) to investigate in the human ciliary epithelium, the molecular mechanism involved in the gene expression, synthesis, processing and signaling pathways of bioactive peptides and its receptors with putative roles in hypertension/ hypotension in normal and glaucoma eyes. 2) The use of established cells lines derived from the inflow system (i.e., NPE, PE) and outflow (i.e., trabecular meshwork), as in vitro cell model systems to define the neuroendocrine properties of the ciliary epithelium. 3) The application of subtractive hybridization to identify novel candidate genes in the human ciliary body associated to high intraocular pressure/low tension glaucoma.
The specific aims are as follows: 1) Determine the regulation of the expresssion of endoproteases (prohormone convertases), and exopeptidases (carboxypeptidases and peptidylglycine (-amidating monooxygenase) involved in the processing of neuropeptides and peptide hormones; 2) Characterize the gene expression of regulatory peptides with hypertensive/hypotensive actions and its receptors; 3) Determine the regulatory mechanism involved in the maturation and secretion of processing enzymes and neuropeptides in normal and glaucoma derived ciliary epithelial cells; 4) Determine the signal transduction pathways involved upon activation of the receptors for the regulatory peptides in NPE/PE and TM cells; 5) Determine the structure-function relationship of a human ciliary body subtracted clone encoding TIGR, a protein involved in a subset of glaucoma (Juvenile Open Angle Glaucoma) and a candidate gene to regulate eye pressure.
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