Lowering intraocular pressure in Primary Open Angle Glaucoma, the most prevalent form of glaucoma, is a major objective in the treatment to prevent the progression of this ocular disease. Our long-term goal is the understanding at the cell and molecular level of the mechanisms involved in the regulation of intraocular pressure. A great body of evidence emerging, for the most part, from studies on molecular biology has supported that the human ciliary epithelium is neuroendocrine and expresses a functional peptidergic system. Many of the peptides identified are vasoactive and they are involved in the regulation of blood pressure in the cardiovascular system. The existence of a peptidergic system in the ciliary epithelium provides suggestive evidence for its involvement in the regulation of eye pressure at a """"""""local"""""""" level by autocrine/paracrine mechanisms. In this application, we propose a 5-year study to examine the hypothesis that intraocular pressure is a neuroendocrine function of the ciliary epithelium, mediated by the expression of regulatory peptides and hormones entrained in a circadian rhythm by a non-visual light-sensing mechanism. The plan comprises three main aims.
Aim 1, biochemical characterization, by HPLC and mass spectrometry, of neuroendocnne regulatory peptides with hypertensive/hypotensive activities expressed in the ciliary epithelium, including neuropeptide Y and natriuretic peptide-C. To study their signaling pathway upon activation of their cognate receptors by measuring second messengers including cAMP, cGMP and Ca2+.
Aim 2, to examine the circadian variations of neuropeptides in experimental animals and cultured cell models of the ciliary epithelium entrained to light/dark cycles. To identify the components of the endogenous """"""""circadian oscillator"""""""" that underlie the circadian gene expression in the ciliary epithelium, including melatonin-rhythm-generating enzymes and clock genes.
Aim 3, to establish the molecular nature of the non-visual phototransduction cascade in the ciliary epithelium, by focusing on the expression of rhodopsin and other opsin-like molecules, and components of the activation and deactivation of rhodopsin, including rhodopsin kinase, recoverin and arrestin. To determine any light-sensing responses in intact and cultured ciliary epithelial cells, by studying the cGMP-gated channel under light and dark conditions.
| Aroca-Aguilar, Jose-Daniel; Sanchez-Sanchez, Francisco; Martinez-Redondo, Francisco et al. (2008) Heterozygous expression of myocilin glaucoma mutants increases secretion of the mutant forms and reduces extracellular processed myocilin. Mol Vis 14:2097-108 |
| Lopez-Martinez, Francisco; Lopez-Garrido, Maria-Pilar; Sanchez-Sanchez, Francisco et al. (2007) Role of MYOC and OPTN sequence variations in Spanish patients with primary open-angle glaucoma. Mol Vis 13:862-72 |
| Coca-Prados, Miguel; Escribano, Julio (2007) New perspectives in aqueous humor secretion and in glaucoma: the ciliary body as a multifunctional neuroendocrine gland. Prog Retin Eye Res 26:239-62 |
| Sanchez-Sanchez, Francisco; Martinez-Redondo, Francisco; Aroca-Aguilar, J Daniel et al. (2007) Characterization of the intracellular proteolytic cleavage of myocilin and identification of calpain II as a myocilin-processing protease. J Biol Chem 282:27810-24 |
| Ghosh, Sikha; Choritz, Lars; Geibel, John et al. (2006) Somatostatin modulates PI3K-Akt, eNOS and NHE activity in the ciliary epithelium. Mol Cell Endocrinol 253:63-75 |
| Li, Yanxia; Aroca-Aguilar, J Daniel; Ghosh, Sikha et al. (2006) Interaction of myocilin with the C-terminal region of hevin. Biochem Biophys Res Commun 339:797-804 |
| Lopez-Garrido, Maria-Pilar; Sanchez-Sanchez, Francisco; Lopez-Martinez, Francisco et al. (2006) Heterozygous CYP1B1 gene mutations in Spanish patients with primary open-angle glaucoma. Mol Vis 12:748-55 |
| Salvador-Silva, Mercedes; Ghosh, Sikha; Bertazolli-Filho, Rubens et al. (2005) Retinoid processing proteins in the ocular ciliary epithelium. Mol Vis 11:356-65 |
| Aroca-Aguilar, J Daniel; Sanchez-Sanchez, Francisco; Ghosh, Sikha et al. (2005) Myocilin mutations causing glaucoma inhibit the intracellular endoproteolytic cleavage of myocilin between amino acids Arg226 and Ile227. J Biol Chem 280:21043-51 |
| Fidzinski, Pawel; Salvador-Silva, Mercedes; Choritz, Lars et al. (2004) Inhibition of NHE-1 Na+/H+ exchanger by natriuretic peptides in ocular nonpigmented ciliary epithelium. Am J Physiol Cell Physiol 287:C655-63 |
Showing the most recent 10 out of 60 publications
