This project is concerned with the role(s) of cAMP and related adrenergic drug mechanisms in aqueous humor dynamics. The proposed studies are focused on cAMP in ciliary processes (CP) and in trabecular tissues (TM). The research approach combines biochemical and molecular biology studies with measurements on aqueous humor dynamics in the living rabbit and monkey eye. Ciliary epithelial transports are postulated to be controlled by anion channels which are in turn controlled by cAMP/adenylyl cyclases (AC) with different regulation on basolateral and apical membranes. A new objective is to fully characterize the AC enzyme systems in TM tissue. Biochemical findings will be followed-up by in vivo experiments on outflow facility in monkeys, and the perfused human anterior segment in vitro. Specific objectives are: Cloning of different adenylyl cyclases in TM and CP tissue; regulation of AC by mechanisms beyond the receptor level especially by intracellular monovalent ions; to define a regulatory site on AC which binds compounds with the general structure XO2-OH; to develop more potent and selective inhibitors to distinguish different types of AC; to study in the primate eye, interactions of FSK with alpha-adrenergic agonists in relation to inflow and outflow mechanisms; a detailed and comprehensive biochemical study of trabecular cAMP/adenylyl cyclase systems in bovine and human trabecular tissue; and to determine facility responses in the perfused anterior segment system. These studies are of fundamental importance to understand the biochemistry and molecular pharmacology of aqueous humor formation by ciliary processes, and of facility changes in trabecular meshwork. They are relevant to the pathophysiology and the therapy of glaucoma. This project provided the first biochemical characterization of ACs with different regulation (such as a bicarbonate sensitive adenylate cyclase in fluid transporting tissues), and led to the discovery of a new regulatory site on AC, and the first compounds with selectivity for various types of AC enzymes. Therefore, this project also has wide implications for cAMP/adenylyl cyclase research in general.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY002619-19
Application #
2158476
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1978-08-01
Project End
1999-01-31
Budget Start
1996-08-01
Budget End
1999-01-31
Support Year
19
Fiscal Year
1996
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Schmidt, Karl-Georg; Geyer, Orna; Mittag, T W (2004) Adenylyl and guanylyl cyclase activity in the choroid. Exp Eye Res 78:901-7
Bayer, A U; Cook, P; Brodie, S E et al. (2001) Evaluation of different recording parameters to establish a standard for flash electroretinography in rodents. Vision Res 41:2173-85
Bayer, A U; Mittag, T; Cook, P et al. (1999) Comparisons of the amplitude size and the reproducibility of three different electrodes to record the corneal flash electroretinogram in rodents. Doc Ophthalmol 98:233-46
Schmidt, K G; von Ruckmann, A; Klingmuller, V et al. (1998) [Peak pulse blood volume in controlled modification of local perfusion parameters] Klin Monatsbl Augenheilkd 213:347-50
Schmidt, K G; von Ruckmann, A; Klingmuller, V et al. (1998) [Ocular pulse amplitude during manipulation of systemic perfusion parameters] Klin Monatsbl Augenheilkd 213:241-4
Schmidt, K G; von Ruckmann, A; Eisenmann, D et al. (1998) [Peak pulse blood volume and topical antiglaucoma drugs in rhesus monkeys with experimental open angle glaucoma] Klin Monatsbl Augenheilkd 213:341-6
Schmidt, K G; von Ruckmann, A; Geyer, O et al. (1997) [Effect of nifedipine on ocular pulse amplitude in normal pressure glaucoma] Klin Monatsbl Augenheilkd 210:355-9
Kuriyama, S; Hall, M O; Abrams, T A et al. (1995) Isoproterenol inhibits rod outer segment phagocytosis by both cAMP-dependent and independent pathways. Invest Ophthalmol Vis Sci 36:730-6
Mittag, T W; Tormay, A; Severin, C (1994) Endotoxins in cholera and pertussis toxins interfere with in vivo responses to these agents in the albino rabbit eye. Curr Eye Res 13:311-3
Mittag, T W; Tormay, A; Severin, C et al. (1994) Role of G-proteins in ciliary process adenylyl cyclase responses of the albino rabbit eye. Curr Eye Res 13:243-50

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