Institute of Clinical Physiology
Researcher: Rita Rosenthal
Cooperation: Olaf Strauss, Experimental ophthalmology, Charité
Hagen Thieme, Ophthalmology, Mainz
We focused on studying the physiology and pathophysiology of various ocular tissues known to malfunction in diseases of the eye. One major topic is glaucoma, where efforts concentrate on the tissues involved in outflow regulation (trabecular meshwork, ciliary muscle and scleral spur). A second main point of interest concerns the study of retinal pigmented epithelium, a tissue involved in various forms of hereditary retinal degeneration.
Glaucoma: Elevated intraocular pressure results in loss of visual function, ultimately leading to blindness. Impaired outflow of aqueous humor through the trabecular meshwork is believed to be one of the factors contributing to glaucoma. Research in this laboratory has demonstrated that trabecular meshwork has contractile properties, is actively involved in outflow regulation, and is therefore a potential target tissue for glaucoma therapy. One of our current concerns is to study the relative contractile response of trabecular meshwork and ciliary muscle in response to various pharmacological agents. In addition, cultured bovine and human trabecular meshwork, ciliary muscle, and scleral spur cells form the basis for patch clamp and molecular biology studies with the goal of elucidating signal transduction pathways linked to contractile response.
Rosenthal R, Fromm M (2011) Endothelin antagonism as an active principle for glaucoma therapy. Br. J. Pharmacol. 62(4): 806-816 [PubMed] [WebPage] [PDF] [Free Teaching Material; Figs as PowerPoint slides]
Renieri G, Choritz L, Rosenthal R, Meissner S, Pfeiffer N, Thieme H (2008) Effects of endothelin-1 on calcium-independent contraction of bovine trabecular meshwork. Graefes Arch. Clin. Exp. Ophthalmol. 246(8): 1107-1115 [PubMed] [WebPage] [PDF]
Thieme H, Schimmat C, Münzer G, Boxberger M, Fromm M, Pfeiffer N, Rosenthal R (2006) Endothelin-antagonism: effects of FP receptor agonists prostaglandin F2a and fluprostenol on trabecular meshwork contractility. Invest. Ophth. Vis. Sci. 47(3): 938-945 [PubMed] [WebPage] [PDF]
Thieme H, Steinhausen K, Ottlecz A, Lambrou GN, Strauss O, Wiederholt M, Rosenthal R (2005) Effects of unoprostone and endothelin-1 on L-type channel currents in human trabecular meshwork cells. Ophthalm. Res. 37(6): 293-300 [PubMed] [PDF]
Choritz L, Rosenthal R, Fromm M, Foerster MH, Thieme H (2005) Pharmacological and functional characterization of endothelin receptors in bovine trabecular meshwork and ciliary muscle. Ophthalm. Res. 37(4): 179-187 [PubMed] [PDF]
Rosenthal R, Choritz L, Schlott S, Bechrakis NE, Jaroszewski J, Wiederholt M, Thieme H (2005) Effects of ML-7 and Y-27632 on carbachol- and endothelin-1-induced contraction of bovine trabecular meshwork. Exp. Eye Res. 80(6): 837-845 [PubMed] [WebPage] [PDF]
Stumpff F, Boxberger M, Krauss A, Rosenthal R, Meissner S, Choritz L, Wiederholt M, Thieme H (2005) Stimulation of cannabinoid (CB1) and prostanoid (EP2) receptors opens BKCa channels and relaxes ocular trabecular meshwork. Exp. Eye Res. 80(5): 697-708 [PubMed] [WebPage] [PDF]
Fidzinski P, Knoll A, Rosenthal R, Schrey A, Vescovi A, Koert U, Wiederholt M, Strauß O (2003) Electrophysiological response of cultured trabecular meshwork cells to synthetic ion channels. Chem. Biol. 10(1): 35-43 [PubMed] [Full text]
Retinal degeneration: The retinal pigmented epithelial cells envelope the outer segments of the light-sensitive photoreceptors, thus enabling them to function and interact with each other. Breakdown of this interactions leads to loss of photoreceptor function and ultimately to retinal degeneration. Currently, retinal dystrophies are being investigated in rat and mouse animal models of retinitis pigmentosa* as well as Norrie's disease. The focus lies in the secretory function of the retinal pigmented epithelium, because there is evidence to suggest that altered growth factor secretion might play an important role in retinal degeneration.
In addition, this altered secretion of growth factors by retinal pigment epithelial cells can be considered as the main cause for the induction of choroidal neovascularization in age-related macular degeneration. In cooperation with the eye hospital we are investigating the underlying mechanisms by studying cells from neovascular membranes which have been isolated by eye surgery of patients with age-related macular degeneration.
Ionic channels and their interaction with regulatory proteins are being investigated with patch-clamp techniques and molecular biological approaches. The interaction of ionic channels with tyrosine kinases is one of the main research topics.
*For excellent and detailed information on retinitis pigmentosa visit the International Retinitis Pigmentosa Association (IRPA) or the Pro Retina Deutschland e.V. (in German).
Wimmers S, Coeppicus L, Rosenthal R, Strauss O (2008)
Expression profile of voltage-dependent Ca2+ channel subunits
in the human retinal pigment epithelium.
Rosenthal R, Heimann H, Agostini H, Martin G, Hansen LL, Strauss O (2007) Ca2+ channels in retinal pigment epithelial cells regulate VEGF secretion rates in health and disease. Mol. Vision 13: 443-456 [PubMed] [WebPage] [PDF]
Wollmann G, Lenzner S, Berger W, Rosenthal R, Karl MO, Strauss O (2006) Voltage-dependent ion channels in the mouse RPE: Comparison with Norrie disease mice. Vision Res. 46(5): 688-698 [PubMed] [WebPage] [PDF]
Rosenthal R, Bakall B, Peachey N, Wimmers S, Wadelius
C, Marmorstein A, Strauss O (2006) Expression of bestrophin-1, the product of the VMD2 gene,
modulates voltage-dependent Ca2+ channels in retinal pigment
epithelial cells. FASEB J. 20(1): 178-180 [PubMed]
Rosenthal R, Malek G, Salomon N, Peill-Meininghaus M, Coeppicus L, Wohlleben H, Wimmers S, Bowes Rickman C, Strauss O (2005) The fibroblast growth factor receptors, FGFR-1 and FGFR-2, mediate two independent signalling pathways in human retinal pigment epithelial cells. Biochem. Biophys. Res. Commun. 337(1): 241-247 [PubMed] [WebPage] [PDF]
Rosenthal R, Wohlleben H, Malek G, Schlichting L, Thieme H, Bowes Rickman C, Strauss O (2004) Insulin-like growth factor-1 contributes to neovascularization in age-related macular degeneration. Biochem. Biophys. Res. Comm. 323: 1203-1208 [PubMed] [WebPage] [PDF]
Rosenthal R, Strauss O (2003) Investigations of RPE cells of choriodal neovascular membranes from patients with age-related macula degeneration. Adv. Exp. Med. Biol. 533: 107-113 [PubMed reference]
Rosenthal R, Strauss O (2002) Ca2+ channels in the RPE. Adv. Exp. Med. Biol. 514: 225-235 [PubMed reference]
Strauss O, Rosenthal R, Dey D, Beninde J, Wollmann G, Thieme H, Wiederholt M (2002) Effects of protein kinase C on delayed rectifier K(+) channel regulation by tyrosine kinase in rat retinal pigment epithelial cells. Invest. Ophthalmol. Vis. Sci. 43(5): 1645-1654 [PubMed] [PDF]
Rosenthal R, Thieme H, Strauss O (2001) Fibroblast growth factor receptor 2 (FGFR2) in brain neurons and retinal pigment epithelial cells act via stimulation of neuroendocrine L-type channels (Ca(v)1.3). FASEB J. 15(6): 970-977 [PubMed] [Full text]
Strauss O, Buss F, Rosenthal R, Fischer D, Mergler S, Stumpff F, Thieme H (2000) Activation of neuroendocrine L-type channels (a1D subunits) in retinal pigment epithelial cells and brain neurons by pp60c-src. Biochem. Biophys. Res. Comm. 270(3): 806-810 [PubMed]
Cell culture techniques: Rat, bovine and human cell cultures (trabecular meshwork, ciliary muscle, scleral spur and retinal pigmented epithelial cells).
Contractility measurements: The contractile force of prepared bovine trabecular meshwork and ciliary muscle strips is measured using a force length transducer system. The response of the strips in response to various pharmacological agents is studied.
Patch-clamp technique: Our interest concerns both characterization of ion channels as well as clarifying signal transduction pathways. Whole cell, perforated patch, and single channel techniques are applied. Calcium, potassium, chloride and sodium channels have been studied in retinal pigmented epithelium, trabecular meshwork, ciliary muscle, or scleral spur.
Intracellular calcium measurements: FURA-2 acts as a calcium sensitive dye and enables direct calcium measurements in living cells. The measurements are performed simultaneously with patch-clamp recordings.
Molecular biology: Cell cultures are investigated by protein blotting methods (Western blotting, immunoprecipitation). The main focus lies on signal transduction proteins, receptors, enzymes and their regulation. In addition, PCR-techniques have been established.