Age-related macular degeneration (ARMD) is a late onset (after age 50), progressive degeneration of the retina associated with accumulation of specific lipid-rich subretinal deposits called drusen. ARMD affects 30% of people older than age 70, and is the leading cause of blindness in the elderly. Fourteen million people may be affected in the United States, and perhaps 1 million in Florida. The prevalence and severity of ARMD is associated with cigarette smoking and hypertension. The initial pathogenic target of the disease is the retinal pigmented epithelium (RPE), the subjacent extracellular matrix (Bruch's membrane or BrM), and the associated microvascular bed called the choriocapillaris. We hypothesize that progression of deposit formation in early ARMD requires two sequential processes: initial RPE injury induced by oxidants in cigarette smoke (especially semiquinone-related compounds found in tar) to cause extrusion of cell membrane """"""""blebs"""""""", which accumulate under the RPE; and subsequent RPE upregulated release or synthesis of molecules responsible for matrix turnover, stimulated by mediators related to HTN leading to admixture of blebs into BrM and formation of new basement membrane under the RPE.
In aim I we will determine the effect of oxidant-injury from the quinone, hydroquinone, (proposed as a surrogate for tar-related oxidants in cigarette smoke), on regulation of cell membrane blebbing and molecules important for ECM turnover in cultured human RPE.
In aim II, we will evaluate the effect of Ang II.
In aim III, we will determine if the inhalation of cigarette smoke alone or combined with HTN causes increased severity and progression of subRPE deposits in a mouse model for age-related retinal degeneration recently developed in our laboratory. ? ?
|Pons, Marianne; Cousins, Scott W; Alcazar, Oscar et al. (2011) Angiotensin II-induced MMP-2 activity and MMP-14 and basigin protein expression are mediated via the angiotensin II receptor type 1-mitogen-activated protein kinase 1 pathway in retinal pigment epithelium: implications for age-related macular degeneration Am J Pathol 178:2665-81|
|Pons, Marianne; Cousins, Scott W; Csaky, Karl G et al. (2010) Cigarette smoke-related hydroquinone induces filamentous actin reorganization and heat shock protein 27 phosphorylation through p38 and extracellular signal-regulated kinase 1/2 in retinal pigment epithelium: implications for age-related macular degenerat Am J Pathol 177:1198-213|
|Alcazar, Oscar; Cousins, Scott W; Striker, Gary E et al. (2009) (Pro)renin receptor is expressed in human retinal pigment epithelium and participates in extracellular matrix remodeling. Exp Eye Res 89:638-47|
|Alcazar, Oscar; Hawkridge, Adam M; Collier, Timothy S et al. (2009) Proteomics characterization of cell membrane blebs in human retinal pigment epithelium cells. Mol Cell Proteomics 8:2201-11|
|Praddaude, Françoise; Cousins, Scott W; Pêcher, Christiane et al. (2009) Angiotensin II-induced hypertension regulates AT1 receptor subtypes and extracellular matrix turnover in mouse retinal pigment epithelium. Exp Eye Res 89:109-18|
|Striker, Gary E; Praddaude, Francoice; Alcazar, Oscar et al. (2008) Regulation of angiotensin II receptors and extracellular matrix turnover in human retinal pigment epithelium: role of angiotensin II. Am J Physiol Cell Physiol 295:C1633-46|
|Alcazar, Oscar; Cousins, Scott W; Marin-Castano, Maria E (2007) MMP-14 and TIMP-2 overexpression protects against hydroquinone-induced oxidant injury in RPE: implications for extracellular matrix turnover. Invest Ophthalmol Vis Sci 48:5662-70|
|Espinosa-Heidmann, Diego G; Suner, Ivan J; Catanuto, Paola et al. (2006) Cigarette smoke-related oxidants and the development of sub-RPE deposits in an experimental animal model of dry AMD. Invest Ophthalmol Vis Sci 47:729-37|
|Marin-Castano, Maria E; Striker, Gary E; Alcazar, Oscar et al. (2006) Repetitive nonlethal oxidant injury to retinal pigment epithelium decreased extracellular matrix turnover in vitro and induced sub-RPE deposits in vivo. Invest Ophthalmol Vis Sci 47:4098-112|
|Marin-Castano, Maria E; Csaky, Karl G; Cousins, Scott W (2005) Nonlethal oxidant injury to human retinal pigment epithelium cells causes cell membrane blebbing but decreased MMP-2 activity. Invest Ophthalmol Vis Sci 46:3331-40|