SMOKING-RELATED OXIDANTS,HTN, & DRY MACULAR DEGENERATION

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DESCRIPTION (provided by applicant): 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.