SMOKING-RELATED OXIDANTS,HTN, & DRY MACULAR DEGENERATION

描述（由申请人提供）：视网膜相关性黄斑变性（ARMD）是一种迟发性（50岁后）、进行性视网膜变性，与称为玻璃疣的特定富脂质视网膜下沉积物的积累相关。ARMD影响30%的70岁以上的人，是老年人失明的主要原因。美国可能有1400万人受到影响，佛罗里达可能有100万人。ARMD的患病率和严重程度与吸烟和高血压有关。该疾病的初始致病靶点是视网膜色素上皮（RPE）、视网膜下细胞外基质（Bruch膜或BrM）和称为脉络膜毛细血管的相关微血管床。我们假设早期ARMD存款形成的进展需要两个连续的过程：香烟烟雾中氧化剂诱导的初始RPE损伤（特别是焦油中发现的与半醌有关的化合物）引起细胞膜“气泡”的挤出，这些气泡积聚在RPE下;并且随后RPE上调负责基质周转的分子的释放或合成，由与HTN相关的介质刺激，导致滤过泡混合到BrM中并在RPE下形成新的基底膜。在目的I中，我们将确定醌，氢醌，（建议作为香烟烟雾中焦油相关氧化剂的替代品）的氧化损伤的影响，对细胞膜起泡和ECM在培养的人RPE中的重要分子的调节。在目的II中，我们将评估Ang II的作用。在目标III中，我们将确定单独吸入香烟烟雾或与HTN结合是否会导致我们实验室最近开发的年龄相关性视网膜变性小鼠模型中RPE下沉积物的严重程度和进展增加。

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.