SMOKING-RELATED OXIDANTS,HTN, & DRY MACULAR DEGENERATION

描述（由申请人提供）：年龄相关性黄斑变性（ARMD）是一种晚发性（50岁以后）的视网膜进行性变性，与称为drusen的特定富含脂质的视网膜下沉积物的积累有关。70岁以上的老年人中有30%患有ARMD，它是老年人失明的主要原因。美国可能有1400万人受到影响，佛罗里达州可能有100万人受到影响。ARMD的患病率和严重程度与吸烟和高血压有关。该疾病最初的致病靶点是视网膜色素上皮（RPE）、下层细胞外基质（Bruch膜或BrM）和相关的称为绒毛膜的微血管床。我们假设早期ARMD沉积形成的进程需要两个连续的过程：香烟烟雾中的氧化剂（特别是焦油中发现的半醌相关化合物）引起的初始RPE损伤导致细胞膜“气泡”挤压，这些气泡在RPE下积累；在HTN相关介质的刺激下，随后的RPE上调了负责基质周转的分子的释放或合成，导致气泡混合到BrM中，并在RPE下形成新的基底膜。在目的1中，我们将确定来自醌，对苯二酚（被提议作为香烟烟雾中焦油相关氧化剂的替代品）的氧化损伤对培养的人RPE中细胞膜起泡和对ECM转换重要分子的调节作用。在目标II中，我们将评估Ang II的效果。在aim III中，我们将确定在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，单独吸入香烟烟雾或合并HTN是否会导致subpe沉积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.