PATHOGENESIS OF RETINAL DEGENERATIONS

描述（改编自申请人的摘要）：视觉系统的发病机制 视网膜变性的丧失是复杂的。 我们对一些 参与该过程的早期分子和细胞事件增加 很大，但所有的机械细节和方法，以停止或扭转 失明还不知道。 最近，有人提出了一个假设， 解释了遗传性视网膜疾病的部分视力丧失， 被认为是AMD的遗传模型之一，AMD是最常见的一种。 老年人失明。 这一假设得到了验证， 向患有遗传性疾病的患者施用营养物， 是他们视力的显著提高 目前的建议是 将这项初步工作扩展到更多的患者， 遗传性视网膜疾病和其他患者谁可能分享这一点 视力丧失的发病机制。 导致这一提议的初步研究的动力是 最近发现，常染色体显性视网膜变性，SFD， 由编码细胞外基质分子的基因突变引起 称为金属蛋白酶组织抑制剂-3（TIMP-3）。 这一发现， 连同早期的临床和组织病理学观察，提示 SFD中细胞外基质异常可能导致 通过干扰视觉（类维生素A）周期， 光感受器中的维生素A缺乏样功能障碍。 在携带TIMP-3基因密码子167的SFD患者中验证了这一假设 突变通过给予他们高剂量的维生素A口服一个 月 几天之内， 早期疾病患者的光感受器功能;晚期患者 例黄斑瘢痕周围视杆细胞和视锥细胞功能增强 一个月后。 非侵入性技术产生的结果可以解释为 生理和生化过程将被用来进一步探索 视力丧失的机制和对药物干预的反应 在大量TIMP-3不同的SFD患者中， 基因型和其他两组显示相同视觉周期的患者 作为SFD的干扰。 其他组包括AMD患者的子集 和迟发性RP 这项研究的结果将导致 关于这些潜在分子事件的假设的制定 疾病，并可能演变为治疗范例的建议， 这些致盲的视网膜退化

DESCRIPTION (Adapted from applicant's abstract): The pathogenesis of visual loss in retinal degenerations is complex. Our understanding of some of the early molecular and cellular events involved in the process has increased greatly, but all the mechanistic details and ways to halt or reverse the blindness are still not known. Recently, a hypothesis was advanced to explain part of the visual loss in a hereditary retinal disease, which has been considered one of the genetic models of AMD, the most common form of blindness in older adults. The hypothesis was tested pharmacologically by administering a nutrient to patients with the genetic disease and the result was a dramatic improvement in their vision. The present proposal is to extend this preliminary work to a larger number of patients with the hereditary retinal disease and to other patients who may share this pathogenesis of visual loss. The impetus for the preliminary studies leading to this proposal was the recent discovery that the autosomal dominant retinal degeneration, SFD, was caused by mutations in the gene encoding an extracellular matrix molecule known as tissue inhibitor of metalloproteinases-3 (TIMP-3). This discovery, together with earlier clinical and histopathological observations, prompted the hypothesis that the extracellular matrix abnormality in SFD could lead to defective vision by disturbing the visual (retinoid) cycle and causing a vitamin A deficiency-like dysfunction in the photoreceptors. The hypothesis was tested in SFD patients with a codon 167 TIMP-3 gene mutation by administering to them high doses of vitamin A orally for one month. Within a few days, there was dramatic restoration of rod photoreceptor function in patients with early disease; in more advanced cases, increases in rod and cone function around macular scars occurred after a month. Non-invasive techniques yielding results that can be interpreted in terms of physiological and biochemical processes will be used to explore further the mechanisms of visual loss and the response to pharmacologic intervention with vitamin A in a larger number of SFD patients with different TIMP-3 genotypes and in two other groups of patients who show the same visual cycle disturbance as SFD. The other groups include a subset of patients with AMD and late-onset forms of RP. The results of this research will lead to the formulation of hypotheses about the underlying molecular events in these diseases and may evolve into recommendations for treatment paradigms in these blinding retinal degenerations.