PATHOGENESIS OF RETINAL DEGENERATIONS

描述(摘自申请者的摘要)：视觉疾病的发病机制 视网膜变性的丢失是复杂的。我们对一些问题的理解 参与这一过程的早期分子和细胞事件有所增加 很大，但所有机械性的细节和阻止或逆转 失明的原因目前还不清楚。最近，一个假说被提出到 解释遗传性视网膜疾病的部分视力丧失，这种疾病有 被认为是AMD的遗传模式之一，AMD是最常见的 老年人的失明。这一假说得到了药理学上的验证 向遗传性疾病患者提供营养及其结果 是他们视力的戏剧性改善。目前的建议是 将这项初步工作扩展到更多的有 遗传性视网膜疾病和其他可能患有此病的患者 视力丧失的发病机制。 导致这项建议的初步研究的推动力是 最近发现常染色体显性遗传性视网膜变性，SFD，是 由编码细胞外基质分子的基因突变引起的 被称为金属蛋白酶组织抑制因子-3(TIMP-3)。这一发现， 结合早期的临床和组织病理学观察，提示 SFD细胞外基质异常可能导致 通过扰乱视觉(视黄醇)循环而导致视力缺陷 光感受器中的维生素A缺乏样功能障碍。 这一假设在携带167个TIMP-3基因密码子的SFD患者中得到了验证 通过给他们口服大剂量维生素A而导致突变 月份。在几天内，棒子戏剧性地修复了 早期疾病患者的光感受器功能；更晚期 4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 将使用生理和生化过程来进一步探索 视力丧失的机制及药物干预的反应 大量TIMP-3不同的SFD患者应用维生素A 在表现出相同视觉周期的另外两组患者中 作为SFD的干扰。其他组包括AMD患者的子集 晚发型反流性肾炎。这项研究的结果将导致 关于这些潜在分子事件的假说的表述 疾病，并可能演变为#年治疗范例的建议 这些眼花缭乱的视网膜退化。

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.