A Perspective on the Role of the Extracellular Matrix in Progressive Retinal Degenerative Disorders
A Perspective on the Role of the Extracellular Matrix in Progressive Retinal Degenerative Disorders
复制标题
DOI：
10.1167/iovs.13-13536
复制
发表时间：
2013-12-01
影响因子：
4.4
通讯作者：
Conley, Shannon M.
中科院分区：
文献类型：
--
作者：
Al-Ubaidi, Muayyad R.;Naash, Muna I.;Conley, Shannon M.
进行性遗传性视网膜退行性疾病（PIRDD）是发达国家失明的主要原因，其中 AMD 和 RP 占 PIRDD 的大多数。目前，超过 800 万美国人患有 PIRDD，预计到本十年末，这一数字将大幅增加。尽管 PIRDD 患者的视网膜发育早期就开始表达突变蛋白，但视网膜变性的症状要到很晚才显现出来。历史上，研究重点是了解突变在蛋白质功能中的作用以及突变蛋白在疾病过程中的作用。然而，目前尚不清楚为什么这种疾病（无论突变如何）在生命的后期才会出现临床表现，而疾病的细胞指标（例如有毒蛋白质产物的积累和细胞死亡）发生在整个早年和中年。在此，我们提出存在一个时间点，在该时间点退化过程加速，导致临床症状的出现。该点由细胞外基质 (ECM) 的结构破坏定义。关键数量的表达 ECM 的突变蛋白视网膜细胞的死亡导致了退化过程中的断点。因此，了解 PIRDD 期间 ECM 发生的变化并在设计治疗方法时考虑到这一点非常重要。
Progressive inherited retinal degenerative disorders (PIRDDs) are the leading cause of blindness in developed countries, with AMD and RP constituting the majority of PIRDDs. Currently, over 8 million Americans have PIRDDs, and that number is estimated to drastically increase by the end of this decade. Although a mutant protein is expressed starting early during retinal development in patients with PIRDDs, symptoms of retinal degeneration do not manifest until much later. Historically, research has focused on understanding the role a mutation has in the function of a protein and what role the mutant protein has in the disease process. However, it remains unknown why the disease, irrespective of the mutation, manifests clinically much later in life, while cellular indicators of disease (e.g., accumulation of toxic protein products and cell death) occur throughout early and middle life. Herein, we propose that there exists a time point at which the degenerative process is accelerated, leading to the appearance of clinical symptoms. This point is defined by structural disruptions of the extracellular matrix (ECM). Death of a critical number of ECM-maintaining mutant protein-expressing retinal cells contributes to that break point in the degenerative process. Therefore, it is important to understand the changes occurring at the ECM during PIRDDs and to take that into account when therapeutic approaches are designed.