Molecular Pathophysiology of Retinal Degeneration in Bardet-Biedl Syndrome

摘要 破坏纤毛组装和运输的突变是遗传性视网膜的常见原因 退化，导致早发性严重失明。Bardet-Biedl综合征(BBS)是人类 与纤毛运输缺陷和光感受器退化相关的遗传病。然而， BBS中光感受器变性的致病机制在很大程度上尚不清楚， 目前还没有开发出有效的治疗方案。这项研究计划的长期目标是 阐明BBS光感受器变性的分子和细胞机制及其研究进展 保护BBS患者视力的治疗性干预。我们之前的研究确定 蛋白质在外节(OS)的堆积可能是光感受器的主要原因 BBS中的变性，代表了光感受器退化的一种新机制。在下一次 Grant Cycle，我们将探索OS中蛋白质积累是如何诱导光感受器退化的。我们的 初步数据表明，OS积累/隔离Stx3(一种便于 膜融合事件)和蛋白酶体超载应激。拟议的研究将 确定这些因素如何导致BBS中的光感受器退化。这项研究的结果 将极大地促进我们对纤毛相关视网膜病变的了解，并提供重要的 为发展以机制为基础的疗法奠定了基础。

Abstract Mutations disrupting ciliary assembly and trafficking are a common cause of inherited retinal degenerations, causing early-onset severe blindness. Bardet-Biedl syndrome (BBS) is one of the human genetic diseases associated with defective ciliary trafficking and photoreceptor degeneration. However, details of the patho-mechanisms underlying photoreceptor degeneration in BBS are largely unknown and no effective treatment options have been developed. The long-term goal of this research program is to elucidate the molecular and cellular mechanisms of photoreceptor degeneration in BBS and develop therapeutic interventions to preserve vision in BBS patients. Our prior study determined that accumulation of proteins in the outer segment (OS) is likely the primary cause of photoreceptor degeneration in BBS, representing a novel mechanism of photoreceptor degeneration. During the next grant cycle, we will explore how protein accumulation in the OS induces photoreceptor degeneration. Our preliminary data suggest that OS accumulation/sequestration of Stx3 (a SNARE protein facilitating membrane fusion events) and proteasomal overload stress are involved. The proposed study will determine how these factors contribute to photoreceptor degeneration in BBS. The outcome of this study will greatly advance our understanding of the cilia-related retinopathies and provide an important foundation for the development of mechanism-based therapies.