Preventing Photoreceptor Degeneration: The Role of ALG-2

预防感光器变性：ALG-2 的作用

• 批准号: 6650719
• 负责人: ARTHUR S POLANS
• 金额: $ 14.55万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6650719
• 关键词: Adenoviridae; apoptosis; calcium binding protein; calcium channel blockers; calcium flux; gene delivery system; gene therapy; nonhuman therapy evaluation; protein structure function; retina degeneration; ribozymes; transfection /expression vector; visual photoreceptor

DESCRIPTION: (Applicant's Abstract) Eye diseases leading to retinal degeneration are the most common cause of hereditary blindness in humans. Prominent among these is retinitis pigmentosa (RP) affecting about 1 in 3000 people. RP consists of a clinically and genetically heterogeneous group of diseases. In more than 50% of the patients the molecular defect has not been determined, and there is no effective treatment available. Most forms of retinal degeneration involve the apoptosis of photoreceptor cells. Animal models of retinal degeneration are being used to test different strategies to either repair the genetic defect or to prevent photoreceptor cell apoptosis. Although gene repair is at least partially effective, this strategy is limited by the heterogeneity of the genetic defects underlying RP. Therefore, the rescue of photoreceptor cells through the prevention of apoptosis holds the promise of effecting multiple forms of the disease. Ample evidence indicates that Ca++ plays a pivotal role in the apoptosis of photoreceptor cells, but the mechanisms are unclear. Studies of ALG-2 presented in this proposal provide an opportunity to better understand how photoreceptor cells die and the role of Ca in this process. In addition, a gene therapy approach targeting ALG-2 may allow disparate genetic diseases to be treated in a single fashion. Specific Aims Include: 1. Deliver ALG-2 ribozymes or antisense ALG-2 constructs via an adeno-associated virus vector to photoreceptor cells of the rd/rd/tg+ mouse in order to interfere with the synthesis of ALG-2 and block apoptosis. 2. Demonstrate that a peptide derived from the ALG-2 sequence can block the formation of an ALG-2 dimer required for function. Vector delivery of a construct encoding the peptide, disrupting function, will augment studies of impaired ALG-2 synthesis and offer an alternative therapeutic approach.

描述：（申请人的摘要）导致视网膜的眼部疾病 退化是人类遗传失明的最常见原因。 其中突出的是色素性视网膜炎（RP），影响3000分之一 人们。 RP由临床和遗传异质组成 疾病。在超过50％的患者中，分子缺陷尚未 确定，并且没有有效的治疗方法。 大多数形式的视网膜变性涉及光感受器的凋亡 细胞。视网膜变性的动物模型被用于测试不同的动物 修复遗传缺陷或预防感光细胞的策略 凋亡。尽管基因修复至少有效地有效，但该策略 受遗传缺陷RP的异质性的限制。 因此，通过预防拯救感受器细胞 凋亡具有影响多种形式的疾病的希望。 充分的证据表明CA ++在凋亡中起关键作用 感光细胞，但机制尚不清楚。提出的ALG-2的研究 在此提案中，有机会更好地了解光感受器 细胞死亡和CA在此过程中的作用。另外，基因疗法 靶向ALG-2的方法可能允许在 一种时尚。 具体目的包括：1。输送ALG-2核糖酶或反义ALG-2构建体 通过与RD/RD/TG+的感光细胞相关的腺相关病毒载体 小鼠以干扰ALG-2和阻断凋亡的合成。 2。 证明从ALG-2序列得出的肽可以阻止 形成功能所需的ALG-2二聚体。向量输送 构建编码肽，破坏功能的构造，将增加对 ALG-2合成受损并提供另一种治疗方法。