Preventing Photoreceptor Degeneration: The Role of ALG-2

预防感光器变性：ALG-2 的作用

• 批准号: 6415754
• 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 2004-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6415754
• 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）导致视网膜病变的眼部疾病 退化是人类遗传性失明的最常见原因。 其中最突出的是视网膜色素变性（RP）影响约1在3000 人RP由一组临床和遗传异质性的 疾病在超过50%的患者中， 目前还没有有效的治疗方法。 视网膜变性的大多数形式都涉及感光细胞的凋亡 细胞视网膜变性的动物模型被用来测试不同的 修复遗传缺陷或防止感光细胞 凋亡虽然基因修复至少部分有效，但这种策略 是有限的遗传缺陷的异质性RP的基础。 因此，通过预防光感受器细胞的损伤来拯救光感受器细胞是非常重要的。 细胞凋亡有望影响多种形式的疾病。 大量的证据表明，Ca ~（++）在细胞凋亡中起着关键作用。 感光细胞，但机制尚不清楚。ALG-2的研究介绍 在该提议中提供了更好地理解光感受器如何 细胞死亡和钙在这个过程中的作用。此外，一种基因疗法 靶向ALG-2的方法可以治疗不同的遗传疾病， 单一的时尚。 具体目标包括：1.递送ALG-2核酶或反义ALG-2构建体 通过腺相关病毒载体到达RD/RD/TG+的感光细胞 目的是干扰ALG-2的合成，阻断细胞凋亡。2. 证明源自ALG-2序列的肽可以阻断 形成功能所需的ALG-2二聚体。a的载体递送 构建编码肽，破坏功能，将增加研究， ALG-2合成受损，并提供了替代的治疗方法。