Models of Hereditary Retinal Degenerations

遗传性视网膜变性模型

• 批准号: 6875910
• 负责人: GREGORY M ACLAND
• 金额: $ 72.54万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6875910
• 关键词: animal breeding; animal colony; apoptosis; cooperative study; disease /disorder model; dogs; gene mutation; gene therapy; genetic mapping; genetic models; genetic strain; inborn biological transport disorder; model design /development; molecular cloning; mutant; nonhuman therapy evaluation; retina degeneration; retinal pigment epithelium; visual photoreceptor

DESCRIPTION (provided by applicant): This application aims to hasten development of specific, safe, and effective therapies for human hereditary retinal degenerations by initiating, conducting and making resources available for studies of well characterized canine strains affected with similar diseases. It has 3 broad aspects: 1) to identify, develop, maintain, and produce canine mutant models for human retinal degenerations; the need for these animals in research and the importance of maintaining them in a centralized facility is addressed; 2) to initiate and continue studies to clone the genes for these diseases, investigate the cellular and molecular biology of these diseases, and develop and test methods for therapeutic intervention; 3) to institute and conduct therapeutic trials in collaborations with independent investigators from either academic or industrial organizations. Each such study is peer reviewed, separately, as part of the collaborative investigators' research protocols. Research investigations will focus on studies appropriate to each strain. Seven of these well characterized mutant canine strains represent identified mutations in 5 different genes (2 allelic achromatopsia models: cd1, cd2; rod-cone dysplasia type 1: rcd1; a canine rpe65- model of Leber Congenital Amaurosis; a T4R Opsin mutant; and 2 allelic RPGRORF15 mutants: XLPRA1 and XLPRA2). Mapping, positional cloning, and candidate gene studies in progress will continue to be undertaken to identify the responsible genes and mutations in the remaining models (early retinal degeneration: erd; progressive rod-cone degeneration: prcd; rod-cone dysplasia type 2: rcd2; and dogs affected with unique cone rod dystrophies). Specific canine strains transmitting each of these disorders, together with appropriate nonaffected control dogs, are currently bred, maintained and studied in this project. They and their progeny will be studied in collaborative research investigations, either directly or by collection, processing and distribution of requested tissues. Collaborations to effectively utilize these mutants will be initiated by the Principal Investigator interacting with independently funded investigators, to develop, implement and conduct specific protocols for optimal utilization of these mutants. Specific collaborative research includes programs to: identify, clone, and characterize the gene mutations for erd; prcd; and rcd2; determine and compare the role of programmed cell death genes in each of the mutant strains; further develop therapies for hereditary retinal degenerations including vector mediated gene transfer into canine photoreceptors; retinoid isomer therapy; modulation of the photoreceptor apoptotic pathway; and application of a visual-prosthetic silicon retinal implant.

描述（由申请人提供）：本申请旨在通过启动，进行和制造资源来加快针对人类遗传性视网膜退化的特定，安全和有效的疗法，以研究受到类似疾病影响的良好表征犬菌株。它有3个广泛的方面：1）识别，发展，维护和生产人类视网膜变性的犬突变模型；解决了这些动物在研究中的需求以及在集中设施中维持它们的重要性； 2）启动和继续研究以克隆这些疾病的基因，研究这些疾病的细胞和分子生物学，并开发和测试治疗干预的方法； 3）与学术或工业组织的独立研究人员合作进行和进行治疗试验。作为协作研究者的研究方案的一部分，分别对每项此类研究进行同行审查。 研究调查将集中于适合每种菌株的研究。这些特征性良好的突变犬菌株中有七个代表了5种不同基因的突变（2种等位基因抗原瘤模型：CD1，CD2; Rod-Cone dyplasia type 1：RCD1; Leber先天性症的犬RPE65-犬RPE65- T4R OPSIN突变型犬和2个PalleLic RPGROR；将继续进行映射，位置克隆和候选基因研究，以确定其余模型中的负责基因和突变（早期视网膜变性：ERD；进行性杆杆孔变性：PRCD； Rod-Cone Dysplasia type 2：RCD2：RCD2； Rod-Cone dosplasia type RCD2；以及受到独特的锥形棒棒杆的影响）。目前在该项目中繁殖，维护和研究了这些疾病中的每一种，以及适当的未影响对照犬的特定犬种菌株。他们和他们的后代将直接或通过收集，加工和分配要求的组织进行协作研究研究。有效利用这些突变体的合作将由与独立资助的研究人员进行交互，以开发，实施和执行特定协议以最佳利用这些突变体的最佳利用。 具体的协作研究包括：识别，克隆和表征ERD的基因突变； prcd;和rcd2;确定并比较程序性细胞死亡基因在每个突变菌株中的作用；进一步开发用于遗传性视网膜变性的疗法，包括载体介导的基因转移到犬类感光体中；视视视网膜异构体治疗；光感受器凋亡途径的调节；以及视觉旋转硅视网膜植入物的应用。