Models of Hereditary Retinal Degenerations

描述（由申请人提供）：本申请旨在通过启动、实施和提供资源用于研究受类似疾病影响的特征良好的犬品系，加速开发针对人类遗传性视网膜变性的特异性、安全性和有效的治疗方法。它有三个广泛的方面：1）鉴定、开发、维持和生产人类视网膜变性的犬突变模型;解决研究中对这些动物的需求以及在集中设施中维持它们的重要性; 2）启动并继续研究克隆这些疾病的基因，调查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开展治疗试验。每一项这样的研究都是单独进行同行评审的，作为合作研究者研究协议的一部分。 研究调查将侧重于适合每种菌株的研究。这些充分表征的突变犬品系中有7个代表了5种不同基因中的已鉴定突变（2种等位基因色盲模型：cd 1、cd 2; 1型视杆-视锥发育不良：rcd 1;犬rpe 65-Leber先天性黑蒙模型; T4 R视蛋白突变体;和2种等位基因RPGRRF 15突变体：XLPRA 1和XLPRA 2）。正在进行的定位、定位克隆和候选基因研究将继续进行，以确定其余模型中的相关基因和突变（早期视网膜变性：erd;进行性视杆细胞-视锥细胞变性：prcd;视杆细胞-视锥细胞发育不良2型：rcd 2;以及受独特视锥细胞-视杆细胞营养不良影响的犬）。本项目目前正在繁殖、饲养和研究传播这些疾病的特定犬品系以及适当的未受影响的对照犬。他们和他们的后代将在合作研究调查中进行研究，直接或通过收集，处理和分配所需的组织。有效利用这些突变体的合作将由主要研究者与独立资助的研究者互动发起，以开发，实施和执行特定的方案，以优化这些突变体的利用。 具体的合作研究项目包括：识别、克隆和表征erd、prcd和rcd 2的基因突变;确定和比较每种突变株中程序性细胞死亡基因的作用;进一步开发遗传性视网膜变性的治疗方法，包括载体介导的基因转移到犬光感受器中;类维生素A异构体治疗;光感受器凋亡途径的调节;以及视觉假体硅视网膜植入物的应用。

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.