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，对受类似疾病影响的具有良好特征的犬种进行研究，加速开发针对人类遗传性视网膜退化的特定、安全和有效的治疗方法。它包括3个主要方面：1)识别、开发、维护和生产人类视网膜变性的犬类突变模型；2)启动和继续研究这些疾病的基因，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)与来自学术或工业组织的独立研究人员合作，开展和进行治疗试验。每项这样的研究都单独进行同行评议，作为合作研究人员研究方案的一部分。 研究调查将集中在适合每种毒株的研究上。在这些特征良好的突变犬株中，有7个代表了5个不同基因的可识别突变(2个等位色盲模型：CD1，CD2；视锥发育不良1型：RCD1；犬RPE65-Leber先天性黑猩猩模型；T4R Opsin突变体；以及2个等位RPGRORF15突变体：XLPRA1和XLPRA2)。正在进行的作图、位置克隆和候选基因研究将继续进行，以确定其余模型中的责任基因和突变(早期视网膜变性：ERD；进行性视锥变性：PRCD；视锥发育不良2型：RCD2；以及受独特视锥视杆营养不良影响的狗)。传播这些疾病的特定犬种，以及适当的未受影响的对照犬，目前正在该项目中培育、维护和研究。他们和他们的后代将直接或通过收集、加工和分发所要求的组织，在合作研究调查中进行研究。有效利用这些突变体的合作将由首席调查员与独立资助的调查人员互动发起，以制定、实施和执行优化利用这些突变体的具体方案。 具体的合作研究包括：识别、克隆和鉴定erd；prcd和rcd2的基因突变；确定和比较程序性细胞死亡基因在每个突变株中的作用；进一步开发治疗遗传性视网膜变性的方法，包括将载体介导的基因转移到犬光感受器；视黄醇异构体治疗；光感受器凋亡途径的调控；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.