Retinal Disease: Molecular Basis and Pathophysiology

视网膜疾病：分子基础和病理生理学

基本信息

批准号：
8884055
负责人：
Patsy M Nishina
金额：
$ 69.09万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-02-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8884055
关键词：
Affect Aging Alleles Award Biochemical Chemicals Clinical Complement Factor H Disease Dysplasia Effectiveness Environment Environmental Risk Factor Ethylnitrosourea Eye Eye Development Family Functional disorder Gene Expression Profiling Gene Mutation Genes Genetic Growth Health Heterogeneity Human Hyperopia Immune Immune response Impairment Individual Inflammatory Knock-out Knowledge Laboratories Laboratory Study Lead Learning Length Lesion Maps Microphthalmos Modification Molecular Mus Mutagenesis Mutation Ophthalmoscopy Optic Disk Drusen Optical Coherence Tomography Pathway interactions Phenotype Population Process Proteins Retina Retinal Retinal Diseases Retinal Dysplasia Retinitis Pigmentosa Severities Severity of illness Spottings Testing Transcript Translational Research Variant Vision Work base disease phenotype improved insight member mouse model mutant novel photoreceptor degeneration postnatal prevent public health relevance response therapeutic target transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Within any given retinal disease, one often observes variability in onset, severity or phenotypic presentation, even among individuals with the same heritable mutation. Although it is generally agreed upon that this variation is largely attributabl to genetic background modifiers, to date only a handful of these have been identified. This is, in part, due to the relatively small number of families available for study with the same gene disruption and the high heterogeneity of the human population. And yet, knowledge of these modifiers may be crucial for a better understanding of the mechanisms underlying the diseases and for discovering key therapeutic targets that may be effective across groups of retinal diseases. Our laboratory has, therefore, focused on identifying such modifiers in mice, where genetic complexity is easier to resolve and what is learned may be applicable to direct translational research for improving eye health in humans. In this proposal, we aim to identify genetic modifiers that modulate photoreceptor degeneration and axial length in four interacting genes: Mfrp, C1qtnf5, Crb1 and Prss56, which our laboratory studied during the past award period. Recent evidence points to intriguing genetic and biochemical connections among these genes. In Aim 1, we will determine shared mechanisms for disease modification of photoreceptor degeneration caused by Mfrprd6/rd6 and Crb1rd8/rd8, focusing particularly upon modifiers such as C1qtnf5-/- and PrckiTvrm258/+ with immune modulatory effects. In Aim 2, we will identify genetic modifiers of axial length to determine the pathway through which Mfrp and Prss56 affect the postnatal development of the eye. Finally, in Aim 3, a global approach of gene profiling will be utilized to identify common sets of dysregulated genes to delineate potential pathways that are shared amongst these genes. At the successful conclusion of the work outlined, we will identify the functional and pathophysiological networks impacted by Mfrp, C1qtnf5, Crb1 and Prss56, and the common pathways that underpin the genetic interactions observed among mutations in these molecules. Identification of common pathways will provide information on how deficits of these encoded genes ultimately lead to the observed disease phenotypes and offer potential therapeutic targets that may reach beyond the effects of the individual molecules themselves.

描述（由申请人提供）：在任何给定的视网膜疾病中，即使在具有相同遗传突变的个体中，人们也经常观察到发病、严重程度或表型表现的变异性，尽管人们普遍认为这种变异很大程度上归因于遗传背景修饰因素。迄今为止，仅发现了其中的一小部分，部分原因是可用于研究的具有相同基因破坏的家庭数量相对较少，而且人类知识的异质性很高。这些修饰因素对于更好地了解疾病的机制以及发现可能对视网膜疾病组有效的关键治疗靶点可能至关重要，因此，我们的实验室致力于在遗传复杂性较高的小鼠中鉴定此类修饰因素。更容易解决，所学到的知识可能适用于改善人类眼睛健康的直接转化研究。在这项提案中，我们的目标是确定调节四个相互作用基因的光感受器变性和眼轴长度的遗传修饰剂：Mfrp、我们的实验室在过去的获奖期间研究了 C1qtnf5、Crb1 和 Prss56，最近的证据表明这些基因之间存在有趣的遗传和生化联系。在目标 1 中，我们将确定 Mfrprd6/rd6 和引起的光感受器变性的疾病修饰的共同机制。 Crb1rd8/rd8，特别关注具有免疫调节作用的修饰因子，例如 C1qtnf5-/- 和 PrckiTvrm258/+在目标 2 中，我们将确定眼轴长度的遗传修饰因子，以确定 Mfrp 和 Prss56 影响眼睛出生后发育的途径。最后，在目标 3 中，将利用基因分析的全局方法来识别常见的组。失调的基因来描述这些基因之间共享的潜在途径在成功完成概述的工作后，我们将确定受 Mfrp、C1qtnf5 影响的功能和病理生理网络。 Crb1 和 Prss56 以及支持这些分子突变之间观察到的遗传相互作用的共同途径将提供有关这些编码基因的缺陷如何最终导致观察到的疾病表型的信息，并提供可能超出范围的潜在治疗靶点。单个分子本身的影响。