Identifying mechanistic pathways underlying RPE pathogenesis in models of pattern dystrophy

识别模式营养不良模型中 RPE 发病机制的机制途径

基本信息

批准号：
10636678
负责人：
JUERGEN K. NAGGERT
金额：
$ 65.09万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636678
关键词：
Actins Affect Age related macular degeneration Aging Alleles Area Back Binding Proteins Biochemical Blindness Butterflies Cell Adhesion Cell Nucleus Cells Characteristics Clinical Communities Complex Computing Methodologies Cytoskeleton Defect Deposition Disease Disease model Elderly Environmental Risk Factor Exhibits Extracellular Matrix Eye Functional disorder Genes Genetic Genomics Goals Heritability Histologic Homeostasis Human Individual Induced Mutation Ions Lead Leber&apos s amaurosis Lesion Light Lipids Maps Measurement Metabolic Modeling Molecular Morphology Mouse Strains Mus Mutation Nuclear Nutrient Online Mendelian Inheritance In Man Other Genetics Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Phenotype Photoreceptors Pigment Epithelium Play Population Process Proteomics Public Health Recycling Reporting Research Resources Retina Retinal Defect Retinal Degeneration Retinal Diseases Role Severities Shapes Signal Transduction Structure of retinal pigment epithelium Testing Therapeutic Tissues Variant Vision Vision research Visual impairment Water absorption alpha catenin disease phenotype disorder of macula of retina druggable target end stage disease gene augmentation therapy genome wide association study genomic data human model inherited retinal degeneration macular dystrophy mass spectrometric imaging metabolomics mouse model mutant novel pattern dystrophies phenotypic data phosphoproteomics pre-clinical prevent programs retinal rods structural determinants therapeutic evaluation therapeutic target therapy development transcriptomics visual cycle

Actins Affect Age related macular degeneration Aging Alleles Area Back Binding Proteins Biochemical Blindness Butterflies Cell Adhesion Cell Nucleus Cells Characteristics Clinical Communities Complex Computing Methodologies Cytoskeleton Defect Deposition Disease Disease model Elderly Environmental Risk Factor Exhibits Extracellular Matrix Eye Functional disorder Genes Genetic Genomics Goals Heritability Histologic Homeostasis Human Individual Induced Mutation Ions Lead Leber&apos s amaurosis Lesion Light Lipids Maps Measurement Metabolic Modeling Molecular Morphology Mouse Strains Mus Mutation Nuclear Nutrient Online Mendelian Inheritance In Man Other Genetics Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Phenotype Photoreceptors Pigment Epithelium Play Population Process Proteomics Public Health Recycling Reporting Research Resources Retina Retinal Defect Retinal Degeneration Retinal Diseases Role Severities Shapes Signal Transduction Structure of retinal pigment epithelium Testing Therapeutic Tissues Variant Vision Vision research Visual impairment Water absorption alpha catenin disease phenotype disorder of macula of retina druggable target end stage disease gene augmentation therapy genome wide association study genomic data human model inherited retinal degeneration macular dystrophy mass spectrometric imaging metabolomics mouse model mutant novel pattern dystrophies phenotypic data phosphoproteomics pre-clinical prevent programs retinal rods structural determinants therapeutic evaluation therapeutic target therapy development transcriptomics visual cycle

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项目摘要

PROJECT SUMMARY/ABSTRACT The retinal pigment epithelium (RPE) plays an important role in the eye transporting nutrients, ions, and water; and serving in absorption of light and protection against photooxidation, recycling of visual cycle components, and providing essential factors for the structural integrity of the retina. Collectively these support metabolic homeostasis and barrier function of the retina. Many RPE disease phenotypes are shared between humans and mouse models carrying mutations in cell- adhesion and extracellular matrix (ECM) molecules. Defining causative pathways and networks that are induced by mutations or pathogenic variants may provide therapeutic targets. Identifying druggable targets that act during the pre-symptomatic stage of the disease is particularly important to enable development of therapies that can prevent, delay onset, or decrease the severity of RPE-associated diseases, irrespective of the initial cause of the disease, before the pathologic changes become irreversible. The goal of this application is to identify shared pre-clinical and end-stage phenotypic and cellular effects of mutations in two genes, Ctnna1 and Lratd2, which are highly expressed in the RPE and lead to similar retinal defects. Mutations in CTNNA1 have been reported in patients with Pattern Dystrophy and Lebers Congenital Amaurosis (LCA), and LRATD2 has been associated with early AMD in a genome wide association study. Our approach is to use clinical, functional and biochemical tests to provide a deep characterization of the models and to analyze associated cellular changes using single-nuclear transcriptomics as well as spatial metabolomic/proteomic measurements. These phenotypic and genomics data will be jointly analyzed using computational methods to identify the shared pathways perturbed in these models. Our use of two models with shared pathologies will let us filter out mutation specific alterations and focus on the shared disease-causing pathways. Using our mouse resources, we also plan to enhance current models. Successful completion of our studies will identify novel pathogenic pathways underlying RPE-related disorders, revealing potential therapeutic targets that could be effective in a broad range of these diseases, regardless of the cause of the disease. These well-characterized models will be made available to the research community for further mechanistic inquiries as well as for testing therapeutic strategies.

项目摘要/摘要视网膜色素上皮（RPE）在运输营养素，离子和水;并在吸收光线和防止光氧化，视觉周期的回收组件，并为视网膜结构完整性提供了基本因素。共同支持这些支持视网膜的代谢稳态和障碍功能。许多RPE疾病表型在人类和小鼠模型之间共享，这些模型在细胞中携带突变粘附和细胞外基质（ECM）分子。定义诱导的致病途径和网络通过突变或致病性变异可能会提供治疗靶标。确定在疾病的症状前阶段对于能够开发可以开发可以预防，延迟发作或减少与RPE相关疾病的严重程度，无论最初的原因在病理变化变得不可逆之前，该疾病。该应用的目的是确定共享的临床前和终末期表型和细胞效应两个基因CTNNA1和LRATD2中的突变，它们在RPE中高度表达并导致类似的视网膜缺陷。据报道，ctNNA1的突变已在患有模式营养不良的患者和先天性的患者中在一项基因组广泛的关联研究中，Amaurosis（LCA）和LRATD2与早期AMD有关。我们的方法是使用临床，功能和生化测试来提供模型的深刻表征和使用单核转录组学和空间分析相关的细胞变化代谢组/蛋白质组学测量。这些表型和基因组学数据将使用识别这些模型中受干扰的共享途径的计算方法。我们使用两种模型与共同的病理将使我们能够过滤突变特定的变化，并专注于共享疾病的共同改变途径。使用鼠标资源，我们还计划增强当前模型。成功完成我们的研究将确定与RPE相关的新型致病途径疾病，揭示了可能在这些疾病广泛的疾病中有效的潜在治疗靶标不管疾病的原因是什么。这些特征良好的模型将用于研究社区进行进一步的机械查询以及测试治疗策略。