Identifying mechanistic pathways underlying RPE pathogenesis in models of pattern dystrophy

项目总结/摘要 视网膜色素上皮细胞（RPE）在眼睛运输营养物质、离子和蛋白质中起重要作用。 水;和服务的吸收光和保护免受光氧化，再循环的视觉周期 这些成分，并为视网膜的结构完整性提供必要的因素。这些共同支持 视网膜的代谢稳态和屏障功能。 许多RPE疾病表型在携带细胞内突变的人类和小鼠模型之间是共享的。 粘附和细胞外基质（ECM）分子。定义诱发的致病途径和网络 通过突变或致病性变体可以提供治疗靶点。确定在药物作用期间起作用的药物靶点 该疾病的症状前阶段对于能够开发治疗是特别重要的， 预防、延迟发作或降低RPE相关疾病的严重程度，无论最初的病因如何。 在病变变得不可逆转之前， 本申请的目的是鉴定与人前列腺癌相关的共同的临床前和终末期表型和细胞效应。 两个基因Ctnna 1和Lratd 2的突变，这两个基因在RPE中高度表达，并导致类似的视网膜病变。 缺陷CTNNA 1的突变已在型营养不良和Lebers先天性 在一项全基因组关联研究中，LRATD 2与早期AMD相关。我们 方法是使用临床、功能和生化测试来提供模型的深入表征， 使用单核转录组学以及空间分析来分析相关的细胞变化， 代谢组学/蛋白质组学测量。这些表型和基因组学数据将使用 计算方法，以确定这些模型中扰动的共享途径。我们使用两个模型， 共同的病理将使我们过滤掉突变特异性改变，并专注于共同的致病因素 途径。利用我们的鼠标资源，我们还计划增强当前的模型。 成功完成我们的研究将确定RPE相关的新的致病途径。 疾病，揭示了潜在的治疗目标，可能是有效的，在广泛的这些疾病， 无论疾病的原因是什么。这些特征良好的模型将提供给研究 社区进行进一步的机制调查以及测试治疗策略。

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.