Molecular Mechanisms of Glaucoma

青光眼的分子机制

基本信息

批准号：
10554978
负责人：
Dorota Skowronska-Krawczyk
金额：
$ 13.83万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10554978
关键词：
9p21 ATAC-seq Adult Affect African American population Age Animal Model Bilateral Biological Models Blindness CDKN2A gene CRISPR/Cas technology Categories Cell Aging Cell Death ChIP-seq Code Complex Development Disease Disease Progression Down-Regulation Engineering Environmental Risk Factor Epigenetic Process Etiology Eye Eye Development Future Gene Expression Regulation Genes Genetic Genetic Risk Genomics Glaucoma Human Human Chromosomes Inherited Laboratories Laboratory mice Linkage Disequilibrium Mediating Methodology Modeling Molecular Molecular Analysis Mouse Strains Mus Nerve Degeneration Nucleic Acid Regulatory Sequences Optic Nerve Pathogenesis Pathology Patients Persons Physiologic Intraocular Pressure Population Positioning Attribute Primary Open Angle Glaucoma Quality of life Research Research Personnel Retina Retinal Ganglion Cells Risk Risk Factors Role Sampling Signal Transduction Technology Testing Tumor Suppressor Proteins United States Up-Regulation Variant Visual impairment Work age related blind design epigenomics genetic association genomic locus human tissue humanized mouse improved mouse model nerve damage novel optic nerve disorder personalized therapeutic protective effect retinal ganglion cell degeneration risk variant senescence therapeutic development transcriptomics

项目摘要

SUMMARY Glaucoma is a group of optic neuropathies characterized by slow, progressive loss of retinal ganglion cells (RGCs), optic nerve degeneration and as a consequence, vision loss. It has been estimated that more than 70 million people are currently affected by glaucoma with approximately 10% being bilaterally blind, making it the leading cause of irreversible blindness in the world. Several glaucoma categories exist, but in United States, most of the cases are primary open-angle glaucoma (POAG), a variant particularly prevalent amongst African Americans. POAG is recognized as a complex disease in which multiple genetic and environmental factors interact. The two leading risk factors, increase intraocular pressure (IOP) and age are related to the extent and rate of RGC loss. Recent advances in genomics have allowed researchers to describe genetic association between the risk of glaucoma and specific genomic loci. Nevertheless, despite years of research, the molecular basis of glaucoma is poorly understood and the factors contributing to its progression have not been fully characterized. In our recent work, we have used a mouse model to study the molecular impact of Six6 risk variant in development of glaucoma and in RGC death. We observed that upon increased IOP, expression of Six6 increases and directly regulates the expression of p16Ink4a, leading to enhanced senescence in RGCs and most likely directly causing RGC death. The gene encoding p16INK4a, CDKN2A, lies within the tumor suppressor locus on human chromosome 9p21. This locus has been independently identified by several groups to have the highest association with POAG in different population samples. Gene regulation within the 9p21 locus has been extensively studied in many laboratories; however, a molecular analysis has never been performed specifically in relation to glaucoma. Mouse Six6 harbors His at position 141 and therefore is ideal to investigate the molecular role of this variant in glaucoma. However, due to the lack of non-risk variant in mouse strains, it is not possible to study the contribution of both variants on RGC development and degeneration in a mouse model. Here, we propose to use CRISPR/Cas9 technology to engineer mice harboring human non-risk variant of SIX6 to study the impact of each variant in pathogenesis of glaucoma. We will use state-of-the art molecular and cellular technologies to study retinal development and RGC degeneration upon elevated intraocular pressure as a function of the particular variant of SIX6. In addition, we will investigate the molecular mechanisms of p16Ink4a upregulation in the etiology of the disease using transcriptomic and epigenomic approaches, and we will propose the methodology to downregulate its expression in the eye. The proposed combination of approaches will move forward the general understanding of the etiology of glaucoma and provide the molecular basis for development of novel, personalized, therapeutic strategies to improve the quality of life for glaucoma patients.

概括青光眼是一组视神经病变，其特征是视网膜神经节细胞缓慢、进行性丧失（RGC）、视神经变性，从而导致视力丧失。据估计，超过70 目前有 100 万人受到青光眼的影响，其中约 10% 双眼失明，这使其成为世界上不可逆转失明的主要原因。存在多种青光眼类别，但在美国，大多数病例是原发性开角型青光眼（POAG），这是一种在非洲人中特别流行的变种美国人。 POAG 被认为是一种复杂的疾病，其中多种遗传和环境因素共同作用。相互影响。眼压 (IOP) 升高和年龄这两个主要危险因素与眼压升高的程度和年龄有关。 RGC 损失率。基因组学的最新进展使研究人员能够描述遗传关联青光眼风险与特定基因组位点之间的关系。然而，尽管经过多年的研究，分子对青光眼的基础了解甚少，导致其进展的因素尚未完全清楚特点。在我们最近的工作中，我们使用小鼠模型来研究 Six6 风险的分子影响青光眼发展和 RGC 死亡的变异。我们观察到，随着眼压的增加， Six6 增加并直接调节 p16Ink4a 的表达，导致 RGC 衰老增强并且很可能直接导致 RGC 死亡。编码 p16INK4a、CDKN2A 的基因位于肿瘤内人类染色体 9p21 上的抑制基因座。该位点已被多个小组独立鉴定在不同人群样本中与 POAG 具有最高的关联性。 9p21 内的基因调控许多实验室已对基因座进行了广泛的研究；然而，分子分析从未专门针对青光眼进行。 Mouse Six6 在位置 141 处含有 His，因此非常适合研究该变异在青光眼中的分子作用。然而，由于小鼠中缺乏非风险变异菌株中，不可能研究这两种变异对 RGC 发育和退化的贡献鼠标模型。在这里，我们建议使用CRISPR/Cas9技术来改造携带人类非风险基因的小鼠 SIX6 的变体，以研究每个变体对青光眼发病机制的影响。我们将使用最先进的分子和细胞技术研究视网膜发育和 RGC 变性眼内压是 SIX6 特定变体的函数。此外，我们还将研究分子使用转录组学和表观基因组学研究疾病病因中 p16Ink4a 上调的机制方法，我们将提出下调其在眼睛中的表达的方法。拟议的多种方法的结合将促进对青光眼病因的普遍了解，并提供开发新颖的个性化治疗策略以改善生活质量的分子基础对于青光眼患者。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evaluating the neuroprotective impact of senolytic drugs on human vision.

DOI：
10.1038/s41598-020-78802-4
发表时间：
2020-12-10
期刊：
Scientific reports
影响因子：
4.6
作者：
El-Nimri NW;Moore SM;Zangwill LM;Proudfoot JA;Weinreb RN;Skowronska-Krawczyk D;Baxter SL
通讯作者：
Baxter SL

Dynamic lipid turnover in photoreceptors and retinal pigment epithelium throughout life.

DOI：
10.1016/j.preteyeres.2021.101037
发表时间：
2022-07
期刊：
PROGRESS IN RETINAL AND EYE RESEARCH
影响因子：
17.8
作者：
Lewandowski, Dominik;Sander, Christopher L.;Tworak, Aleksander;Gao, Fangyuan;Xu, Qianlan;Skowronska-Krawczyk, Dorota
通讯作者：
Skowronska-Krawczyk, Dorota

Emerging Concepts for RNA Therapeutics for Inherited Retinal Disease.