Modulators for Retinal Ganglion Cell Injury

视网膜神经节细胞损伤的调节剂

基本信息

批准号：
10576310
负责人：
ELDON E GEISERT
金额：
$ 49.56万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576310
关键词：
Activities of Daily Living Acute Adult Age American Anatomy Antibodies Binding Biological Markers Birth Blindness Cell Survival Cells Cessation of life Classification Collaborations Collection Contrast Sensitivity Cornea Data Data Set Dendrites Detection Development Disease Drops Electroretinography Embryo Experimental Models Eye Eye Development Genes Genetic Genetic Transcription Glaucoma High-Throughput Nucleotide Sequencing Human Injections Injury Intervention Knock-out Knockout Mice Label Link Measures Mediating Metadata Microspheres Modeling Molecular Monitor Morphology Mouse Strains Mus Nature Nerve Crush Optic Nerve Partner in relationship Pathway interactions Patients Pattern Phase Physiologic Intraocular Pressure Population Predisposition Proteins Research Design Resistance Retina Retinal Ganglion Cells Risk Risk Factors Role Structure Technology Testing Thick Thinness Variant Visual Visual Acuity cell injury cell type chromatin immunoprecipitation experimental study ganglion cell genome wide association study improved magnetic beads mouse model novel outcome prediction pharmacologic rational design response retinal progenitor cell transcription factor

项目摘要

Summary The leading cause of blindness in Americans over the age of 60 is glaucoma. One risk factor for glaucoma is central corneal thickness. The thinner the cornea, the greater the risk of developing glaucoma. Recently, we have identified a transcription factor, POU6F2, that modulates central corneal thickness in the mouse and that is a risk factor for human glaucoma. The Pou6f2 knockout mouse has a thinner cornea than its wild-type littermates, while there is no apparent change in intraocular pressure. We propose that POU6F2 is expressed in novel subclasses of retinal ganglion cells (RGCs) that are sensitive to glaucomatous injury. Premise: Our four findings lead us to hypothesize that POU6F2 is in a transcriptional cascade responsible for the susceptibility and early death of a novel collection of ON-OFF directionally selective RGC subtypes. To test this hypothesis, we will focus on the role of POU6F2 in the response of RGCs in models of experimentally-induced and naturally- occurring glaucoma. The proposed experiments will uncover the POU6F2 molecular cascade that induces glaucomatous damage. We will relate our findings in the mouse to the human, through a collaboration with Dr. Janey Wiggs and the NEIGHBORHOOD consortium, interrogating the NEIGHBORHOOD meta-dataset to define molecular pathway associated with POU6F2 targets. We will determine if any of these downstream targets and their associated pathways represent factors for glaucoma risk. This basic understanding of the molecular interactions of POU6F2 will inform the rational design of strategies to improve detection of and therapy for glaucoma.

概括 60岁以上美国人失明的主要原因是青光眼。青光眼的一个危险因素是中央角膜厚度。角膜越薄，培养青光眼的风险越大。最近，我们已经确定了一个转录因子POU6F2，该因子调节了小鼠中心角膜厚度是人类青光眼的危险因素。 POU6F2敲除鼠标的角膜比野生型薄同窝窝，虽然眼内压没有明显的变化。我们建议在对青光眼损伤敏感的视网膜神经节细胞（RGC）的新型亚类。前提：我们的四个调查结果使我们假设POU6F2是负责易感性和的转录级联新颖的on On-Off定向选择性RGC亚型的新颖集合的早期死亡。为了检验这一假设，我们将侧重于POU6F2在RGC在实验诱导和自然的模型中的响应中的作用发生青光眼。提出的实验将发现诱导的POU6F2分子级联青光眼损害。我们将通过与Dr. Janey Wiggs和社区财团，询问社区元数据以定义与POU6F2靶标相关的分子途径。我们将确定这些下游目标是否以及它们相关的途径代表了青光眼风险的因素。对分子的基本理解 POU6F2的相互作用将为改善检测和治疗的策略的合理设计提供信息青光眼。