Activation of the Angiopoietin-Tie2/TEK Pathway to Treat Ocular Hypertension and Glaucoma

激活血管生成素-Tie2/TEK 通路治疗高眼压和青光眼

基本信息

批准号：
10450834
负责人：
Jing Jin
金额：
$ 58.29万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450834
关键词：
3&apos Untranslated Regions ANGPT1 gene ANGPT2 gene Adult Affect Angiopoietins Animal Model Aqueous Humor Binding Sites Biological Assay Biomedical Engineering Blindness Blood Vessels Cell Death Cell Lineage Cell Survival Cells Child Childhood Clinic Collaborations Defect Development Disease Dose Endothelial Cells Endothelium Eye Failure Family Funding Gene Expression Gene Mutation Genes Genetic Genomic Segment Glaucoma Grant Hydrophthalmos Individual International Lead Ligands Link Liquid substance Maintenance MicroRNAs Modeling Molecular Monkeys Mus Mutation Ocular Hypertension Pathogenesis Pathway interactions Patients Persons Phenotype Phosphoric Monoester Hydrolases Physiologic Intraocular Pressure Population Primary Open Angle Glaucoma Receptor Protein-Tyrosine Kinases Reporting Resistance Retinal Ganglion Cells Risk Risk Factors Rodent Role Seminal Severities Signal Pathway Signal Transduction Structure Structure of sinus venosus of sclera Structure of thyroid parafollicular cell TEK gene TIE-2 Receptor Testing Tissues Trabecular meshwork structure Variant Work anterior chamber base cell type clinical development cohort design disease phenotype disorder risk effectiveness testing functional restoration genetic variant human disease improved insight limbal loss of function loss of function mutation mimetics mouse model novel novel therapeutics pressure prevent primary congenital glaucoma repaired risk variant single cell analysis single-cell RNA sequencing targeted treatment

项目摘要

SUMMARY - Glaucoma is a leading cause of blindness affecting more than 60 million people worldwide. Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of glaucoma and results from increased resistance to aqueous humor outflow. IOP reduction has been shown to reduce the risk of conversion to glaucoma in eyes with ocular hypertension and reduce the risk of disease worsening in eyes with existing glaucoma damage. While IOP-lowering therapies capable of restoring structure and function of the diseased tissues that increase outflow resistance are particularly desirable, few such therapies currently exist. These diseased tissues reside in the conventional outflow tract that is comprised of the trabecular meshwork (TM) and Schlemm’s canal (SC). In 2013, our group discovered that reduced activity of the Angiopoietin (Angpt)- TEK vascular signaling pathway results in a severe form of primary congenital glaucoma (PCG) in mice due to failure of the SC to form. During the last grant cycle, we showed that the Angiopoietin1 ligand is expressed in the TM and is required to activate the Tie2/TEK receptor in the SC and that severity of glaucoma disease phenotype correlates tightly with the dose of Angpt/TEK signal strength. We were able to rescue the PCG disease phenotype in mice, by inhibiting the vascular-specific phosphatase PTPRB, thereby boosting TEK signal strength in a ligand-independent manner. In collaboration with an international team, we have now identified 20 unique loss-of-function mutations in the TEK and ANGPT1 genes in 20 individuals, providing a new genetic cause of PCG and confirming the importance of this pathway in human disease. In adult patients with primary open angle glaucoma (POAG), risk variants in the Angpt/TEK pathway have been identified and a pepti-body targeting Angiopioetin ligands causes rapid onset of high pressure OAG in adult monkeys by reducing outflow facility, extending importance of this pathway beyond childhood glaucoma. Altogether, our findings, largely funded by the first cycle of this grant, have led to major new insights into the pathogenesis of glaucoma and development of the outflow tract and have led directly to the identification of a new genetic cause of glaucoma. In this competitive renewal, we propose to leverage these seminal discoveries to:1) fully characterize the cellular basis of Angpt-TEK signaling in development of the outflow tract and pathogenesis of glaucoma through single cell analysis 2) functionally annotate 2 new disease genes identified in patients with PCG and POAG and determine how they modulate Angpt/TEK signal strength and 3) test the ability of a novel ANGPT1-mimetic to repair defective SC and TM in glaucoma models and enhance outflow facility. By the end of the next cycle, we will have characterized specific cell populations in the TM and SC, identified new genes responsible for glaucoma and provide lead compounds to take forward to clinical development.

摘要 - 青光眼是失明影响全球超过6000万人的主要原因。升高的眼压（IOP）是青光眼发展和发展的主要危险因素对水性幽默出口的阻力增加的结果。已显示IOP减少可降低风险眼睛高血压的眼睛转化为青光眼，并降低眼睛担心疾病的风险现有的青光眼损害。而降低IOP的疗法能够恢复增加出口耐药性的患病组织尤其是，目前很少存在此类疗法。这些解剖的组织驻留在小梁网的传统出口段中（TM）和Schlemm的运河（SC）。 2013年，我们的小组发现，血管生成素（Angpt）的活动减少 - TEK血管信号通路导致小鼠在小鼠中产生严重的原发性前先天青光眼（PCG） SC未能形成。在上一个赠款周期中，我们证明了angiopietin1配体在 TM并需要激活SC中的TIE2/TEK受体，并且青光眼疾病的严重程度表型与Angpt/Tek信号强度的剂量密切相关。我们能够营救PCG 小鼠疾病表型，通过抑制血管特异性磷酸酶PTPRB，从而增强TEK信号以配体无关的方式强度。与国际团队合作，我们现在已经确定了20 TEK和ANGPT1基因的独特功能丧失突变在20个个体中，提供了新的通用 PCG的原因并证实了该途径在人类疾病中的重要性。在成年患者中已经确定了Angpt/Tek途径中的风险变体（POAG），并且已经确定了胡椒体靶向血管蛋白配体通过减少出口流量，导致成人猴子的高压OAG快速发作设施，将这一途径的重要性扩展到儿童青光眼之外。总共，我们的发现很大程度上由这笔赠款的第一个周期资助，导致了对青光眼和青光眼发病机理的主要新见解出口大道的发展，直接导致了青光眼的新遗传原因。在这种竞争性更新中，我们建议利用这些第二个发现来：1）完全表征蜂窝在出口道的发展和青光眼发育中的呼吸tek信号传导的基础细胞分析2）在功能上注释2个新疾病基因，在PCG和POAG患者和确定它们如何调节Angpt/Tek信号强度和3）测试新型Angpt1模拟的能力在青光眼模型中修复有缺陷的SC和TM，并增强流出设施。在下一个周期结束时，我们将在TM和SC中表征特定细胞群，确定了负责青光眼的新基因并提供铅化合物来促进临床开发。