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：
10673706
负责人：
Jing Jin
金额：
$ 60.1万
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/10673706
关键词：
3&apos Untranslated Regions ANGPT1 gene ANGPT2 gene Acceleration 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 Maps MicroRNAs Modeling Molecular Monkeys Mus Mutation Ocular Hypertension Open-Angle Glaucoma 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 Risk Reduction Rodent Role Seminal Severities Signal Pathway Signal Transduction Structure Structure of sinus venosus of sclera TEK gene TIE-2 Receptor Testing Tissues Trabecular meshwork structure Variant Work anterior chamber 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 - 青光眼是导致失明的主要原因，影响着全世界超过 6000 万人。眼内压升高（IOP）是青光眼发生和进展的主要危险因素增加对房水流出的抵抗力降低眼压已被证明可以降低风险。降低高眼压症眼睛转化为青光眼的风险，并降低眼睛疾病恶化的风险现有的青光眼损伤，而降低眼压的疗法能够恢复青光眼的结构和功能。增加流出阻力的患病组织是特别需要的，但目前很少有这样的疗法。这些患病组织位于由小梁网组成的传统流出道中 (TM) 和施累姆氏管 (SC) 2013 年，我们的小组发现血管生成素 (Angpt) 的活性降低-。 TEK 血管信号通路导致小鼠出现严重的原发性先天性青光眼 (PCG) 在最后一个授予周期中，我们发现血管生成素1配体在SC中表达失败。 TM 需要激活 SC 中的 Tie2/TEK 受体以及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，我们能够挽救 PCG。通过抑制血管特异性磷酸酶 PTPRB，从而增强 TEK 信号，从而改变小鼠的疾病表型通过与国际团队合作，我们现已鉴定出 20 种不依赖配体的强度。 20 名个体的 TEK 和 ANGPT1 基因出现独特的功能丧失突变，提供了一种新的遗传 PCG 的病因并确认该途径在人类原发性疾病患者中的重要性。开角型青光眼 (POAG)，Angpt/TEK 通路中的风险变异已被识别，肽体靶向血管生成素配体通过减少流出导致成年猴快速发生高压 OAG 总而言之，我们的发现在很大程度上扩展了这一途径的重要性。由本次赠款的第一周期资助，对青光眼的发病机制产生了重大的新见解，流出道的发育并直接导致了青光眼新遗传原因的鉴定。在这次竞争性更新中，我们建议利用这些开创性的发现来：1）充分表征细胞 Angpt-TEK信号在青光眼流出道发育和发病机制中的基础细胞分析 2) 对在 PCG 和 POAG 患者中发现的 2 个新疾病基因进行功能注释确定它们如何调节 Angpt/TEK 信号强度，并 3) 测试新型 ANGPT1 模拟物的能力修复青光眼模型中有缺陷的 SC 和 TM 并增强流出设施到下一个周期结束时，我们。将表征 TM 和 SC 中的特定细胞群，确定导致青光眼的新基因并提供先导化合物以推进临床开发。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Angiopoietins bind thrombomodulin and inhibit its function as a thrombin cofactor.

DOI：
10.1038/s41598-017-18912-8
发表时间：
2018-01-11
期刊：
Scientific reports
影响因子：
4.6
作者：
Daly C;Qian X;Castanaro C;Pasnikowski E;Jiang X;Thomson BR;Quaggin SE;Papadopoulos N;Wei Y;Rudge JS;Thurston G;Yancopoulos GD;Davis S
通讯作者：
Davis S

Endothelial mineralocorticoid receptor ablation does not alter blood pressure, kidney function or renal vessel contractility.

DOI：
10.1371/journal.pone.0193032
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Laursen SB;Finsen S;Marcussen N;Quaggin SE;Hansen PBL;Dimke H
通讯作者：
Dimke H

Morphological Analysis of Schlemm's Canal in Mice.

DOI：
10.1007/978-1-4939-8712-2_10
发表时间：
2018
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Thomson BR;Quaggin SE
通讯作者：
Quaggin SE

Angiopoietin-1 deficiency increases renal capillary rarefaction and tubulointerstitial fibrosis in mice.

DOI：
10.1371/journal.pone.0189433
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Loganathan K;Salem Said E;Winterrowd E;Orebrand M;He L;Vanlandewijck M;Betsholtz C;Quaggin SE;Jeansson M
通讯作者：
Jeansson M

Angiopoietin-1 deficiency increases tumor metastasis in mice.