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

• 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
• 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' 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

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.

青光眼是全球超过6000万人失明的主要原因。