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

激活血管生成素-Tie2 通路治疗高眼压和青光眼

• 批准号: 9106642
• 负责人: SUSAN E. QUAGGIN
• 金额: $ 70.9万
• 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 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9106642
• 关键词: ANGPT1 gene; Accounting; Affect; Alleles; Angiopoietins; Anterior; Aqueous Humor; Biological Assay; Blindness; Blood; Blood Vessels; Caliber; Cells; Child; Childhood; Cornea; DNA Sequence Alteration; Data; Defect; Development; Disease; Drainage procedure; Event; Eye; Eye diseases; Eyedrops; Genes; Genetic; Genetically Engineered Mouse; Glaucoma; Growth; Hand; Heterozygote; Human; Hydrophthalmos; In Vitro; Knock-out; Lead; Ligands; Limbus Corneae; Link; Liquid substance; Lymphatic; Lymphatic vessel; Medical; Molecular; Mus; Mutant Strains Mice; Mutation; Ocular Hypertension; Operative Surgical Procedures; Ophthalmologist; Optic Nerve; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Physiologic Intraocular Pressure; Play; Proteomics; Reagent; Receptor Protein-Tyrosine Kinases; Registries; Retinal Ganglion Cells; Risk Factors; Rodent; Role; Schools; Scientist; Signal Pathway; Signal Transduction; Structure of sinus venosus of sclera; TEK gene; TIE-2 Receptor; Testing; Therapeutic; Transgenic Mice; Vision; anterior chamber; base; blind; curative treatments; design; exome sequencing; high intraocular pressure; human disease; in vivo; innovation; limbal; mouse model; multidisciplinary; novel; novel therapeutics; pressure; prevent; primary congenital glaucoma; public health relevance; receptor; small molecule; small molecule inhibitor; targeted sequencing; targeted treatment; therapy design; therapy development; vascular endothelial protein tyrosine phosphatase

 DESCRIPTION (provided by applicant): Glaucoma is a leading cause of blindness, afflicting more than 60 million people worldwide. Vision loss in glaucoma is due to progressive loss of retinal ganglion cells leading to deformation of the optic nerve. While the pathogenic events triggering the various forms of glaucoma remain obscure, increased intraocular pressure (IOP) due to impaired aqueous humor drainage has been identified as a major risk factor. Accordingly, current medical and surgical therapies are designed to promote fluid drainage from the anterior chamber to reduce ocular hypertension. While these therapies show some benefit, none are curative. The greatest obstacle to finding a cure has been a poor understanding of the molecular events leading to decreased aqueous humor drainage and retinal ganglion loss, preventing the development of therapies based on underlying disease mechanisms. We have shown that genetic disruption of the Angiopoietin-Tie2 signaling pathway in mice results in high IOP, bupthalmos and classic features of primary congenital glaucoma (PCG), a particularly devastating form of the disease in children that accounts for 5% of childhood blindness and 18% of blind-school registry. The primary defect in our mice is loss of Schlemm's canal and corneal limbal lymphatics resulting in defects of aqueous humor drainage. In 174 children with PCG, we have identified 10 mutations in the TIE2 gene and its ligand, Angiopoietin 1 (ANGPT1), suggesting this pathway plays a major role in human disease. In this proposal we will test the hypotheses that: 1) The development of the anterior angle of the eye including the outflow tract is dependent on the level of activity of the Tie2 receptor and reduced size and/or function of the draining vessels is sufficient to cause ocular hypertension, resulting in retinal ganglion cell los and glaucoma. 2) The TIE2 and ANGPT1 mutations observed in children with PCG reduce signaling function of the TIE2 receptor leading to alterations in Schlemm's canal and outflow of the anterior chamber. 3) Activation of TIE2 signaling within the corneal limbal region will enhance the size and function of Schlemm's canal, promoting aqueous humor drainage, reducing IOP and preventing retinal ganglion and vision loss. To test these hypotheses we have assembled a multidisciplinary team of ophthalmologists, vision scientists, geneticists, proteomics experts, vascular biologists and a number of unique reagents permitting us to determine: 1) the impact of a range of reductions in Angpt-Tie2 signaling on development of the irido-corneal angle, IOP and features of glaucoma in genetically engineered mice 2) how the TIE2 and ANGPT1 mutations in children with PCG affect activity of the receptor 3) whether activation of TIE2 using genetic or small molecule approaches rescues the glaucoma phenotype. Our studies provide an unprecedented opportunity to determine novel molecular mechanisms of glaucoma and ocular hypertension and an innovative approach to treat glaucoma and ocular hypertension through development of the first biologically-targeted therapy.

 描述（由申请人提供）：青光眼是失明的主要原因，困扰着全世界6000多万人。青光眼中的视力丧失是由于视网膜神经节细胞的进行性丧失导致视神经变形。虽然引发各种形式青光眼的致病事件仍然不清楚，但由于房水引流受损而导致的眼内压（IOP）升高已被确定为主要风险因素。因此，目前的医疗和手术治疗被设计成促进流体从前房排出以减少高眼压。虽然这些疗法显示出一些益处，但没有一种是治愈性的。寻找治愈方法的最大障碍是对导致房水引流减少和视网膜神经节损失的分子事件的理解不足，从而阻止了基于潜在疾病机制的治疗方法的发展。我们已经证明，小鼠中血管生成素-Tie 2信号通路的遗传破坏导致高IOP、眼睑下垂和原发性先天性青光眼（PCG）的典型特征，这是儿童中特别具有破坏性的疾病形式，占儿童失明的5%和盲人学校登记的18%。我们的小鼠的主要缺陷是Schlemm管和角膜缘水肿的丧失，导致房水引流的缺陷。在174例PCG患儿中，我们发现了TIE 2基因及其配体血管生成素1（ANGPT 1）的10个突变，表明该途径在人类疾病中起着重要作用。在该提议中，我们将测试以下假设：1）包括流出道的眼睛的前角的发育取决于Tie 2受体的活性水平，并且引流血管的尺寸和/或功能的减小足以引起高眼压，导致视网膜神经节细胞损失和青光眼。2)在患有PCG的儿童中观察到的TIE 2和ANGPT 1突变降低了TIE 2受体的信号传导功能，导致施累姆氏管和前房流出的改变。3)角膜缘区域内TIE 2信号传导的激活将增强施累姆氏管的大小和功能，促进房水引流，降低IOP并防止视网膜神经节和视力丧失。为了验证这些假设，我们组建了一个由眼科医生、视觉科学家、遗传学家、蛋白质组学专家、血管生物学家和一些独特的试剂组成的多学科团队，使我们能够确定：1）Angpt-Tie 2信号传导的一系列减少对虹膜-角膜角发育的影响，遗传工程小鼠的IOP和青光眼特征2）PCG儿童中TIE 2和ANGPT 1突变如何影响受体活性3）使用遗传或小分子方法激活TIE 2是否挽救青光眼表型。我们的研究为确定青光眼和高眼压症的新分子机制提供了前所未有的机会，并通过开发第一种生物靶向治疗提供了治疗青光眼和高眼压症的创新方法。