Modulating intraocular pressure to treat ocular hypotony and glaucoma

调节眼压治疗眼压低和青光眼

• 批准号: 8952180
• 负责人: JOCHEN BUCK
• 金额: $ 22.66万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8952180
• 关键词: Activator Appliances; Adenylate Cyclase; Adverse effects; Animal Model; Anions; Applications Grants; Bicarbonates; Biological Assay; Blindness; Carbonic Anhydrase Inhibitors; Cells; Characteristics; Ciliary Body; Complication; Cyclic AMP; Development; Dose; Drainage procedure; Drug Industry; Eye; FDA approved; Foundations; Genetic; Glaucoma; Goals; Label; Laboratories; Lead; Libraries; Liquid substance; Location; Methods; Mus; Ocular Hypotension; Ophthalmologic Surgical Procedures; Optic Nerve Injuries; Patients; Pharmaceutical Preparations; Pharmacopoeias; Physiologic Intraocular Pressure; Proteins; Relative (related person); Research Support; Second Messenger Systems; Signal Transduction; Source; Testing; Therapeutic; Trabecular meshwork structure; Trabeculectomy; Uveitis; Visual impairment; Wild Type Mouse; Work; adenylyl cyclase 8; aqueous; base; effective therapy; inhibitor/antagonist; mouse model; novel; novel therapeutics; pressure; public health relevance; screening; second messenger; small molecule; small molecule libraries; therapeutic target; tool; treatment strategy

 DESCRIPTION (provided by applicant): Severe ocular hypotony [too low intraocular pressure (IOP)] can lead to blindness via Phthisis bulbi (shrunken, non-functional eyes). Currently, there are no effective treatments for hypotony. We recently showed that pharmacologic or genetic inhibition of bicarbonate-regulated soluble adenylyl cyclase (sAC) elevates IOP in wild type mice as well as in a mouse model of ocular hypotony. We have identified inhibitors of sAC in a small molecule screen, and we propose to develop these sAC inhibitors into first-in-class therapeutics for treatment of ocular hypotony. Our small molecule screen also identified the first known pharmacological tools for increasing sAC activity, and we propose to test whether they define lead compounds for a new therapeutic strategy for lowering IOP to treat glaucoma.

 描述（由申请人提供）：严重的眼张力减退[过低的眼内压（IOP）]可通过眼球萎缩（萎缩、无功能的眼睛）导致失明。目前，对于张力减退症没有有效的治疗方法。我们最近发现，在野生型小鼠和眼张力减退小鼠模型中，对碳酸氢盐调节的可溶性腺苷酸环化酶（sAC）进行药理学或遗传学抑制可升高IOP。我们已经在小分子筛选中鉴定了sAC的抑制剂，并且我们建议将这些sAC抑制剂开发成用于治疗眼张力减退的一流疗法。我们的小分子筛选还确定了第一个已知的增加sAC活性的药理学工具，我们建议测试它们是否为降低IOP治疗青光眼的新治疗策略定义了先导化合物。