Stimulation of Tear Secretion by a Novel Glycoprotein

新型糖蛋白刺激泪液分泌

• 批准号: 6742153
• 负责人: JOHN D SHEPPARD
• 金额: $ 10.49万
• 依托单位: EYERX RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6742153
• 关键词: biological models; biotherapeutic agent; calcium flux; cell proliferation; corneal epithelium; drug design /synthesis /production; drug screening /evaluation; eye disorder chemotherapy; eye pharmacology; fluid flow; glycoproteins; keratoconjunctivitis sicca; laboratory rabbit; lacrimal apparatus; nonhuman therapy evaluation; pharmacokinetics; protein binding; salivary glands; secretion; tear; topical drug application

DESCRIPTION (provided by applicant): Dry eye is a ubiquitous, often overlooked, underdiagnosed and poorly understood affliction of the ocular surface. This common opthalmological complaint can markedly affect a patient's quality of life. As a multifactorial disease, dry eye has hyposecretory, auto-immune, inflammatory, hormonal, neurogenic, toxic, and iatrogenic components. Common to all etiologies is a decrease in both volume and quality of tear secretion. Current therapy ranges from topical application of aqueous, oil and gel tear film constituent replacement "artificial" tears, to topical anti-inflammatory drugs, to oral secretagogues. There are currently no approved topical agents indicated for enhancement of tear flow and production, which would address the primary defect in aqueous deficiency dry eye disease. Lacritin is a stable, novel human tear glycoprotein produced solely by lacrimal and salivary glands. It binds to and stimulates a rapid, sustained release of calcium in cultured corneal epithelial cells, which suggests topical application of lacritin may stimulate the cornea/lacrimal gland axis to increase tear production. Based upon these properties elucidated in cell culture, we hypothesize that lacritin has potential as a therapeutic agent to promote tear production. Compared to current therapy, as an ocular-specific prosecretory glycoprotein, lacritin has a unique mechanism of action. We expect that topical application of lacritin will increase tear production by stimulation of the lacrimal gland/corneal axis. The long-term goals of this translational research project are to develop lacritin as an efficacious, nontoxic topical treatment. Specific aims for this proposal are (1) demonstration, using an in vivo rabbit model, of the ability of lacritin to increase tear production after topical administration, (2) determination of the effect of lacritin on the normal composition of tears, and (3) examination of lacritin-treated ocular tissues for signs of adverse effects. The primary outcome measurement is lacritin's ability to increase tear production. In vivo analysis also includes confocal microscopy, slit lamp biomicroscopy, digital photography, application of the MacDonald-Shadduck Scale for Ocular Toxicity, tear break up time, vital dye assessment with fluorescein and Lissamine green, and Schirmer's test for tear production.

描述（由申请人提供）：干眼症是一种普遍存在、经常被忽视、诊断不足且了解甚少的眼表疾病。这种常见的眼科疾病会显着影响患者的生活质量。作为一种多因素疾病，干眼具有分泌不足、自身免疫、炎症、激素、神经源性、毒性和医源性成分。所有病因的共同点是泪液分泌量和质量下降。目前的治疗范围从局部应用水性、油性和凝胶泪膜成分替代“人工”眼泪，到局部抗炎药物，到口服促分泌素。目前尚无批准的局部药物可用于增强泪液流动和产生，从而解决水液缺乏性干眼病的主要缺陷。 泪素是一种稳定的新型人类泪液糖蛋白，仅由泪腺和唾液腺产生。它与培养的角膜上皮细胞结合并刺激钙的快速、持续释放，这表明局部应用泪泌素可以刺激角膜/泪腺轴以增加泪液产生。 基于细胞培养中阐明的这些特性，我们假设泪泌素具有作为促进泪液产生的治疗剂的潜力。与现有疗法相比，作为一种眼部特异性原分泌糖蛋白，泪素具有独特的作用机制。我们预计局部应用泪泌素将通过刺激泪腺/角膜轴来增加泪液产生。 该转化研究项目的长期目标是开发乳泌素作为一种有效、无毒的局部治疗药物。该提案的具体目标是（1）使用体内兔模型证明泪液素在局部给药后增加泪液产生的能力，（2）确定泪液素对泪液正常成分的影响，以及（3 ）检查经泪泌素处理的眼组织是否有不良反应的迹象。主要结果测量是乳泌素增加泪液产生的能力。体内分析还包括共焦显微镜、裂隙灯生物显微镜、数码摄影、MacDonald-Shadduck 眼毒性量表的应用、泪液破裂时间、荧光素和丽丝胺绿活体染料评估以及泪液产生的 Schirmer 测试。