The Role of Selectin-Mediated Recognition in Glaucoma

选择素介导的识别在青光眼中的作用

• 批准号: 6820998
• 负责人: Noorjahan Panjwani
• 金额: $ 16.35万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6820998
• 关键词: carbohydrate receptor; cell adhesion; clinical research; extracellular matrix; glaucoma; glycoproteins; human old age (65+); human subject; human tissue; immunocytochemistry; pathologic process; receptor binding; selectins; trabecular meshwork; western blottings

DESCRIPTION (provided by applicant): Glaucoma is the second leading cause of blindness in the world after cataract, affecting approximately 70 million people. Elevated intraocular pressure due to the obstruction of the aqueous outflow pathway is a major causal risk factor in the development of primary open-angle glaucoma. Treatment of this blinding disease is compromised because of the lack of understanding of the molecular mechanism responsible for the resistance to the outflow facility. In a recent study, a carbohydrate-binding protein, E-selectin (ELAM-1, CD62E), was identified as a specific molecular marker of glaucoma. It was demonstrated that while E-selectin is consistently present on trabecular meshwork (TM) cells in the outflow pathways of eyes of glaucomas of diverse etiology, it was absent in the outflow pathway of all normal eyes examined. We propose a unique hypothesis that TM cell surface E-selectin, by binding to its putative glycoprotein counterreceptors on adjacent cells or in aqueous humor activates key signaling pathways, which in turn, by promoting cell-matrix and/or cell-to-cell interactions and cytoskeletal changes, provide a protective stress response specific to the aqueous outflow pathway of the eye. In this NEI R03 application, we propose pilot studies to determine whether the hypothesis merits a detailed investigation. In Aim 1, using immunohistochemical and Western blot analysis, we shall establish which specific carbohydrate ligands of selectins, if any, are expressed on the TM cells and in the aqueous humor of normal and glaucomatous eyes. In Aim 2, we shall determine whether the selectins/carbohydrate-mediated signaling promotes adhesion of TM cells to a variety of extracellular matrix molecules in vitro. The proposed studies will determine whether the selectin-based carbohydrate recognition system plays a role in the pathogenic mechanisms of aqueous outflow resistance in glaucoma.

描述（由申请人提供）：青光眼是世界上仅次于白内障的第二大致盲原因，影响约7000万人。 由于房水流出道阻塞导致的眼内压升高是原发性开角型青光眼发生的主要危险因素。 由于缺乏对流出道阻力的分子机制的了解，这种致盲性疾病的治疗受到影响。 在最近的研究中，糖结合蛋白E-选择素（ELAM-1，CD 62 E）被鉴定为青光眼的特异性分子标志物。 结果表明，虽然E-选择素是一贯存在于小梁网（TM）细胞的流出途径的眼的不同病因的青光眼，它是不存在的流出途径的所有正常的眼睛检查。 我们提出了一个独特的假设，TM细胞表面的E-选择素，通过结合到其推定的糖蛋白反受体在相邻的细胞或在房水激活关键的信号传导途径，这反过来又通过促进细胞基质和/或细胞间的相互作用和细胞骨架的变化，提供了一个保护性的压力反应，具体的水流出途径的眼睛。 在NEI R 03申请中，我们建议进行试点研究，以确定该假设是否值得进行详细调查。 在目标1中，使用免疫组织化学和Western印迹分析，我们将建立选择素的特定碳水化合物配体，如果有的话，在TM细胞和正常和青光眼眼的房水中表达。 在目标2中，我们将确定选择素/碳水化合物介导的信号传导是否促进TM细胞在体外与各种细胞外基质分子的粘附。 这项研究将确定选择素为基础的碳水化合物识别系统是否在青光眼房水流出阻力的发病机制中发挥作用。