GLAUCOMA DAMAGE--TROPHIC FACTORS AND GENE THERAPY

青光眼损伤——营养因子和基因治疗

• 批准号: 2608677
• 负责人: SANSAR C SHARMA
• 金额: $ 23.96万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-12-08 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2608677
• 关键词: apoptosis; denervation; gene expression; gene therapy; genetic manipulation; glaucoma; intraocular pressure; laboratory rat; neurotrophic factors; protooncogene; retinal ganglion; transfection

DESCRIPTION (Adapted from applicant's abstract): Glaucomatous disorders leading to optic neuropathies cause blindness in humans. These diseases cause primary damage to the ganglion cell axons initiating secondary demise of ganglion cells. The applicant's recent findings in either axotomized or glaucomatous (elevated intraocular pressure or IOP) rats show that ganglion cell death in adult eye is apoptotic. In optic nerve- axotomized eye, apoptotic death is controllable by providing neurotrophic factors which activate receptors, thereby signaling pathways within the cells that stimulate gene expression and protein synthesis. The applicants have induced a secondary glaucoma in rats by selective blocking of episcleral venous drainage. Resultant elevated IOP is stable for many weeks. It is proposed to study in controlled elevated IOP eyes and optic nerve-axotomized eye: (1) temporal sequence of ganglion cell death and (2) the rescuing effort by applying various neurotrophic factors. Since the applicants have demonstrated that plasmid DNA can be inserted in vivo in adult ganglion cells and that transfected cells produce specific proteins, the experimental strategy will be to use specific proto-oncogenes to transfect ganglion cells in vivo in optic nerve-axotomized and glaucomatous (elevated IOP) animals. These genes will constitutively stimulate the internal domains of Trk receptors present on the cells, thereby alleviating ligand-specific stimulation of the receptor. This rat model for glaucomatous eyes showing apoptotic cell death of retinal ganglion cells is stated to offer unique opportunities to establish evaluation of cell death and/or rescue. The approach of trophic factor application and gene therapy will be tested for effectiveness in rescuing cell death using various anatomical and biochemical methods. The proposed studies will serve as an experimental model system for development of technology necessary to use direct application of trophic factors and genetic manipulations to treat disorders of optic neuropathy specially elevated IOP related glaucoma.

描述（改编自申请人的摘要）：青光眼疾病 导致视神经病变引起人类失明。这些疾病 对发起次级的神经节细胞轴突造成主要损害 神经节细胞的灭亡。申请人最近的发现 轴向或青光眼（眼内压或IOP）大鼠 表明成人眼神的神经节细胞死亡是凋亡的。在视神经中 通过提供神经营养性，轴承眼，凋亡死亡是可控制的 激活受体的因素，从而发出信号通路 刺激基因表达和蛋白质合成的细胞。这 申请人通过选择性诱导大鼠的次级青光眼 封闭缔局静脉排水。最终升高的IOP是稳定的 好几个星期。提议在受控的IOP眼中研究 和视神神经轴的眼睛：（1）神经节细胞的时间序列 死亡和（2）应用各种神经营养的救援工作 因素。由于申请人已经证明质粒DNA可以是 在成人神经节细胞中插入体内并转染细胞 产生特定蛋白质，实验策略将是使用 特定的原始癌基因在视体内转染神经节细胞在光学中 神经轴和青光眼（升高的IOP）动物。这些基因 将构成刺激TRK受体的内部结构域 存在于细胞上，从而减轻了配体特异性刺激 受体。 该大鼠模型用于青光眼的眼睛，显示了凋亡细胞死亡的死亡 据说视网膜神经节细胞为 确定细胞死亡和/或救援的评估。方法 将测试营养因子的应用和基因治疗 使用各种解剖学和 生化方法。拟议的研究将作为实验 开发使用直接技术所需技术的模型系统 营养因素和遗传操作的应用 视神经病的疾病特别升高IOP相关的青光眼。