GYRATE ATROPHY: TREATMENT AND PATHOPHYSIOLOGY

脑回萎缩：治疗和病理生理学

• 批准号: 3257244
• 负责人: DAVID VALLE
• 金额: $ 13.82万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-04-01 至 1989-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3257244
• 关键词: aminoacid metabolism; cataract; congenital vision disorder; creatine; creatine phosphate; disease /disorder model; drug metabolism; electron microscopy; eye pharmacology; fibroblasts; gene expression; genetic models; heterokaryon; human subject; human therapy evaluation; molecular cloning; nuclear magnetic resonance spectroscopy; nutrition related tag; ornithine oxoacid transaminase; ornithinemia; proline; pyridoxine; retina degeneration; retina disorder; retinaldehyde; tissue /cell culture; transaminases; vitamin therapy

Gyrate atrophy of the choroid and retina (GA) is a rare inherited form of chorioretinal degeneration characterized by 10 x 15 x fold increases in the concentration of ornithine in all body fluids and deficiency of the mitochondrial matrix enzyme ornithine-Delta-aminotransferase (OAT). The goals of the proposed research include: (1) delineation of heterogeneity in the mutations leading to GA and relating this to clinical variability; (ii) elucidating the pathophysiologic mechanisms involved in the chorioretinal degeneration and cataract formation; (iii) evaluating the therapeutic efficacy of an arginine-restricted diet and several dietary adjuncts; and (iv) Screening the offspring of chemically mutagenized mice for a genetic model of GA. The methodologies used to approach these goals will include: detailed ophthalmologic examination; analysis of amino acids and their metabolites and guanidino compounds in patient and animal samples; somatic cell genetic techniques including assay of OAT activity, antigen and processing and complementation by cell fusion; molecular analysis by cloning human OAT to examine the mutations and their effect on the processing of OAT RNA and its translate; delineation of the ornithine and guanidino metabolism of ocular tissues and culture SV40 transformed human retinal pigment epithelium; long term ophthalmologic and biochemical assessment of patients on diet therapy and OAT analysis in the livers of mutagenized mice. These studies should provide insight not only into the mechanism of chorioretinal degeneration and cataract formation in GA but also suggest possible explanations for related disorders. Increased knowledge of the heterogeneity and response to experimental therapy should lead to the development of effective therapy.

脉络膜和视网膜（GA）的回旋萎缩是一种罕见的遗传形式 以10 x 15 x倍的特征在于脉络膜视网膜变性。 鸟氨酸在所有体液中的浓度和缺乏 线粒体基质酶鸟氨酸 - 二氨基转移酶（OAT）。 这 拟议研究的目标包括：（1）划定异质性 在导致GA的突变中，并将其与临床变异性有关； （ii）阐明涉及的病理生理机制 脉络化变性和白内障形成； （iii）评估 精氨酸限制饮食和几种饮食的治疗功效 辅助； （iv）筛选化学诱变小鼠的后代 用于GA的遗传模型。 用于实现这些目标的方法将包括：详细 眼科检查；分析氨基酸及其代谢物 患者和动物样品中的鸟养鸟尼诺化合物；体细胞遗传 技术包括燕麦活性，抗原和加工的测定以及 细胞融合的互补；通过将人燕麦克隆到分子分析 检查突变及其对燕麦RNA及其加工的影响 翻译;鸟氨酸和鸟养界代谢的描述 组织和培养SV40转化了人类视网膜色素上皮；长的 饮食治疗中患者的术语眼科和生化评估 和诱变小鼠肝脏中的燕麦分析。 这些研究不仅应洞悉 GA中的脉络膜视网膜变性和白内障形成，但也建议 相关疾病的可能解释。 越来越了解 异质性和对实验疗法的反应应导致 开发有效的疗法。