GYRATE ATROPHY: TREATMENT AND PATHOPHYSIOLOGY

脑回萎缩：治疗和病理生理学

• 批准号: 3257242
• 负责人: DAVID VALLE
• 金额: $ 9.84万
• 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 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3257242
• 关键词: aminoacid metabolism; arginine; arginosuccinate synthetase deficiency; carbamoyl phosphate synthetase deficiency; chromatography; congenital vision disorder; creatine; diet therapy; disease /disorder model; eye pharmacology; gene expression; gene mutation; genetic manipulation; genetic recombination; genetic transcription; human subject; laboratory mouse; laboratory rat; messenger RNA; model design /development; molecular cloning; molecular pathology; ornithine; ornithine oxoacid transaminase; ornithinemia; retina disorder; tissue /cell culture

Gyrate atrophy (GA) of the choroid and retina is a rare, inherited, blinding chorioretinal degeneration caused by deficiency of the mitochondrial matrix enzyme, ornithine-delta-aminotransferase (OAT). Aside from their visual symptoms, most GA patients are asymptomatic; thus, GA is perhaps the only isolated chorioretinal degeneration for which the biochemical defect is known. The human OAT cDNA and structural gene have been cloned, sequenced and mapped (10q26). A cluster of OAT processed pseudogenes map to Xp11 - Xp21. There are four long-term objectives of this proposal. The first is to extend our understanding of the molecular basis of GA by determining the cis- and trans- acting regulators of OAT transcription in various tissues; delineating the mutations causing OAT deficiency in GA; determining the distribution of these mutations in our large collection of GA families (72 pedigrees); determining the functional consequences of these mutations; and correlating the molecular defects with phenotypic variation in our large patient population. The second goal is to investigate potential pathophysiologic mechanisms in GA to determine why the retina is particularly sensitive to this systemic biochemical defect. Studies to this end will include comparison of guanidino compound metabolism in patients with GA and a related inborn error of ornithine metabolism (the hyperornithinemia-hyperammonemia-homocitrullinemia syndrome) which does not involve the eye; examination of expression of OAT mRNA in human ocular tissues; determination of the ocular consequences of pharmacologic perturbation of guanidino compound metabolism in animals and investigation of ornithine and guanidino compound metabolism in cultured retinal cells. The third goal is to continue our long-term evaluation of the therapeutic effects of reduction of ornithine accumulation with an arginine-restricted diet, focusing particularly on the outcomes of younger patients. Lastly, an animal model of GA will be developed either by identifying a naturally-occurring mutation or by molecular methods including expression in transgenic mice of mutant OAT subunits which have negative effects on the function of wild-type subunits assembled in the same multimeric enzyme (suicide subunits) or, alternatively, by knocking out the expression of an endogenous OAT gene by homologous recombination in embryonic stem (ES) cells and subsequently developing a strain of homozygous deficient mice by way of chimeric animals.

脉络膜和视网膜的回旋萎缩（GA）是罕见的，遗传的， 由于缺乏 线粒体基质酶，鸟氨酸 - 二氨基转移酶（OAT）。 除了视觉症状外，大多数GA患者都是无症状的。 因此，GA也许是唯一的孤立的脉络膜视网膜变性 生化缺陷是已知的。 人燕麦cDNA和结构 基因已被克隆，测序和映射（10q26）。 一群燕麦 加工的假基因映射到XP11 -XP21。 该提案有四个长期目标。 首先是 通过确定 各种燕麦转录的顺式和转移调节剂 组织；描述引起GA燕麦缺乏的突变； 确定这些突变在我们的大型收藏中的分布 GA家族（72个血统）；确定功能后果 这些突变；并将分子缺陷与表型相关联 我们庞大的患者人群的差异。 第二个目标是 研究GA中潜在的病理生理机制，以确定为什么 视网膜对这种系统性的生化缺陷特别敏感。 到此为止的研究将包括鸟养鸟尼诺化合物的比较 GA患者的代谢和相关的鸟氨酸的先天误差 代谢（高义血症 - 杂氨菌血症 - 富氨基血症 综合征）不涉及眼睛；考察表达的表达 人眼组织中的燕麦mRNA；眼睛的确定 鸟翼尼诺化合物的药理学扰动的后果 动物的代谢以及对鸟氨酸和鸟养界的研究 培养的视网膜细胞中的复合代谢。 第三个目标是 继续我们对减少治疗作用的长期评估 用精氨酸限制的饮食聚焦的鸟嘌呤积累 特别是在年轻患者的结果上。 最后，动物 GA的模型将通过识别自然出现来开发 突变或通过分子方法包括转基因小鼠的表达 对突变燕麦亚基，对 野生型亚基组装在同一多聚酶（自杀中） 亚基），或者，通过淘汰 内源燕麦基因通过胚胎茎（ES）中的同源重组（） 细胞，随后形成纯合缺乏小鼠的菌株 通过嵌合动物。