GYRATE ATROPHY--TREATMENT AND PATHOPHYSIOLOGY

脑回萎缩——治疗和病理生理学

基本信息

批准号：
2710825
负责人：
DAVID VALLE
金额：
$ 14.41万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-04-01 至 1999-06-30
项目状态：
已结题

项目摘要

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 one of a small number of isolated chorioretinal de generations 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. More than 50 mutant OAT alleles have been identified in GA. Despite this progress, there is much that remains to be learned about the regulation of OAT, the pathophysiology of the chorioretinal degeneration and how we can prevent it in patients with GA. There are four long-term objectives of this proposal. The first is to extend our understanding of the molecular basis of GA by identifying the cis- and trans-acting regulators of OAT transcription responsible for its localized expression in liver; delineating the mutations causing OAT deficiency in GA; determining the distribution of these mutations in our large collection of GA families (92 pedigrees); determining the functional consequences of these mutations; and correlating the molecular defects with phenotypic variation. The second goal is to investigate potential pathophysiologic mechanisms in GA in order to determine why the retina is particularly sensitive to this systemic biochemical defect. Studies to this end will include an examination of the pattern of expression of enzymes and transport proteins metabolically related to OAT in human ocular tissues. These studies should establish the metabolic requirements met by OAT in the various cell types of the retina. The third aim is to continue our long-term evaluation of possible treatments of GA, focusing particularly on reduction of ornithine accumulation with an arginine- restricted diet, focusing particularly on the outcomes of younger patients. The fourth aim is to produce and characterize a mouse model of GA by homologous recombination mediated gene knockout. The resultant animals will be characterized biochemically by amino acid and OAT activity determinations and ophthalmologically by ophthalmoscopy, electroretinography and by histopathologic studies of the retinas of affected mice at various ages. The last aim is to utilize these mice for studies relevant to our understanding of the pathophysiology and to determine the requirements (location, amount of activity and optimal timing) for effective somatic gene therapy of GA.

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）。旁边从他们的视觉症状中，大多数GA患者无症状；因此，GA是少数孤立的脉络膜视网膜De世代之一已知生化缺陷。人燕麦cDNA和结构基因已被克隆，测序和映射（10q26）。一群燕麦加工假基因映射到XP11-XP21。超过50个突变燕麦等位基因已经在GA中确定。尽管取得了这些进展，还有很多还有很多了解燕麦的调节，脉络化视网膜变性以及我们如何在GA患者中预防它。该提案有四个长期目标。首先是通过识别我们对GA的分子基础的理解燕麦转录的顺式和反式调节器负责其肝脏中的局部表达；描述引起燕麦的突变 GA缺乏；确定这些突变在我们的大量的GA家族（92个血统）；确定功能这些突变的后果；并关联分子缺陷与表型变化。第二个目标是调查潜力 GA中的病理生理机制是为了确定为什么视网膜是对这种系统性的生化缺陷特别敏感。研究此目的将包括对表达方式的检查酶和转运蛋白质与人类燕麦的代谢相关眼组织。这些研究应确定代谢要求通过燕麦在视网膜的各种细胞类型中满足。第三个目标是继续我们对GA可能治疗的长期评估，重点特别是在用精氨酸降低鸟氨酸积累的过程中限制饮食，特别关注年轻的结果患者。第四个目的是生产和表征鼠标模型 GA通过同源重组介导的基因敲除。结果动物将通过氨基酸和燕麦活性在生化上表征确定和通过眼镜的眼科检查，电子视网膜图和通过组织病理学研究影响各个年龄的小鼠。最后的目的是利用这些老鼠与我们对病理生理学的理解相关的研究和确定要求（活动的位置，活动量和最佳定时）用于有效的GA的体细胞基因疗法。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pyridoxine-responsive gyrate atrophy of the choroid and retina: clinical and biochemical correlates of the mutation A226V.

吡哆醇反应性脉络膜和视网膜回旋萎缩：突变 A226V 的临床和生化相关性。

DOI：
发表时间：
1995
期刊：
American journal of human genetics
影响因子：
9.8
作者：
Michaud,J;Thompson,GN;Brody,LC;Steel,G;Obie,C;Fontaine,G;Schappert,K;Keith,CG;Valle,D;Mitchell,GA
通讯作者：
Mitchell,GA

Gyrate atrophy of the choroid and retina.

脉络膜和视网膜旋转萎缩。