Investigation of glutaric acidemia type I.

描述(申请人提供)：戊二酸血症I型(GA-I)是一种遗传性氨基酸代谢障碍，其常见形式会导致进行性锥体外系运动障碍和生命最初十年的死亡。我们最近通过胚胎干细胞中的基因打靶产生了GA-I的小鼠模型。受影响的小鼠表现出在GA-I患者中看到的许多表型特征。这项建议的目标是使用这个动物模型来回答关于GA-I的病理生理学的一个基本问题。具体地说，神经损伤是由于循环中有毒代谢物的水平，还是由于单个神经元内缺乏戊二酰辅酶A脱氢酶(GCDH)活性(即它是一种细胞自主表型)。这项建议的具体目的是验证这样一种假设，即在Gcdh 1“小鼠的肝脏中表达GCDH基因将使有毒代谢物(戊二酸和3-羟基戊二酸)的循环水平正常化，并防止这些动物的脊髓病和运动障碍的发展。我们将使用的方法是利用白蛋白启动子在Gcdh/动物的肝脏中表达Gcdh基因。目前对GA-I的治疗主要包括限制蛋白质饮食，这是基于最大限度地减少戊二酸和3-羟基戊二酸水平是有益的假设。这项提议中的实验将直接检验这一假设。如果我们的假设是正确的，那么随后的治疗方法的开发，如肝脏导向基因治疗和肝干细胞治疗，就可以开始了。或者，如果确定代谢物水平的正常化不足以预防GA-I的神经病理，则需要开发替代的治疗方法。

DESCRIPTION (provided by applicant): Glutaric acidemia type I (GA-I) is an inherited disorder of amino acid metabolism, which in its usual form, causes a progressive extrapyramidal movement disorder and death during the first decade of life. We have recently generated a mouse model of GA-I via gene targeting in embryonic stem cells. The affected mice demonstrate many of the phenotypic features seen in GA-I patients. The goal of this proposal is to use this animal model to answer a fundamental question regarding the pathophysiology of GA-I. Specifically, is the neurologic damage the result of circulating levels of toxic metabolites, or due to the lack of glutaryl CoA-dehydrogenase (GCDH) activity within individual neurons (i.e. is it a cell autonomous phenotype). The specific aim of this proposal is to test the hypothesis that expression of the GCDH cDNA in the liver of Gcdh 1" mice will normalize the circulating levels of toxic metabolites (glutaric and 3-OH glutaric acids), and prevent the development of the myelinopathy and motor deficits seen in these animals. The approach we will use is to express the Gcdh cDNA in the liver of Gcdh / animals using the albumin promoter. Current therapy of GA-I consists primarily of a protein-restricted diet, which is based on the assumption that minimizing the levels of glutaric and 3-OH glutaric acids is beneficial. The experiments in this proposal will directly test that assumption. If our hypothesis is correct, the subsequent development of therapies such as liver directed gene therapy and liver stem cell therapy could then begin. Alternatively, if it is determined that normalization of metabolite levels is insufficient to prevent neuropathology in GA-I, alternative approaches to therapy need to be developed.