Investigation of glutaric acidemia type I.

描述（由申请人提供）：I型谷氨酸血症（GA-I）是一种遗传性氨基酸代谢障碍，其通常形式会导致进行性锥体外系运动障碍，并在生命的前十年死亡。我们最近通过胚胎干细胞中的基因靶向产生了GA-I的小鼠模型。受影响的小鼠表现出许多在GA-I患者中观察到的表型特征。本提案的目标是使用该动物模型来回答关于GA-I的病理生理学的基本问题。具体而言，神经系统损伤是由于毒性代谢物的循环水平，还是由于单个神经元内缺乏戊二酰CoA-脱氢酶（GCDH）活性（即它是细胞自主表型）。本提案的具体目的是检验以下假设：GCDH cDNA在Gcdh 1-小鼠肝脏中的表达将使毒性代谢物（谷氨酸和3-OH谷氨酸）的循环水平正常化，并防止在这些动物中观察到的髓鞘病和运动缺陷的发展。我们将使用的方法是使用白蛋白启动子在Gcdh /动物的肝脏中表达Gcdh cDNA。GA-I的当前疗法主要由蛋白质限制饮食组成，其基于使谷氨酰胺和3-OH谷氨酰胺酸的水平最小化是有益的假设。本提案中的实验将直接验证这一假设。如果我们的假设是正确的，那么随后的治疗发展，如肝定向基因治疗和肝干细胞治疗，就可以开始。或者，如果确定代谢物水平的正常化不足以预防GA-I中的神经病理学，则需要开发替代治疗方法。

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.