Creatine Transport Across the Blood Brain Barrier

肌酸跨血脑屏障转运

基本信息

批准号：
7062430
负责人：
JOSEPH Floyd CLARK
金额：
$ 14.99万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-15 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7062430
关键词：
aminoacid transport bioenergetics blood brain barrier blood tests brain disorders brain metabolism cognition disorders creatine disease /disorder model drug design /synthesis /production drug screening /evaluation gene mutation genetically modified animals immunocytochemistry laboratory mouse model design /development nuclear magnetic resonance spectroscopy urinalysis

项目摘要

DESCRIPTION (provided by applicant): Recently, we described severe expressive and cognitive delays in a 6-year-old boy, who has a unique creatine (Cr) deficiency in the brain, which was diagnosed by proton magnetic resonance spectroscopy (MRS). Upon further analysis, we found that he has a nonsense mutation in the X-lined Cr transporter gene (CT1;SLC6A8), which resulted in the expression of a truncated (non-functional) Cr transporter protein. Since that study, four additional families have been recognized in Cincinnati with mutations in the X-linked Cr transporter gene and nearly 30 families worldwide. These patients all have mental retardation, severe expressive language disorder and mild epilepsy. Despite a growing body of knowledge about the Cr, Cr kinase and phosphocreatine system in the brain, there is no standardized method for improving brain function when the brain creatine transporter is deficient. What is clearly needed is a suitable animal model of this disease such that methods to get creatine across the blood brain barrier can be developed and tested. In this project we will develop a Cr transporter knockout mouse model, such that the efficacy of new treatment paradigms, drugs, and other therapies can be tested. For this research project, we propose to test the following hypotheses: 1) a mouse knockout of this Cr transport defect can model the human disease, and 2) that therapeutic strategies can be given to normalize brain function in these mice. This mouse knockout will model the Cr transporter defect we have discovered in that the brain will lack the ability to transport creatine across the blood brain barrier. To address Hypothesis 1, we will generate a Cr transporter knockout mouse. Cr levels will be determined in the brains of these mice and we will characterize the functional, and biochemical changes observed in Cr transporter knockout mice. Having an animal model that closely mirrors the human disease will enable adequate testing and development of therapies designed at getting creatine across the blood brain barrier and improving brain function. To address Hypothesis 2, the Cr transporter knockout mice and control mice will be treated with Cr formulations that may be capable of transporting creatine across the blood brain barrier and improve brain metabolism and cognitive function of the mice. The goal for Hypothesis 2 is to develop methods and drugs to improve brain energy metabolism by getting creatine into the brain.

描述（由申请人提供）：最近，我们描述了一个6岁男孩的严重表达和认知延迟，该男孩在大脑中具有独特的肌酸（CR）缺乏，该肌酸（通过质子磁共振光谱（MRS）诊断出来）。经进一步的分析，我们发现他在X层的Cr转运蛋白基因（CT1; SLC6A8）中具有胡说八道突变，这导致表达截短的（非功能）CR转运蛋白。自这项研究以来，在辛辛那提（Cincinnati）中认识到了另外四个家庭，并在全球X连锁的CR转运蛋白基因和近30个家庭中发生了突变。这些患者都患有智力低下，严重的表达语言障碍和轻度癫痫。尽管对大脑中的CR，CR激酶和磷酸蛋白系统的了解越来越大，但是当脑肌酸转运蛋白不足时，没有改善大脑功能的标准化方法。显然需要的是该疾病的合适动物模型，以便可以开发和测试使肌酸遍及血脑屏障的方法。在这个项目中，我们将开发CR转运蛋白敲除小鼠模型，以便可以测试新的治疗范式，药物和其他疗法的功效。对于该研究项目，我们建议测试以下假设：1）CR转运缺陷的小鼠敲除可以对人类疾病进行建模，2）可以给出治疗策略以使这些小鼠的脑功能正常化。这种小鼠敲除将对我们发现的CR转运蛋白缺陷进行建模，因为大脑将缺乏在血脑屏障上运输肌酸的能力。为了解决假设1，我们将生成一个CR转运蛋白基因敲除小鼠。 CR水平将在这些小鼠的大脑中确定，我们将表征功能，并且在CR转运蛋白基因敲除小鼠中观察到的生化变化。拥有紧密反映人类疾病的动物模型将使设计和开发旨在使肌酸在血脑屏障上造成的疗法进行足够的测试和开发。为了解决假设2，CR转运蛋白基因敲除小鼠和对照小鼠将用CR配方处理，CR制剂可能能够在血液脑屏障中运输肌酸并改善小鼠的脑代谢和认知功能。假设2的目的是开发方法和药物来通过将肌酸进入大脑来改善大脑能量代谢。