The role of Na+, K+-ATPase function in Creatine Transporter Deficiency

 描述(由申请人提供)：大脑内能量供应和利用的中断会造成严重的功能后果。特别是，肌酸(Cr)-磷酸肌酸(PCR)穿梭的丧失会导致严重的智力残疾、癫痫和失语症。铬-聚合酶链式反应航天飞机负责快速补充三磷酸腺苷。大脑中最常见的铬丢失原因是X连锁铬转运蛋白(CRT)的突变。到目前为止，还没有治疗CRT缺乏症的方法。为了更好地了解CRT缺陷的病理生理机制以及开发和筛选治疗方法，我们产生了CRT基因敲除(CRT-/y)小鼠，它们表现出与CRT缺陷患者类似的严重认知缺陷。虽然铬缺乏是认知障碍的根源，但它可能不会对认知功能起到直接作用。我认为，铬的丧失很可能会导致直接参与神经功能的系统受到更大的干扰。识别这些系统并确定铬的损失如何影响其功能是至关重要的。Na+，K+-ATPase(NKA)对正常的认知功能是必不可少的，它消耗了大脑静止代谢输出的50%-60%。先前的研究以及我们实验室的初步数据表明，铬对NKA的正常功能是必不可少的。铬-聚合酶链式反应穿梭系统对NKA功能的作用机制尚未阐明。这项提议的目的是确定NKA和肌酸之间相互作用的机制。这一提议的假设是，由铬-聚合酶链式反应穿梭提供的快速的ATP周转是适当的NKA活动所必需的。在目标1中，将评估铬-聚合酶链式反应穿梭的每个组成部分(铬、聚合酶链式反应、三磷酸腺苷)对NKA功能的作用。一种治疗铬缺乏的潜在治疗方法--环肌酸对NKA功能的影响也将被确定。在目标2中，将评估缺铬对单个NKA催化亚基功能的影响。每个亚单位在大脑中都有独特的功能，因此确定铬的损失如何扰乱它们的功能是至关重要的。这些研究完成后，将建立肌酸丢失与NKA功能之间的直接联系，揭示NKA的功能，NKA是大脑功能所必需的蛋白质，并促进对CRT缺乏症的理解，CRT缺乏症是人类的一种重大疾病。

 DESCRIPTION (provided by applicant): Disruptions in energy supply and utilization within the brain have severe functional consequences. In particular, the loss of the creatine (Cr)-phosphocreatine (PCr) shuttle leads to severe intellectual disability, epilepsy and aphasia. The Cr-PCr shuttle is responsible for rapid ATP replenishment. The most prevalent cause of Cr loss in the brain is due to mutations in the X-linked Cr transporter (CrT). To date, there are no treatments available for CrT deficiency. In order to better understand the pathophysiology of CrT deficiency as well as to develop and screen treatments, we generated CrT knockout (CrT-/y) mice that show severe cognitive deficits similar to CrT deficient patients. While Cr deficiency is the root of the cognitive disorders, it likely does not play a direct role in cognitive function. I is likely that the loss of Cr leads to larger disruptions of systems directly involved in neuronal function. It is essential to identify these systems and determine how the loss of Cr affects their function. Na+,K +-ATPases (NKA) are essential for proper cognitive function and consume 50-60% of the brain's resting metabolic output. Previous studies, along with preliminary data from our lab, show that Cr is essential for proper function of NKA. The mechanisms underlying the role of the Cr-PCr shuttle on NKA function has not been elucidated. The purpose of this proposal is to identify the mechanisms underlying the interaction between NKA and Cr. The hypothesis for this proposal is that the rapid ATP turnover provided by Cr-PCr shuttle is required for proper NKA activity. In aim 1, the role of each component of the Cr-PCr shuttle (Cr, PCr, ATP) on NKA function will be evaluated. The effects of a potential treatment for Cr deficiency, cyclocreatine, on NKA function will be determined as well. In aim 2, the effect of Cr-deficiency on the individual NKA catalytic subunits function will be evaluated. Each subunit has a unique function within the brain, making it essential to determine how the loss of Cr disrupts their function. Upon the completion of these studies, a direct link between the loss of Cr and NKA function will be established, shedding light onto the function of NKA, an essential protein for brain function as well as advancing the understanding of CrT deficiency, a significant human disorder.