Creatine Transporter Deficiency and Brain Energetics

项目概要（说明） 肌酸（Cr）及其高能产物磷酸肌酸（PCr）是磷酸化酶的关键成分 一种沿着糖酵解分解ATP以提供正常细胞功能所需燃料的系统。的 人体利用精氨酸和甘氨酸合成约50%的每日铬需求 精氨酸：甘氨酸脒基转移酶（AGAT，在肾脏中）和胍基乙酸甲基转移酶（GAMT，在肾脏中） 肝脏），另一半Cr来自食物。虽然其亚细胞定位仍不清楚，肌酸 转运蛋白（CrT）是建立/维持人类脑Cr浓度所必需的，这显然是 在2001年首次发现的CrT缺乏症中得到证实。在没有CrT的情况下（ 位于X染色体），受影响的儿童表现出严重的认知缺陷和接近完全的 磁共振波谱（MRS）上无脑Cr/PCr。重要的是，与Cr 合成酶突变，CrT缺乏者对Cr补充治疗反应差。因此，我们认为， 需要确定CrT的功能及其缺乏的神经病理学基础， 开发有效的临床治疗方法。 基于这些结果，我们假设Cr/PCr的缺失促进AMPK和自噬， 信号通路，同时抑制大脑中的mTOR活性，导致树突棘发育不全， 缺氧缺血性损伤的易感性。此外，CrT介导Cr跨周细胞和/或外周细胞的转运。 大脑中的星形胶质细胞末端最后，鼻内Cr应用可恢复脑Cr/PCr水平并纠正 CrT缺乏的神经病理学后果。我们将在三个具体目标中检验这些假设。 目的1：明确CrT在脑内的功能及亚细胞定位。 目的2：探讨CrT缺乏对细胞信号转导和脑缺血的影响。 目的3：开发治疗CrT缺乏症的神经病理和认知缺陷的方法。

PROJECT SUMMARY (Description) Creatine (Cr) and its high-energy product phosphocreatine (PCr) are key components of the phosphagen system that, along with glycolysis, replenishes ATP to provide the fuels for proper cellular functions. The human body synthesizes approximately 50% of the daily need for Cr from arginine and glycine using arginine:glycine amidinotrasnferase (AGAT, in kidney) and guanidinoacetate methyltransferase (GAMT, in liver), and the other half of Cr is derived from food. While its subcellular localization remains unclear, creatine transporter (CrT) is essential for building/maintaining the brain Cr concentration in humans, which is clearly demonstrated in the disease CrT deficiency that was first discovered in 2001. In the absence of CrT (which is located in the X-chromosome), the afflicted children manifest severe cognitive deficits and near-complete absence of the brain Cr/PCr on magnetic resonance spectroscopy (MRS). Importantly, unlike patients with Cr synthesis enzyme mutations, those with CrT deficiency respond poorly to Cr supplement treatment. Hence, there is a need to determine the functions of CrT and the neuropathological basis of its deficiency in order to develop effective clinical treatments. Based on these results, we hypothesize that the absence of Cr/PCr promotes the AMPK and autophagic signaling pathways, while suppressing mTOR activity in the brain, leading to dendritic spine dysgenesis and susceptibility to hypoxic-ischemic injury. Further, CrT mediates the transport of Cr across pericytes and/or the astroglial end-feet in the brain. Finally, intranasal Cr application can restore the brain Cr/PCr level and correct neuropathological consequences of CrT deficiency. We will test these hypotheses in three specific aims. Aim 1: To determine the functions and sub-cellular location of CrT in the brain. Aim 2: To determine the impacts of CrT deficiency on cell signaling and cerebral ischemia. Aim 3: To develop treatments of the neuropathological and cognitive deficits in CrT deficiency.