Creatine Transporter Deficiency and Brain Energetics

肌酸转运蛋白缺乏和脑能量学

• 批准号: 10217271
• 负责人: Chia-Yi Kuan
• 金额: $ 44.98万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217271
• 关键词: Affect; Age; Anabolism; Arginine; Astrocytes; Attenuated; Autophagocytosis; Behavioral; Blood - brain barrier anatomy; Brain; Caring; Cell physiology; Cellular Stress; Cerebral Ischemia; Child; Clinical Management; Clinical Treatment; Cognitive deficits; Conflict (Psychology); Creatine; Creatine Supplement; Dendritic Spines; Diet; Disease; Early treatment; Electron Microscopy; Energy-Generating Resources; Enzymes; Epilepsy; FRAP1 gene; Food; Glucose; Glycine; Glycolysis; Guanidinoacetate N-Methyltransferase; Human; Human body; In Vitro; Intravenous; Ischemic Brain Injury; Kidney; Kinetics; Knockout Mice; Learning Disabilities; Liver; Location; Magnetic Resonance Spectroscopy; Mediating; Mus; Mutation; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neuroglia; Neurons; Oral; Oxygen; Pathway interactions; Patients; Pericytes; Phenotype; Phosphocreatine; Phosphorus; Predisposition; Presynaptic Terminals; Proteins; Protons; Recovery; Role; Signal Pathway; Signal Transduction; Singlet Oxygen; Stress; Synapses; System; Testing; Therapeutics for Rare and Neglected Diseases; United States; United States Food and Drug Administration; United States National Institutes of Health; X Chromosome; X-linked mental retardation 4; acute stroke; analog; autistic behaviour; base; behavior test; biological adaptation to stress; creatine transporter; deprivation; design; effective therapy; experimental study; foot; hypoxic ischemic injury; improved; in vivo; male; neuropathology; neuroprotection; novel strategies; prevent; programs; public health relevance; repository; stroke therapy; success; uptake

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.

项目概要（描述） 肌酸 (Cr) 及其高能产物磷酸肌酸 (PCr) 是磷酸原的关键成分 该系统与糖酵解一起补充 ATP，为正常的细胞功能提供燃料。这 人体通过精氨酸和甘氨酸合成大约 50% 的 Cr 每日需求 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，但肌酸 转运蛋白 (CrT) 对于建立/维持人类大脑 Cr 浓度至关重要，这显然是 在 2001 年首次发现的 CrT 缺乏症中得到了证明。在缺乏 CrT 的情况下（即 位于X染色体上），患病儿童表现出严重的认知缺陷和近乎完全的认知缺陷 磁共振波谱 (MRS) 上没有脑 Cr/PCr。重要的是，与 Cr 患者不同 由于合成酶突变，CrT 缺乏症患者对 Cr 补充治疗反应不佳。因此， 有必要确定 CrT 的功能及其缺陷的神经病理学基础，以便 开发有效的临床治疗方法。 基于这些结果，我们假设 Cr/PCr 的缺失会促进 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 穿过周细胞和/或 大脑中的星形胶质细胞末端。最后，鼻内Cr应用可以恢复大脑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测试这些假设。 目标 1：确定 CrT 在大脑中的功能和亚细胞位置。 目标 2：确定 CrT 缺乏对细胞信号传导和脑缺血的影响。 目标 3：开发 CrT 缺乏引起的神经病理学和认知缺陷的治疗方法。