Creatine Transporter Deficiency and Brain Energetics

肌酸转运蛋白缺乏和脑能量学

基本信息

批准号：
10442483
负责人：
Chia-Yi Kuan
金额：
$ 42.39万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
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/10442483
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

项目摘要

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.

项目摘要（描述）肌酸（CR）及其高能产物磷酸蛋白（PCR）是磷脂的关键组成部分系统，与糖酵解一起补充ATP以提供适当的细胞功能的燃料。这人体综合了使用精氨酸和甘氨酸每日需要的50％精氨酸：甘氨酸酰胺酸酶（AGAT，在肾脏中）和圭尼二乙酸甲酯甲基转移酶（Gamt，In in in in In 肝脏），另一半的CR源自食物。虽然其亚细胞定位尚不清楚，但肌酸转运蛋白（CRT）对于在人类中建立/维持脑CR浓度至关重要，这显然是在2001年首次发现的疾病CRT缺乏症中证明。在没有CRT的情况下（这是受苦的儿童位于X-chromosoms中），表现出严重的认知缺陷和接近完整的缺陷在磁共振光谱（MRS）上没有脑CR/PCR。重要的是，与CR患者不同合成酶突变，患有CRT缺乏症的患者对CR补充治疗的反应不佳。因此，有必要确定CRT的功能和其缺乏的神经病理学基础，以便为了开发有效的临床治疗。基于这些结果，我们假设不存在CR/PCR会促进AMPK和自噬信号通路，同时抑制大脑中的MTOR活性，导致树突状脊柱发病障碍和缺氧 - 缺血性损伤的敏感性。此外，CRT介导CR跨周细胞和/或大脑中的星形胶质末端。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。我们将以三个特定目标来检验这些假设。目标1：确定CRT在大脑中的功能和细胞次位置。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缺乏症中神经病理学和认知缺陷的治疗方法。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

(Phospho)creatine: the reserve and merry-go-round of brain energetics.

DOI：
10.4103/1673-5374.346470
发表时间：
2023-03
期刊：
NEURAL REGENERATION RESEARCH
影响因子：
6.1
作者：
Chen, Hong-Ru;DeGrauw, Ton;Kuan, Chia-Yi
通讯作者：
Kuan, Chia-Yi

Monocytes promote acute neuroinflammation and become pathological microglia in neonatal hypoxic-ischemic brain injury.

DOI：
10.7150/thno.64033
发表时间：
2022
期刊：
Theranostics
影响因子：
12.4
作者：
Chen HR;Chen CW;Kuo YM;Chen B;Kuan IS;Huang H;Lee J;Anthony N;Kuan CY;Sun YY
通讯作者：
Sun YY

Impaired post-stroke collateral circulation in sickle cell anemia mice.

DOI：
10.3389/fneur.2023.1215876
发表时间：
2023
期刊：
Frontiers in neurology
影响因子：
3.4
作者：
通讯作者：

Stroke propensity in the Th3+/ mouse model of β-thalassemia intermedia.

DOI：
10.1016/j.nbd.2022.105802
发表时间：
2022-09
期刊：
NEUROBIOLOGY OF DISEASE
影响因子：
6.1
作者：
Sun, Yu-Yo;Yao, Hui-Wen;Chen, Hong-Ru;Chen, Ching-Wen;Kinkaid, Melissa M.;Kuan, Chia-Yi
通讯作者：
Kuan, Chia-Yi

Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism.

DOI：
10.1016/j.redox.2021.102197
发表时间：
2021-11-22
期刊：
Redox biology
影响因子：
11.4
作者：
Yang C;Lavayen BP;Liu L;Sanz BD;DeMars KM;Larochelle J;Pompilus M;Febo M;Sun YY;Kuo YM;Mohamadzadeh M;Farr SA;Kuan CY;Butler AA;Candelario-Jalil E
通讯作者：
Candelario-Jalil E