Role of Glut4 in TBI Pathophysiology

Glut4 在 TBI 病理生理学中的作用

• 批准号: 8906305
• 负责人: PRAMOD K DASH
• 金额: $ 33.69万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8906305
• 关键词: 5' -AMP-activated protein kinase; Acute; Address; Adipose tissue; Affect; Animals; Astrocytes; Binding; Blood - brain barrier anatomy; Blood Circulation; Brain; Brain Injuries; Brain region; Cell membrane; Cerebellum; Cessation of life; Cognition; Coupled; Disease; Endothelial Cells; Energy Metabolism; Functional disorder; Glucose; Glucose Transporter; Hippocampus (Brain); Human; Immunohistochemistry; Injury; Ischemia; Knock-out; Knockout Mice; Lead; Measures; Membrane; Memory; Memory impairment; Metabolic; Metabolism; Metformin; Mus; Muscle; Neocortex; Neurocognitive; Neurons; Outcome; Pathology; Pattern; Phosphorylation; Phosphotransferases; Protein Isoforms; Public Health; Regulation; Role; Skeletal Muscle; Testing; Thalamic structure; Therapeutic; Time; Transgenic Mice; Traumatic Brain Injury; Vesicle; base; brain metabolism; cell type; cognitive function; disability; glucose metabolism; glucose uptake; improved; inhibitor/antagonist; injured; interstitial; nervous system disorder; neuron loss; neuronal survival; neuroprotection; novel; public health relevance; research study; response; sensor

 DESCRIPTION (provided by applicant): Although the brain has a high metabolic demand, it has a low capacity for storing energy and is dependent on a continuous supply of glucose from the circulation. Disturbed brain metabolism is a well- characterized secondary pathology of Traumatic Brain Injury (TBI). A biphasic change in brain glucose metabolism has been documented in which an acute, transient increase in brain glucose metabolism is followed by a prolonged suppression in metabolism lasting for days. This decreased glucose metabolism occurs in the absence of ischemia and in brain regions critical to cognition such as the hippocampus and the neocortex. There are four primary classes of mammalian glucose transporters, Glut 1-4, with Glut3 being the principal glucose transporter for neurons. However, a recent study has demonstrated that Glut3 expression patterns did not correlate with brain glucose uptake in a linear manner, a disparity that was especially evident in the hippocampus. Glut4 is expressed at high levels in muscle and adipose tissue, and is unique in that under basal conditions, a relatively large proportion of the transporter is retained in intracellular Glut4- containing storage vesicles (GSVs). Recent studies have shown that the energy sensor AMP-activated protein kinase (AMPK) can mobilize Glut4 by phosphorylating the regulatory molecule AS160. As TBI alters brain glucose metabolism, it is plausible that this will result in a change in AMPK activity and Glut4 mobilization within the injured brain. While the role of Glut4 in energy metabolism in the periphery is well appreciated, its role in TBI pathophysiology has not been examined. We propose to test the hypotheses that Glut4 acts to protect neurons and lessen TBI-associated memory impairments. Its mobilization by activators of AMPK will offer neuroprotection and improve memory in brain injured animals. We outline three Specific Aims to test the above hypotheses. Specific Aim 1: Determine if manipulating Glu4 activity/levels can influence neuroprotection. Specific Aim 2: Determine if increasing Glut4 mobilization offers neuroprotection. Specific Aim 3: Examine if activators of AMPK can improve memory in TBI animals. These experiments will examine if modulating Glut4 expression can be used a potential therapeutic and will reveal the influence of this transporter on the neuronal death and dysfunction associated with TBI. The proposed studies have translational relevance and, if successful, may have implications for other neurological disorders and diseases in which altered brain metabolism are features.

 描述(申请人提供)：虽然大脑有很高的新陈代谢需求，但它储存能量的能力很低，依赖于循环中持续的葡萄糖供应。脑代谢紊乱是创伤性脑损伤的一种常见的继发性病理改变。脑部葡萄糖代谢的两相改变已被记录在案，在这种变化中，大脑葡萄糖代谢的急性、一过性增加之后是持续数天的长期代谢抑制。这种葡萄糖代谢的降低发生在没有缺血的情况下，发生在大脑中对认知至关重要的区域，如海马体和新皮质。哺乳动物葡萄糖转运蛋白主要有四类，GLUT1-4，其中GLUT3是神经元的主要葡萄糖转运蛋白。然而，最近的一项研究表明，GLUT3的表达模式与大脑葡萄糖摄取并不是线性相关，这种差异在海马区尤为明显。GLUT4在肌肉和脂肪组织中高水平表达，其独特之处在于在基础条件下，相对较大比例的转运蛋白保留在含有GLUT4的细胞内储存小泡(GSV)中。最近的研究表明，能量传感器AMP激活的蛋白激酶(AMPK)可以通过磷酸化调节分子AS160来动员GLUT4。由于脑外伤改变了大脑的葡萄糖代谢，这可能会导致脑部 损伤脑内AMPK活性和GLUT4动员。虽然GLUT4在外周能量代谢中的作用得到了很好的认识，但它在脑损伤病理生理学中的作用还没有被研究过。我们建议测试GLUT4保护神经元和减轻与脑损伤相关的记忆损伤的假设。AMPK激活剂的动员将为脑损伤动物提供神经保护和改善记忆。我们概述了三个具体目标来检验上述假设。具体目标1：确定操纵Glu4活性/水平是否会影响神经保护。具体目标2：确定增加GLUT4动员是否提供神经保护。具体目标3：检测AMPK激活剂是否能改善脑外伤动物的记忆。这些实验将检验调节GLUT4表达是否可以作为一种潜在的治疗方法，并将揭示这种转运蛋白对与脑外伤相关的神经元死亡和功能障碍的影响。拟议的研究具有翻译相关性，如果成功，可能会对其他神经疾病和以大脑新陈代谢改变为特征的疾病产生影响。