Epigenetic Regulation of Kir4.1 and GLT1 in Pathophysiology

Kir4.1 和 GLT1 在病理生理学中的表观遗传调控

• 批准号: 8578279
• 负责人: Michelle L Olsen
• 金额: $ 32.13万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578279
• 关键词: Acute; Address; Adult; Affect; American; Apoptosis; Area; Astrocytes; Biological Assay; Blood Vessels; Brain; Brain Injuries; Buffers; Cause of Death; Cells; Cerebrum; Child; Childhood; Clinical; Cognitive deficits; Comorbidity; Craniocerebral Trauma; DNA Methylation; DNA Methyltransferase Inhibitor; Data; Dependovirus; Development; Disease; Electrophysiology (science); Engineering; Enzymes; Epigenetic Process; Epilepsy; Excitatory Amino Acid Transporter 2; Extracellular Space; FDA approved; Failure; Functional disorder; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Glutamate Transporter; Glutamates; Homeostasis; Human; Injury; Ions; Lateral; Lead; Luciferases; Mediating; Methylation; Modeling; Nature; Neurons; Patients; Pharmaceutical Preparations; Physiology; Play; Post-Traumatic Epilepsy; Process; Property; Proteins; Regulation; Reporter; Research; Risk; Rodent; Role; Secondary to; Seizures; Spinal Cord; Swelling; Synapses; Testing; Therapeutic; Tissues; Transcriptional Regulation; Traumatic Brain Injury; United States; age group; clinically relevant; critical developmental period; disability; excitotoxicity; extracellular; fluid percussion injury; functional loss; gene delivery system; gene repression; injured; inward rectifier potassium channel; neuron loss; neuronal excitability; novel therapeutics; pediatric traumatic brain injury; postnatal; promoter; protein expression; protein function; public health relevance; research study; response to injury; spatiotemporal; synaptogenesis

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) affects over 1.7 million Americans each year and is the leading cause of death and disability in young children in the United States. For children with TBI, current treatment options are largely extrapolated from studies on adults, despite significant differences between pediatric and adult brains. Therefore, this proposal aims to specifically study pediatric injury, using clinically-relevant models of childhood disease. Specifically, we will focus on the role of astrocytes in pediatric TBI, a highly understudied area of research. It is well established that astrocytes in the brain and spinal cord play a major role in both acute and long term response to injury. Astrocytes associated with injured tissue, termed reactive astrocytes, are characterized by profound changes in protein expression leading to changes in the fundamental properties of these cells. Yet, little is known about the genetic regulation of the astrocytic injury response. This proposal seeks to address this question by examining the regulation of two essential functions of astrocytes following injury: the ability to buffer extracellular K+ ions and to regulate extracellular glutamate concentrations. These two astrocytic functions are largely mediated via the inwardly-rectifying potassium channel, Kir4.1, and the astrocytic glutamate transporter, GLT-1. In the adult spinal cord and brain, dysregulated K+ and glutamate homeostasis in the extracellular space leads to neuronal hyperexcitability, changes in synaptic physiology, and plasticity. Furthermore, both proteins are developmentally regulated with the most significant increases in expression in humans and rodents during early postnatal development at the peak of glutamatergic synaptogenesis, establishing an important role for these two proteins in the immature brain. This developmental period also correlates with the age group highest at risk for TBI. Despite the importance of these two proteins in brain function, very little is known regarding their regulation during development or in response to injury. Using a highly clinical relevant model of TBI, this proposal aims to specifically ask the following questions: 1) Following pediatric injury, is there persistent decrease in Kir4.1 and GLT-1, leading to neuronal hyperexcitability? 2) Is loss of these proteins a direct result of epigenetic modulation of gene transcription? 3) Can manipulation of DNA methylation using FDA-approved drugs reverse the loss of Kir4.1 and GLT-1 in pediatric injury models? This proposal seeks to enhance our understanding of the role of astrocytes, the most abundant cells in the CNS, in the pathophysiology of pediatric traumatic brain injury and abnormal brain development following injury. Results from these experiments could lead to novel therapeutic strategies using FDA-approved drugs for the treatment of TBI in pediatric patients.

描述（由申请人提供）：创伤性脑损伤（TBI）每年影响超过170万美国人，是美国幼儿死亡和残疾的主要原因。对于TBI儿童，目前的治疗方案主要是从成人研究中推断出来的，尽管儿童和成人大脑之间存在显着差异。因此，本提案旨在使用儿童疾病的临床相关模型专门研究儿科损伤。具体来说，我们将重点关注星形胶质细胞在儿科TBI中的作用， 未被充分研究的领域。已经确定脑和脊髓中的星形胶质细胞在对损伤的急性和长期反应中起主要作用。与受损组织相关的星形胶质细胞，称为反应性星形胶质细胞，其特征在于蛋白质表达的深刻变化，导致这些细胞的基本性质发生变化。然而，对星形胶质细胞损伤反应的遗传调控知之甚少。该提案旨在通过检查损伤后星形胶质细胞的两个基本功能的调节来解决这个问题：缓冲细胞外K+离子和调节细胞外谷氨酸浓度的能力。这两种星形胶质细胞功能主要通过内向整流钾通道Kir4.1和星形胶质细胞谷氨酸转运蛋白GLT-1介导。在成人脊髓和脑中，细胞外空间中的K+和谷氨酸稳态失调导致神经元过度兴奋、突触生理学变化和可塑性。此外，这两种蛋白质的发育调节与最显着的增加在人类和啮齿类动物的表达在出生后早期发育的高峰期的突触，建立了一个重要的作用，这两种蛋白质在未成熟的大脑。这个发育期也与TBI风险最高的年龄组相关。尽管这两种蛋白质在大脑功能中的重要性，但对它们的调节知之甚少 在发育过程中或对损伤的反应中。使用高度临床相关的TBI模型，本提案旨在具体提出以下问题：1）儿科损伤后，Kir4.1和GLT-1是否持续降低，导致神经元过度兴奋？2)这些蛋白质的丢失是基因转录表观遗传调节的直接结果吗？3)使用FDA批准的药物操纵DNA甲基化能否逆转儿科损伤模型中Kir4.1和GLT-1的丢失？该建议旨在提高我们对星形胶质细胞（CNS中最丰富的细胞）在小儿创伤性脑损伤和损伤后异常脑发育的病理生理学中的作用的理解。这些实验的结果可能导致使用FDA批准的药物治疗儿科患者TBI的新治疗策略。