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GABA-inflammation interplay in infantile spasms

GABA-炎症在婴儿痉挛症中的相互作用

基本信息

批准号：
8984570
负责人：
Aristea S Galanopoulou
金额：
$ 2.95万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8984570
关键词：
4-Aminobutyrate aminotransferase Abbreviations Accounting Acids Adult Adverse effects Affect Age Anti-Inflammatory Agents Anti-inflammatory Biological Markers Brain Bumetanide Cells Cerebrospinal Fluid Cerebrum Chronic Cognitive Cortical Dysplasia Corticotropin Development Electroencephalography Electrophysiology (science)Encephalopathies Enhancers Enzyme-Linked Immunosorbent Assay Epilepsy Etanercept Etiology Flexor Future Gene Expression Gramicidin Histology Image In Vitro Incidence Infantile spasms Inflammation Inflammatory Injection of therapeutic agent Interleukin-1 Interleukins Knockout Mice Lead Life Lipopolysaccharides Membrane Potentials Methods Modeling Molecular Molecular Target Monitor Motor Seizures Neurons Operative Surgical Procedures Outcome Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Pharmaceutical Preparations Phenotype Predisposition Process Rattus Receptor Signaling Refractory Reporting Rest Reverse Transcriptase Polymerase Chain Reaction Rodent Seizures Serum Severities Signal Pathway Signal Transduction Spasm Specificity Steroids Testing Tetrodotoxin Therapeutic Intervention Time Tumor Necrosis Factor-alpha Vigabatrin anakinra base boys chloride-cotransporter potassium cytokine design gamma-Aminobutyric Acid hippocampal pyramidal neuron human FRAP1 protein immunoreactivity induced pluripotent stem cell infancy inhibitor/antagonist mouse model novel novel therapeutics outcome forecast patch clamp postnatal postsynaptic prevent protein expression public health relevance receptor research study sex toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): Infantile spasms are epileptic seizures that appear within a spectrum of infantile epileptic encephalopathies with poor prognosis. They are age-specific and have different mechanisms and pharmacosensitivity from other seizures. They have multiple etiologies, among which inflammatory processes have been implicated. An important feature of early brain development is the presence of depolarizing GABAA receptor signaling, needed for normal development, which gradually shifts to the normal hyperpolarizing GABAA receptor signaling seen in more mature ages. Using rat and mouse models of infantile spasms, we have found evidence that the presence of depolarizing GABAA receptor signaling in the setting of focal cortical inflammation, may underlie the age-specific susceptibility to inflammation-induced spasms and may predispose to a more severe phenotype. Here we investigate the interactions between depolarizing GABAA receptor signaling and inflammation that lead to age-specific expression of spasms and predispose to a more severe phenotype. We will also investigate whether this GABA inflammation interaction affects subsequent epilepsy in adulthood. We will use a combination of stereotactic surgeries, video-EEG monitoring, histology, gene and protein expression studies, in vitro electrophysiology, and drug administrations to determine the molecular and electrophysiological mechanisms involved and identify new candidate targets for novel treatments for infantile spasms. Our studies are expected to deliver new candidate targets for the development of new therapeutics for infantile spasms and subsequent epilepsies.

描述（由申请人提供）：婴儿痉挛症是一种癫痫发作，出现在一系列婴儿癫痫性脑病中，预后不良。它们具有年龄特异性，并且具有与其他癫痫发作不同的机制和药物敏感性。它们有多种病因，其中涉及炎症过程。早期大脑发育的一个重要特征是正常发育所需的去极化 GABAA 受体信号传导的存在，该信号传导逐渐转变为成熟年龄中常见的正常超极化 GABAA 受体信号传导。使用婴儿痉挛症的大鼠和小鼠模型，我们发现证据表明，局灶性皮质炎症中去极化 GABAA 受体信号传导的存在可能是炎症诱发痉挛的年龄特异性易感性的基础，并且可能导致更严重的表型。在这里，我们研究去极化 GABAA 受体信号传导与炎症之间的相互作用，炎症会导致年龄特异性的痉挛表达并容易出现更严重的表型。我们还将研究这种 GABA 炎症相互作用是否会影响成年后的癫痫。我们将结合立体定向手术、视频脑电图监测、组织学、基因和蛋白质表达研究、体外电生理学和药物管理来确定所涉及的分子和电生理机制，并确定婴儿痉挛症新疗法的新候选靶点。我们的研究预计将为开发婴儿痉挛症和随后的癫痫新疗法提供新的候选靶标。