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：
9116308
负责人：
Aristea S Galanopoulou
金额：
$ 36.53万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
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 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9116308
关键词：
4-Aminobutyrate aminotransferase Accounting Adult Adverse effects Affect Age Anti-Inflammatory Agents Anti-inflammatory Biological Markers Brain Cells Chronic Cognitive Cortical Dysplasia Corticotropin Development Electroencephalography Electrophysiology (science)Encephalopathies Enzyme-Linked Immunosorbent Assay Epilepsy Etiology FRAP1 gene Flexor Future Gene Expression Gramicidin Health Histology Image In Vitro Incidence Infantile spasms Inflammation Inflammatory Injection of therapeutic agent Interleukin-1 beta Knockout Mice Lead Life Lipopolysaccharides 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 Reverse Transcriptase Polymerase Chain Reaction Rodent Seizures Serum Severities Signal Pathway Signal Transduction Spasm Specificity Steroids TLR4 gene TNF gene Testing Therapeutic Intervention Vigabatrin base boys cytokine design gamma-Aminobutyric Acid hippocampal pyramidal neuron infancy mouse model novel novel therapeutics outcome forecast patch clamp prevent protein expression receptor sex

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）：婴儿痉挛是癫痫发作，出现在婴儿预后不良的婴儿癫痫性脑病中。它们是特定年龄的，具有不同的机制和药物敏感性。它们具有多种病因，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，逐渐转移到更成熟的年龄中正常的超极化GABAA受体信号传导。使用婴儿痉挛的大鼠和小鼠模型，我们发现证据表明，在局灶性皮质炎症的情况下，去极化GABAA受体信号传导的存在可能是年龄特异性易感性诱导痉挛的敏感性的基础，并且可能易感到更严重的表型。在这里，我们研究了去极化GABAA受体信号传导和炎症之间的相互作用，这些相互作用导致痉挛的年龄特异性表达和易感性更严重的表型。我们还将研究这种GABA炎症相互作用是否会影响成年后的随后癫痫。我们将结合立体定位手术，视频EEG监测，组织学，基因和蛋白质表达研究，体外电生理学和药物施用来确定所涉及的分子和电生理机制，并确定针对婴儿痉挛的新型治疗方法。我们的研究有望为开发针对婴儿痉挛和随后的癫痫的新疗法提供新的候选靶标。