The role of brainstem in the generation of infantile spasms

脑干在婴儿痉挛症发生中的作用

基本信息

批准号：
7514095
负责人：
Aristea S Galanopoulou
金额：
$ 19.05万
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：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7514095
关键词：
6-Cyano-7-nitroquinoxaline-2,3-dione Abbreviations Adverse effects Age Agonist Antiepileptic Agents Appearance Area Behavioral Benchmarking Bilateral Biological Markers Brain Brain Stem Cerebrospinal Fluid Chloride Channels Clinical Corticotropin Development Disease Disease regression Dopamine Doxorubicin Drug Combinations Electrophysiology (science)Encephalopathies Enzyme-Linked Immunosorbent Assay Enzymes Epilepsy Evolution Exhibits Fenclonine Fire - disasters Functional disorder Funding Future Gene Expression Generations Glutamate Decarboxylase Hormones Hypsarrhythmia Image Immunofluorescence Immunologic In Vitro Infant Infantile spasms Injection of therapeutic agent Intractable Epilepsy Intraperitoneal Injections Intraventricular KLK3 gene Laboratories Lesion Link Lipopolysaccharides Mediating Medicine Membrane Potentials Methods Microscope Modeling Monitor NMDA receptor antagonist Neurocognitive Neurodevelopmental Deficit Neurodevelopmental Impairment Neurons Operative Surgical Procedures Outcome Study Pathogenesis Pathway interactions Patients Pattern Pharmaceutical Preparations Physiology Placement Predisposition Process Protein Isoforms Rattus Research Personnel Rest Reverse Transcriptase Polymerase Chain Reaction Rodent Model Role Screening procedure Seizures Signal Transduction Sodium-Potassium-Chloride Symporters Spasm Staining method Structure Substantia nigra structure Symptomatic West Syndrome Syndrome Techniques Testing Therapeutic Therapeutic Intervention Time Treatment Efficacy Tryptophan 5-monooxygenase Tube Tyrosine 3-Monooxygenase Vigabatrin Work base carbonate dehydratase chloride-cotransporter potassium college day design dopaminergic neuron functional restoration gamma-Aminobutyric Acid improved in vivo infancy insight novel outcome forecast pars compacta patch clamp postnatal postsynaptic programs pup receptor research study response therapy development

项目摘要

DESCRIPTION (provided by applicant): Infantile spasms are an age-specific epileptic syndrome manifesting as clusters of spasms, impaired neurocognitive development, and often evolution to intractable epilepsy. The current treatment of infantile spasms is not always effective and is often associated with serious side effects. There is an urgent need to develop new effective therapies for this syndrome, as recognized recently in the NINDS-funded Curing Epilepsy meeting (2007). In this project, we plan to use a novel and only model of symptomatic infantile spasms in rats, to investigate the pathophysiology of this syndrome, identify biomarkers of therapeutic efficacy, upon which to screen new therapies. In preliminary studies, we have identified abnormalities in the physiology and function of the dopaminergic substantia nigra pars compacta neurons. Our specific aims are to determine whether these are ictal or interictal phenomena linked with the expression or predisposition to spasms and determine whether drugs that enhance the hyperpolarizing effects of GABAA receptors may increase the efficacy of existing GABAAergic antiepileptic drugs in suppressing the in vitro abnormalities associated with spasms as well as in treating spasms. To this end, we will use a combination of techniques, including stereotactic surgery and microinfusion of drugs, behavioral monitoring, in vivo and in vitro electrophysiology, histological and immunofluorescence methods of staining and confocal imaging, and gene expression analysis by quantitative RT-PCR. It is expected that at the conclusion of this study we will know whether the identified in vitro abnormalities are valid in vitro biomarkers for rapid screening of new therapies for infantile spasms. Furthermore, a potentially beneficial method of improving currently used antiepileptic drugs may be proven to-be beneficial in the treatment of infantile spasms. Lay Summary: Infantile spasms are an age-specific, difficult to treat, epileptic syndrome, often associated with neurodevelopmental impairments, especially in infants with pre-existing brain abnormalities (symptomatic infantile spasms). Given the urgency to identify new effective therapies, we plan to study a novel model of symptomatic infantile spasms, to identify and validate novel in vitro biomarkers of therapeutic efficacy, which will allow rapid screening of novel candidate therapies. We anticipate that the outcome of this study will provide new insights into the pathophysiology of the disease opening new avenues for effective treatments.

描述（由申请人提供）：婴儿痉挛是一种年龄特异性的癫痫综合征，表现为痉挛的簇，神经认知的发育受损，并且通常会发展为顽固性癫痫。当前对婴儿痉挛的治疗并不总是有效的，并且通常与严重的副作用有关。正如最近在NINDS资助的治疗癫痫会议（2007年）中所认识到的那样，迫切需要为该综合症开发新的有效疗法。在这个项目中，我们计划使用大鼠中症状性婴儿痉挛的新颖和唯一的模型，以研究该综合征的病理生理学，鉴定治疗疗效的生物标志物，并在其上筛选新疗法。在初步研究中，我们已经确定了多巴胺能细菌的生理和功能异常。我们的具体目的是确定这些目的是与痉挛的表达或易感性有关，并确定是否增强GABAA受体超极化作用的药物是否会增加现有的GABAA能抗抗精神病药的功效，以抑制抑制体内异常与跨度痉挛相关的跨度和治疗痉挛。为此，我们将使用多种技术的组合，包括立体定向手术和药物的微灌注，行为监测，体内和体外电生理学，染色和共焦成像的组织学和免疫荧光方法，以及通过定量RT-PCR进行基因表达分析。可以预期，在这项研究的结论中，我们将知道所鉴定的体外异常是否在体外生物标志物中有效，以快速筛查婴儿痉挛的新疗法。此外，可以证明一种可能有益的改善当前使用的抗癫痫药的方法可以证明是有益于治疗婴儿痉挛。摘要摘要：婴儿痉挛是一种特定年龄的，难以治疗的，癫痫综合征，通常与神经发育障碍有关，尤其是在患有脑部异常的婴儿（有症状的婴儿痉挛）。考虑到确定新有效疗法的紧迫性，我们计划研究一种新型的有症状婴儿痉挛模型，以识别和验证新型治疗疗效的体外生物标志物，这将允许快速筛查新型候选疗法。我们预计，这项研究的结果将为疾病的病理生理提供新的见解，以开辟有效治疗的新途径。