SCN1A dysfunction and neuropsychiatric comorbidities

SCN1A 功能障碍和神经精神合并症

基本信息

批准号：
8702781
负责人：
Andrew P Escayg
金额：
$ 23.3万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8702781
关键词：
Acute Address Adult Age Age-Months Agreement Ataxia Behavioral Behavioral Paradigm Brain Clinical Clinical Management Cognitive Comorbidity Complex Data Development Disease Drug Controls Encephalopathies Epilepsy Etiology Event Exhibits Exons Family Febrile Convulsions Foundations Frequencies Functional disorder Generations Genes Genetic Human Hyperactive behavior Hyperthermia Inborn Genetic Diseases Induced Hyperthermia Infant Intellectual functioning disability Intervention Knock-in Mouse Knock-out Knockout Mice Knowledge Laboratories Lead Learning Life LoxP-flanked allele Modeling Mus Mutant Strains Mice Mutation Neurons Outcome Patients Play Quality of life Recurrence Research Resistance Risk Role SCN1A protein Seizures Severities Site Sleep Architecture Social Interaction Sodium Channel Syndrome TNFRSF5 gene Tamoxifen Testing Time Transgenic Organisms Translational Research Valproic Acid base clinically relevant experience genetic variant innovation insight loss of function mutation mouse model mutant neuropsychiatry novel patient population postnatal prevent public health relevance recombinase research study therapy development trait voltage

项目摘要

DESCRIPTION (provided by applicant): Mutations in the SCN1A voltage-gated sodium channel (VGSC) are responsible for a growing number of disorders, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+). DS is a catastrophic early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), treatment-resistant afebrile epilepsy, ataxia, and intellectual disability. GEFS+ is an inherited disorder characterized by FSs that persist beyond the age of six and the development of a wide range of adult epilepsy subtypes. To date, research has focused mainly on the seizure component of these disorders; however, we now recognize that seizure onset is often followed by cognitive stagnation/decline, hyperactivity, and the development of a number of behavioral comorbidities, including autistic and psychotic traits. Although seizure frequency does tend to decline during adulthood, these comorbidities persist and are a major challenge in the clinical management of this patient population. Currently, the cognitive and behavioral outcomes associated with SCN1A dysfunction are poorly characterized, and the factors that influence the severity of these deficits unknown. Mitigating the impact of these comorbidities on quality-of-life outcomes will require broader research efforts to better characterize these cognitive and behavioral deficits, as well as identify factors that influence their severity. Towards this end, te proposed experiments in this R21 application will use Scn1a mouse models developed in our laboratory to address several fundamental gaps in our knowledge. Specifically, we will 1) better define the cognitive and behavioral deficits that result from altered SCN1A function, 2) determine whether prolonged early-life FSs, which are a common clinical feature of SCN1A-derived epilepsies, are likely to contribute to the worsening of cognitive and behavioral outcomes, and 3) determine whether the emergence of cognitive and behavioral abnormalities requires altered SCN1A function during the early period of postnatal brain development or is an invariant (age-independent) outcome of altered SCN1A function. These experiments are both innovative and clinically relevant, and will stimulate much-needed translational research.

描述（由申请人提供）：SCN1A电压门控钠通道（VGSC）中的突变负责越来越多的疾病，包括Dravet综合征（DS）和带有发热性癫痫发作的遗传性癫痫以及GEFS+GEFS+（GEFS+）。 DS是一种灾难性的早期生活脑病，与长期和经常性的早期寿命癫痫发作（FSS），耐药性癫痫，共济失调和智力残疾相关。 GEFS+是一种遗传性疾病，其特征是FSS持续超过六岁，并且发展了广泛的成年癫痫亚型。迄今为止，研究主要集中在这些疾病的癫痫发作部分上。但是，我们现在认识到，癫痫发作通常是认知停滞/下降，多动症以及许多行为合并症的发展，包括自闭症和精神病性状。尽管癫痫发作的频率确实在成年期会下降，但这些合并症仍然存在，并且是该患者人群临床管理的主要挑战。当前，与SCN1A功能障碍相关的认知和行为结果的特征很差，并且影响这些缺陷的严重性的因素未知。减轻这些合并症对生活质量的影响结果将需要更广泛的研究工作，以更好地描述这些认知和行为缺陷，并确定影响其严重程度的因素。为此，此R21应用程序中提出的实验将使用我们实验室中开发的SCN1A小鼠模型来解决我们知识中的几个基本差距。具体而言，我们将1）更好地定义由SCN1A功能变化而导致的认知和行为缺陷，2）确定长期延长的早期FSS是否是SCN1A衍生的癫痫的常见临床特征，这些癫痫的常见临床特征，可能会导致认知和行为的变化，以及在COPNION中是否需要coptionniistion1 Abcnibalientians，是否需要进行CONCONTIS，而SCONTIS是否有效地行为性。产后大脑发育的早期或SCN1A功能改变的结果（与年龄无关）。这些实验既具有创新性又具有临床相关性，并且会刺激急需的翻译研究。