Murine Knockout Model of 4-Hydroxybutyric Aciduria

4-羟基丁酸尿症小鼠敲除模型

基本信息

批准号：
7541805
负责人：
K Michael GIBSON
金额：
$ 8.64万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-30 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7541805
关键词：
Ablation Absence Epilepsy Accounting Address Adult Affect Animals Baclofen Binding Brain Cells Child Clinic Clinical Complex Defect Development Diazepam Disease Doctor of Philosophy Down-Regulation Electroencephalography Embryo Epileptogenesis Evaluation Functional disorder GABA Receptor Generalized convulsive epilepsy Growth Hepatic Hepatocyte Human Intervention Ion Channel Knock-out Liver Longevity Mediating Metabolism Methods Modality Modeling Morbidity - disease rate Motor Seizures Mus Mutant Strains Mice Nature Neurologic Neurotransmitters Oral Patients Pharmacotherapy Phenotype Play Role Secondary to Seizures Site Status Epilepticus Succinate-semialdehyde dehydrogenase Succinate-semialdehyde dehydrogenase deficiency Syndrome System Taurine Testing Therapeutic Tissues Tonic - clonic seizures Vigabatrin Work combinatorial design gamma hydroxybutyrate gamma-Aminobutyric Acid insight intraperitoneal mouse model mutant neurochemistry neurogenetics neuropathology neurophysiology novel pre-clinical receptor receptor function restoration tool topiramate valproate

项目摘要

Human succinic semialdehyde dehydrogenase (SSADH) deficiency [ganmia-hydroxybutyric (GHB) aciduriaj is one of the tew neurogenetic disorders affecting the GABA neurotransmitter system, and one in which two neuroactive compounds, GAB A and GHB, accumulate. SSADH'''mice manifest early absence seizures which evolve into lethal generalized convulsive epilepsy, similar to seizure phenotypes observed in the clinical syndrome. Our main objectiveis to delineate basic mechanisms at play in the protean clinical manifestationsin SSADH deficiency. In the current project, we will address the following hypotheses (H) and aims (A): HI: pharmacotherapy broadly targeting the GABAergic/GHBergic receptor systems in SSADH"" mice will extend lifespan and provide insight into treatment paradigms for humans. Al: To examine novel phurmacotherapeutics in SSADH"''mice in order to rescue these animals from early lethality and explore neuropathology in surviving, adult mutants. H2. Absence seizures in SSADH"' mice result from elevated GHB, whereas generalized convulsive seizures and status epilepticus arise from decreased GABAAR-mediatedinhibition induced by GABA-dependent down regulation of GABA^ receptors. A2.1) to assess the role of GHB in absence seizures and the role of absence seizures in the development of generalized convulsive seizures in SSADH''' mice, and to examine pharmacotherapeutics aimed at suppressing motor seizures and status epilepticus; A2.2) to define perturbations of the GABAA receptor (GABAAR) in SSADH"' mice ¿ motor seizures and ¿ absence seizures and the relation of these to the onset of generalized convulsive seizures; A2.3) to ascertain GABAAR receptor conductances and the regulatory functions of GABABR receptors in SSADH"' mice ¿ motor seizures and ¿ absence seizures; and 2.4) to determine the effect of excess GABA and/or GHB on GABAAR function and subunit composition. H3. Systemic GHB clearance is primarily limited by the total amount of SSADH activitypresent in liver. Aim 3: To perform liver repopulation with SSADH'" hepatocytes in SSADH** mice utilizing a selective growth advantage, in order to estimate the number of SSADH^ hepatocytes necessary to correct gamma-hydroxybutyric aciduria. The methods to achieve our objectives include therapeutics, neurophysiology and neurochemistry, and hepatocyte repopulation, among others. The SSADH"'" mouse model represents a powerful investigativetool for understanding thepathophysiology associated with human SSADH deficiency. Our experimental approach possesses therapeutic import for human patients, and may have ramifications for understanding the fundamental mechanisms of epileptogenesis that extend far beyond SSADH deficiency.

人琥珀酸半二氢脱氢酶（SSADH）缺乏症[ganmia-hydroxybutyric（GHB）酸性影响GABA神经递质系统的TEW神经遗传疾病，一种神经递质系统，其中两种神经活性化合物， GAB A和GHB，积累。 ssadh''小鼠表现出早期的癫痫发作，这些癫痫发作变成致命的广泛性抽搐性发作，类似于临床综合征中观察到的癫痫发作表型。我们划定的主要目标 SSADH缺乏症的蛋白临床表现中的基本机制。在当前项目中，我们将解决以下假设（h）和目标（a）：HI：药物治疗广泛针对Gabaergic/Ghbergic SSADH“”小鼠的受体系统将延长寿命，并洞悉对人类的治疗范例。 AL：要检查SSADH的新型phurmacotherapeics“”'''''为了从早期的致死性中挽救这些动物并进行探索生存的成人突变体中的神经病理学。 H2。 ssadh的缺失''小鼠由GHB升高而导致普遍的抽搐性癫痫发作和癫痫持续性是由加巴式 - 介导的抑制作用改善引起的 GABA依赖性调节GABA受体。 A2.1）评估GHB在缺席癫痫发作中的作用和作用在ssadh'''''''''''''''''''''''''''''''''''''''''''''''''''''的情况下缺席的癫情并检查旨在抑制运动癫痫发作和癫痫状态的药物治疗药； a2.2）定义 ssadh中的gabaa受体（gabaar）“小鼠»运动癫痫发作和缺席癫痫发作以及它们与普遍的抽搐性发作； A2.3）确定GABAAR受体电导和调节功能 ssadh“''小鼠的gababr受体的运动癫痫发作和癫痫发作；和2.4）确定 GABA和/或GHB过多的GABAAR功能和亚基组成。 H3。系统性GHB清除是主要的受肝脏中SSADH活动的总量的限制。目标3：与ssadh'进行肝脏重生'” Ssadh **的肝细胞利用选择性增长优势，以估计ssadh^的数量校正γ-羟基丁香酸尿所需的肝细胞。实现我们目标的方法包括治疗剂，神经生理学和神经化学以及肝细胞再生等。 ssadh“'”鼠标模型代表了一个有力的研究，用于理解与人类萨德相关的人病生理学不足。我们的实验方法假设人类患者的治疗性进口，可能会影响了解癫痫发生的基本机制远远超出了Ssadh缺乏症。