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：
7168212
负责人：
K Michael GIBSON
金额：
$ 27.47万
依托单位：
CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
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 2009-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7168212
关键词：
Ablation Absence Epilepsy Accounting Adult Affect Animals Astrocytes Baclofen Binding Biochemical Brain Breeding CGP 35348 Cells Child Childhood Clinic Clinical Complex Convulsions Defect Development Diazepam Disease Disruption Doctor of Philosophy Down-Regulation Electroencephalography Elevation Embryo Enzymes Epilepsy Epileptogenesis Evaluation Evolution Functional disorder Generalized convulsive epilepsy Glutamates Glutamine Growth Hepatic Hepatocyte Human Intervention Ion Channel Knock-out Liver Longevity Magnetic Resonance Spectroscopy Measurement Mediating Metabolism Methods Modality Modeling Morbidity - disease rate Motor Seizures Mus Mutant Strains Mice Nature Neurologic Neurons Neurotransmitters Numbers Oral Oxidants Pathology Patients Phenotype Play Rate Role Secondary to Seizures Site Status Epilepticus Stress Succinate-semialdehyde dehydrogenase Succinate-semialdehyde dehydrogenase deficiency Syndrome System Taurine Testing Tissues Tonic - clonic seizures Vigabatrin Work clinically relevant combinatorial day design gamma hydroxybutyrate gamma-Aminobutyric Acid insight intraperitoneal mouse model mutant neurochemistry neurogenetics neuropathology neurophysiology neuropsychiatry neurotransmission novel pre-clinical receptor receptor binding restoration tool topiramate valproate

项目摘要

DESCRIPTION (provided by applicant): Human succinic semialdehyde dehydrogenase (SSADH) deficiency [gamma-hydroxybutyric (GHB) aciduria] is one of the few neurogenetic disorders affecting the GABA neurotransmitter system, and one in which two neuroactive compounds, GABA and GHB, accumulate. SSADH-/- mice manifest early absence seizures that evolve into lethal generalized convulsive epilepsy, comparable to pediatric patients with absence epilepsy whose seizures follow a similar clinical evolution. Our long-term objective is to delineate basic mechanisms at play in the protean pathology manifested in SSADH deficiency, and to develop novel preclinical treatment paradigms, through evaluation of the following hypotheses (H) and aims (A): HI. Disruption of the neuronal-glial glutamate/GABA/glutamine axis, oxidant stress and the accumulation of toxic carbonyls underlie the transition of absence seizures into generalized convulsions in the SSADH-/- mouse. A1. To characterize glutamate/GABA/glutamine neurotransmitter cycling between neurons and astroglia, oxidant stress, and carbonyl accumulation in the pathology of the SSADH / mouse. H2. Perturbed GABA-mediated neurotransmission causes generalized absence seizures to evolve into generalized convulsive seizures. A2. To define the developmental critical window for the transition of absence seizures to generalized convulsive seizures in SSADH/ mice, assess GABAAR- and GABABR-mediated function during this critical transition period, and determine whether over-expression of GABABR1 will rescue these animals from the onset of generalized convulsive seizures. 1-13. Systemic gamma-hydroxybutyrate clearance is primarily limited by the total amount of SSADH activity present in liver. A3. To perform liver repopulation with SSADW-/- hepatocytes in SSADH+/+ mice utilizing a selective growth advantage. Elucidation of biochemical and neurochemical pathology, and evaluation of long-term enzyme replacement in the mouse model, work in unison toward our long-term objective. The methods to achieve our objectives include biochemical measurements, magnetic resonance spectroscopy, neurophysiology, receptor binding, hepatocyte repopulation, and mouse breeding among others. Our studies in murine SSADH deficiency possess broad clinical relevance: 1) biochemical and neurochemical characterization of pathology is directly pertinent to human SSADH deficiency; 2) determining the mechanism of seizure evolution will provide novel insight into the transition from absence to generalized convulsive seizures in children with absence epilepsy; and 3) understanding alterations of the GABA/glutamate/glutamine axis will provide pathomechanistic insight into other epileptic and neuropsychiatric disorders in which this axis is likely disturbed.

描述（由申请人提供）：人类琥珀二氢脱氢酶（SSADH）缺乏症[γ-羟基羟基丁基（GHB）酸性]是影响GABA神经释放剂系统的少数神经遗传疾病之一，其中一种是神经性化合物，而两种神经性化合物的复合性gaba，ghba，ghba，comka，comka，commuct，累积。 SSADH - / - 小鼠表现出早期的癫痫发作，这些癫痫发作演变成致命的抽搐性癫痫，可与缺乏癫痫的小儿患者相当，其癫痫发作遵循类似的临床进化。我们的长期目标是通过评估以下假设（H）和AIMS（A）：HI：通过评估SSADH缺乏症的蛋白质病理学中的基本机制，并开发新的临床前治疗范式。神经元 - 胶质谷氨酸/GABA/谷氨酰胺轴的破坏，氧化剂应激和有毒羰基的积累是ssadh - / - 小鼠中缺乏癫痫发作向普遍抽搐的过渡。 A1。为了表征谷氨酸/GABA/谷氨酰胺神经递质在神经元和星形胶质细胞之间循环，氧化剂应激和羰基在SSADH/小鼠病理学中的积累。 H2。扰动的GABA介导的神经传递导致全身性癫痫发作演变为普遍的抽搐性癫痫发作。 A2。为了定义发育临界窗口，以过渡到Ssadh/小鼠中的全身性抽搐癫痫发作，评估在此关键过渡期间的Gabaar-和Gababr介导的功能，并确定Gababr1的过度表达是否会使这些动物从普遍的脉冲癫痫发作中拯救这些动物。 1-13。系统性伽马 - 羟基丁酸清除率主要受肝脏中存在的SSADH活性总量的限制。 A3。用SSADW - / - 肝细胞在SSADH+/+小鼠中使用选择性的生长优势进行肝脏重生。阐明生化和神经化学病理学以及对小鼠模型中长期酶替代的评估，与我们的长期目标一致工作。实现我们目标的方法包括生物化学测量，磁共振光谱，神经生理学，受体结合，肝细胞再现以及小鼠育种等。我们在鼠SSADH缺乏症中的研究具有广泛的临床相关性：1）病理学的生化和神经化学特征与人类SSADH缺乏直接相关； 2）确定癫痫发作的机制将提供从缺席癫痫病儿童中从缺席到普遍的抽搐性癫痫发作的过渡； 3）理解GABA/谷氨酸/谷氨酰胺轴的改变将为其他癫痫病和神经精神疾病提供病理学洞察力，其中该轴可能会受到干扰。