The role of GABA-mimetic metabolites in neurodevelopmental and neuropsychiatric d

GABA 模拟代谢物在神经发育和神经精神疾病中的作用

基本信息

批准号：
8675291
负责人：
JOSEPH A GOGOS
金额：
$ 24万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-11 至 2015-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675291
关键词：
22q11.2 Acute Intermittent Porphyria Affect Aminolevulinic Acid Biochemical Biological Assay Brain Chemical Structure Chemicals Chromosome Mapping Databases Detection Development Diagnostic Disease Electrophysiology (science)Epilepsy Foundations Frequencies Functional disorder Future GABA transporter GABA-A Receptor GABA-B Receptor Genes Human Individual Ion Channel Link Lysine Degradation Pathway Medial Modeling Mus Mutant Strains Mice Neuronal Dysfunction Neurons Neurotransmitters Patients Phenotype Physiology Pipecolic Acids Play Prefrontal Cortex Process Proline Property Psychotic Disorders Research Design Risk Role Schizoaffective Disorders Schizophrenia Seizures Series Severities Slice Structure Synapses Synaptic Transmission Syndrome System Testing Vitamin B6 analog base clinically relevant drug development enzyme activity gamma-Aminobutyric Acid heme biosynthesis high risk human disease in vivo information processing insight interest loss of function mutation meetings microdeletion mimetics neuropsychiatry novel public health relevance receptor function research study small molecule synaptic function

项目摘要

DESCRIPTION (provided by applicant): Hyperprolinemia has been shown to correlate with the risk of psychosis, schizophrenia, schizoaffective disorder, and seizures in a number of human diseases. One cause of hyperprolinemia is loss-of-function mutations of the PRODH gene, which is involved in L-proline degradation. The PRODH gene maps in the 22q11.2 locus, and is heterozygously deleted in the 22q11.2 microdeletion syndrome, which is associated with high-risk for neurodevelopmental abnormalities and psychosis. One hypothesis explaining the effects of elevated L-proline within the CNS is that L-proline may act as a neuroactive small molecule that interferes with the normal function of other neurotransmitter systems within the brain. In preliminary studies we have found that L-proline is a GABA-mimetic metabolite capable of activating GABA-A receptor ion channels. Based on chemical structural database searches we have identified two additional "proline-like" metabolites that are known to accumulate in two other human neuropsychiatric diseases: -aminolevulinic acid, which accumulates in acute intermittent porphyria, a disease associated with psychosis and seizures, and L-pipecolic acid, which accumulates in pyridoxine (vitamin B6) dependent epilepsy, a disease associated with seizures. Similar to L-proline, we have found that both of these metabolites are also GABA-mimetic and capable of activating GABA-A receptors. We hypothesize that accumulation of these GABA-mimetic metabolites within the CNS may disrupt normal GABA-ergic synaptic transmission in these diseases with overlapping neuropsychiatric symptomatology. To test this hypothesis we have proposed the following Specific Aims: (1) to determine whether these metabolites interfere with normal GABA processing, handling, and detection by the components of the GABA-system and (2) to determine the impact of L-proline accumulation upon GABA-ergic synaptic transmission and network properties within the medial prefrontal cortex. The results of our proposed studies will provide important initial insights into the role of accumulated metabolites in GABA-ergic dysfunction in these clinically relevant human diseases with overlapping neurodevelopmental and neuropsychiatric dysfunction. These results will also lay the foundation for guiding future studies targeted at the development of pharmacological rescue strategies for these diseases.

描述（由申请人提供）：已证明高原血症与精神病，精神分裂症，精神分裂症障碍和癫痫发作的风险相关。高丙烯酸血症的原因之一是涉及L-丙酸酯降解的PODH基因的功能丧失突变。 22q11.2基因座中的PODH基因地图，并在22q11.2微缺失综合征中删除，该综合征与高危神经发育异常和精神病有关。一个假设解释了中枢神经系统内L-丙酸酯升高的作用的一种假设是，L-丙啉可以充当神经活性的小分子，该分子会干扰大脑内其他神经递质系统的正常功能。在初步研究中，我们发现L-丙啉是一种能够激活GABA-A受体离子通道的GABA模拟代谢产物。基于化学结构数据库搜索，我们已经确定了另外两个“脯氨酸样”代谢产物，这些代谢物已知会在其他两个人类神经精神疾病中积聚， - 氨基乙酸酸会累积在急性间歇性斑岩中，这种疾病与精神病和癫痫病和癫痫发作，并累积了毛酸含量（鸟类），该疾病与甲基化的症状相关，鸟类是鸟类的，鸟类是鸟类的，鸟类是鸟类的，鸟类是鸟类的综合症，这些症状是鸟类的综合症。与癫痫发作有关。与L-丙酸酯类似，我们发现这两种代谢产物也是GABA模拟物，并且能够激活GABA-A受体。我们假设这些GABA模拟代谢产物在中枢神经系统中的积累可能会破坏这些疾病中正常的GABA - 凝胶突触传播，并具有重叠的神经精神症状学。为了检验这一假设，我们提出了以下具体目的：（1）确定这些代谢产物通过GABA系统的组成部分干扰正常的GABA处理，处理和检测，并确定（2）确定L-丙烯酸积累对GABA抗突变传输和网络属性的影响。我们提出的研究的结果将为您提供重要的初始见解在这些临床相关的人类疾病中，累积代谢物在GABA - 迫切功能障碍中的作用，神经发育和神经精神上的功能障碍重叠。这些结果还将为指导未来研究的基础，以制定这些疾病的药理救援策略。