Mitochondrial Abnormalities in Schizophrenia and Bipolar Disorder

精神分裂症和双相情感障碍的线粒体异常

基本信息

批准号：
8444608
负责人：
MARQUIS PHILIP VAWTER
金额：
$ 36.35万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444608
关键词：
Age Alleles Autopsy Base Pairing Base of the Brain Biological Assay Bipolar Disorder Blood Brain Brain region Cell physiology Chronic Code Collecting Cell DNA DNA Sequence DNA copy number Data Data Set Defect Disease Early Diagnosis Early treatment Etiology Family Study Functional disorder Future Gene Expression Profile Gene Mutation Genes Genetic Genome Germ Lines Grant Health Hippocampus (Brain)Individual Information Networks Inherited Lead Longevity Medicine Mental disorders Metabolic Mitochondria Mitochondrial DNA Mutation Nuclear Organelles Oxidative Phosphorylation Patients Play Prefrontal Cortex Proteomics Psychotic Mood Disorders Relative (related person)Reporting Research Personnel Risk Risk Factors Role Schizophrenia Structure System Testing Tissues Transcript Variant base brain cell brain tissue case control data integration disorder control genetic association genome wide association study high risk improved in vivo metabolomics mitochondrial dysfunction mitochondrial genome neuroimaging novel risk variant transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Mitochondria are organelles that provide most of the energy for brain cells by the process of oxidative phosphorylation. Mitochondrial abnormalities and deficiencies in oxidative phosphorylation have been reported in individuals with schizophrenia (SZ) and bipolar disorder (BD). The overarching hypothesis for this grant is that mitochondrial dysfunction is one of the risk factors for SZ and BD based upon evidence of mitochondrial dysfunction in transcriptomic, proteomic, and metabolomic studies, genetic studies of families, in vivo neuroimaging studies, and mitochondrial DNA (mtDNA) sequence variations. Several mildly deleterious mutations in mtDNA have been reported in SZ and BD patients. The investigators found deletion of a large portion of mtDNA was increased in the brain, dorsolateral prefrontal cortex (DLPFC), of BD subjects relative to age-matched controls. The substitution of synonymous base pairs in the entire mtDNA genome was elevated in DLPFC of individuals with SZ compared to controls and subjects with SZ had a significantly decreased expression of 10 mtDNA transcripts. The decreased expression of mtDNA transcripts in SZ might be related to increased mtDNA substitution in the control or coding regions which will be tested. The causes for increased base pair substitutions in SZ might be inherited or accumulated substitutions in brain. Two of the aims for this grant are to study mtDNA substitutions in brain and to compare the substitution rate in the same subjects9 germ line tissue. This grant proposes to examine mtDNA common deletion, copy number, and transcript abundances in brain from individuals with SZ and BD and compare to controls. The accumulation of novel mtDNA substitutions and deletions in brain might be a risk factor for BD and SZ, and has a great potential significance in determining future targets for therapy of chronic mood and psychotic disorders. This study fills a void as there has not been an integrative brain study of the entire mitochondrial genome and transcriptome conducted in the same subjects with psychiatric disorders. A comprehensive integration of data from the genome and transcriptome of brain mitochondria can show whether moderate dysfunction in one or both systems leads to disease threshold. Focusing on the mitochondria, as a target organelle of functional brain deficits, may lead to improvements in integrative treatments that improve mitochondrial health and brain function.

描述（由申请人提供）：线粒体是通过氧化磷酸化的过程为脑细胞提供大部分能量的细胞器。精神分裂症（SZ）和双相情感障碍（BD）的个体已经报道了线粒体异常和氧化磷酸化缺陷。这笔赠款的总体假设是，基于线粒体功能障碍的证据，线粒体功能障碍是SZ和BD的危险因素之一。）序列变化。在SZ和BD患者中，已经报道了mtDNA中有几种有害的突变。研究人员发现，相对于年龄匹配的对照组，BD受试者的大脑，背外侧前额叶皮层（DLPFC）的大部分MTDNA的缺失增加。与对照组相比，SZ个体的DLPFC中，整个mtDNA基因组中的同义基本对的取代升高，患有SZ的受试者的表达显着降低了10 mtDNA转录本。 SZ中mtDNA转录本的表达降低可能与将测试的对照或编码区中的mtDNA取代增加有关。 SZ中基本对取代增加的原因可能是大脑中遗传的或累积的取代。该赠款的两个目的是研究大脑中的mtDNA取代，并比较同一受试者的生殖系组织中的取代率。该赠款提议检查MTDNA常见缺失，拷贝数和大脑中SZ和BD个体的成绩单丰度，并与对照相比。大脑中新型mtDNA取代和缺失的积累可能是BD和SZ的危险因素，并且在确定未来的慢性情绪和精神疾病治疗目标方面具有巨大的潜在意义。这项研究填补了一个空白，因为没有对整个线粒体基因组和在具有精神疾病的同一受试者进行的整个线粒体基因组和转录组的整合研究。来自脑线粒体基因组和转录组的数据的全面整合可以表明一个或两个系统中的中等功能障碍是否导致疾病阈值。作为功能性脑缺陷的目标细胞器，专注于线粒体，可能会改善整合治疗，从而改善线粒体健康和大脑功能。