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

• 批准号: 8241152
• 负责人: MARQUIS PHILIP VAWTER
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241152
• 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; transcriptomics

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. PUBLIC HEALTH RELEVANCE: Project Narrative/Relevance The causes of schizophrenia and bipolar disorder have not been discovered. This grant proposes to analyze mitochondrial DNA, contained in brain cells, which might harbor abnormal structure and sequence. Alterations in mitochondrial sequence during the lifespan in brain might contribute to risk of developing a serious mental disorder. By understanding the accumulation of mitochondrial DNA defects in brain, it will advance mitochondrial medicine for earlier diagnosis and treatment of brain related disorders.

描述（由申请人提供）：线粒体是通过氧化磷酸化过程为脑细胞提供大部分能量的细胞器。据报道，精神分裂症（SZ）和躁郁症（BD）患者存在线粒体异常和氧化磷酸化缺陷。这项资助的总体假设是，线粒体功能障碍是 SZ 和 BD 的危险因素之一，基于转录组学、蛋白质组学和代谢组学研究、家庭遗传学研究、体内神经影像研究和线粒体 DNA (mtDNA) 中线粒体功能障碍的证据。 ) 序列变异。据报道，精神分裂症和双相情感障碍患者的线粒体 DNA 中存在一些轻微有害的突变。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) 中大部分 mtDNA 的缺失增加。与对照组相比，SZ 患者的 DLPFC 中整个 mtDNA 基因组中同义碱基对的替换升高，并且 SZ 患者的 10 个 mtDNA 转录物的表达显着降低。 SZ 中 mtDNA 转录物表达的减少可能与将要测试的对照或编码区中 mtDNA 替换增加有关。 SZ 中碱基对取代增加的原因可能是遗传或大脑中累积的取代。这笔拨款的两个目的是研究大脑中的 mtDNA 替代，并比较同一受试者9种系组织中的替代率。这笔资助计划检查 SZ 和 BD 患者大脑中 mtDNA 常见缺失、拷贝数和转录本丰度，并与对照组进行比较。大脑中新的 mtDNA 替换和缺失的积累可能是 BD 和 SZ 的危险因素，并且对于确定慢性情绪和精神障碍的未来治疗目标具有巨大的潜在意义。这项研究填补了一项空白，因为尚未对同一患有精神疾病的受试者进行整个线粒体基因组和转录组的综合大脑研究。脑线粒体基因组和转录组数据的全面整合可以显示一个或两个系统的中度功能障碍是否会导致疾病阈值。关注线粒体作为功能性大脑缺陷的目标细胞器，可能会导致改善线粒体健康和大脑功能的综合治疗的改进。公共卫生相关性：项目叙述/相关性 精神分裂症和双相情感障碍的病因尚未被发现。这笔资助计划分析脑细胞中可能含有异常结构和序列的线粒体 DNA。大脑生命周期中线粒体序列的改变可能会增加患严重精神障碍的风险。通过了解大脑中线粒体 DNA 缺陷的积累，将推动线粒体医学的发展，以实现大脑相关疾病的早期诊断和治疗。