Mitochondrial Deletions in Mood Disorders

情绪障碍中的线粒体缺失

基本信息

批准号：
8605235
负责人：
MARQUIS PHILIP VAWTER
金额：
$ 23.14万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-14 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8605235
关键词：
Accounting Affect Affective Age Anhedonia Animals Area Autopsy Base Pairing Biological Assay Bipolar Disorder Brain Brain region Cell physiology Cells Cognition Complementary DNA Corpus striatum structure Custom DNA Data Decision Making Dependence Direct Costs Energy Metabolism Energy-Generating Resources Enzyme-Linked Immunosorbent Assay Facilities and Administrative Costs Foundations Functional disorder Gene Mutation Genetic Variation Genomics Human In Vitro Inherited Knowledge Lead Life Lithium Longevity Major Depressive Disorder Mental disorders Messenger RNA Metabolic Mitochondria Mitochondrial DNA Mitochondrial Diseases Monoclonal Antibodies Mood Disorders Morphologic artifacts Motor output Muscle Neurons Nuclear Organ Organelles Oxygen Consumption Pharmaceutical Preparations Predisposition Preparation Process Protein Truncation Proteins Proteomics RNA Reading Regulation Reporting Research Research Personnel Risk Role Sampling Sequence Analysis Sequence Deletion Somatic Mutation Source Time Tissues Translations Variant age related base case control disability improved insertion/deletion mutation interest mRNA Transcript Degradation mitochondrial dysfunction mutant neuroimaging neuronal cell body next generation sequencing novel public health relevance screening single molecule success transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial Deletions in Mood Disorders Mood disorders (bipolar disorder, BD; major depressive disorder, MDD) account for a high percentage of life- time disability on a world-wide basis, shortened life span, and devastating personal impacts. The pathophysiology of mood disorders, implicates major abnormalities in energy metabolism and mitochondrial function. Mitochondrial dysfunction and disease can be inherited from genetic mutation and can affect multiple target organs, including the brain. We believe that part of the risk for developing mood disorders is genetic variation involving mitochondria DNA (mtDNA). We have replicated our initial findings that a large common somatic deletion of 4,977 base pairs of mtDNA is increased in mood disorders compared to controls. It is important to note that these large deletions of mtDNA appear more frequently in tissues with high metabolic rates, such as brain and muscle and accumulate in an age dependent manner. We believe the study of the full spectrum of large deletions and possible translation into protein will provide substantial evidence supporting the role of mitochondrial dysfunction in mood disorders. In this proposal we hypothesize that large somatic mtDNA deletions accumulate in brain to high levels in mood disorders leading to abnormalities in mitochondrial function. We propose three Specific Aims focusing on the accumulation of large deletions in MDD and BD. 1) Collect fresh mitochondria from human brain (10 MDD, 10 BD, and 10 controls) from which we will sample fourteen brain regions implicated in cognition, affective regulation, and anhedonia in mood disorders. 2) Generate a spectrum of large deletion sequences in mtDNA and cDNA in human brain. 3) Determine the impact of large deletion sequences on proteins and on mitochondria function. We have already discovered novel large somatic mtDNA deletions in postmortem human brains, and are now ready to screen the full spectrum of mtDNA deletions that might cause mitochondrial dysfunction in psychiatric disorders. These novel deletions occur in brain samples at even higher levels compared to the known common deletion of mtDNA. Currently, there are no reports of either protein translation or functional effects of these large deletions i human brain. In the interest of collaborative research, we will share all mtDNA deletion sequences at NCBI. These results could lead to novel treatments that target mitochondrial functional deficits and reduce the accumulation of somatic deletions, thereby improving therapy of mood disorders.

描述（由申请人提供）：情绪障碍的线粒体缺失情绪障碍（双相情感障碍，BD；主要抑郁症，MDD）在全球范围内占终身残疾的比例很高，寿命缩短，损坏了个人的个人残疾影响。情绪障碍的病理生理学意味着能量代谢和线粒体功能的主要异常。线粒体功能障碍和疾病可以从遗传突变中遗传，并可能影响包括大脑在内的多个目标器官。我们认为，发展情绪障碍的一部分风险是涉及线粒体DNA（mtDNA）的遗传变异。我们已经复制了我们的初步发现，与对照组相比，情绪障碍的4,977个碱基对的大型躯体缺失增加了情绪障碍。重要的是要注意，这些大的mtDNA缺失在具有高代谢率（例如大脑和肌肉）的组织中更频繁地出现，并且以年龄的依赖方式积累。我们认为，对大量缺失以及可能转化为蛋白质的研究将提供大量证据，以支持线粒体功能障碍在情绪障碍中的作用。在此提案中，我们假设大型体细胞mtDNA缺失在大脑中积累到高水平的情绪障碍，导致线粒体功能异常。我们提出了三个特定的目标，重点是在MDD和BD中的大量缺失。 1）从人脑（10 MDD，10 BD和10个对照）中收集新鲜的线粒体，从中我们将采样涉及认知，情感调节和Anhedonia在情绪障碍中的十四个大脑区域。 2）在人脑中的mtDNA和cDNA中产生大量缺失序列。 3）确定大缺失序列对蛋白质和线粒体功能的影响。我们已经发现了尸体人类大脑中新型的大型体细胞mtDNA缺失，现在可以筛选出可能引起精神病障碍线粒体功能障碍的MTDNA缺失。与已知的MTDNA公共缺失相比，这些新型的缺失在更高水平的大脑样品中发生。当前，尚无关于这些大型缺失I人脑的蛋白质翻译或功能效应的报道。为了协作研究，我们将在NCBI共享所有mtDNA缺失序列。这些结果可能导致新的治疗方法，以靶向线粒体功能缺陷并减少体细胞缺失的积累，从而改善情绪障碍的治疗。