Contributions of MTHFR Genotype to Frontal Lobe Dysfunction in Schizophrenia

MTHFR 基因型对精神分裂症额叶功能障碍的影响

基本信息

批准号：
7739938
负责人：
Joshua Lawrence Roffman
金额：
$ 18.62万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7739938
关键词：
Accounting Affect Alleles Antipsychotic Agents Back Behavior Biochemical Pathway Brain Brain imaging Catechol O-Methyltransferase Clinical Investigator DNA Methylation Development Diagnostic Disadvantaged Disease Dopamine Epigenetic Process Event Folate Fostering Foundations Functional Magnetic Resonance Imaging Functional disorder Genes Genetic Genetic Epistasis Genetic Polymorphism Genetic Variation Genotype Heritability Image Image Analysis Impaired cognition Individual Instruction Intervention Investigation K-Series Research Career Programs Maintenance Maps Measures Memory impairment Mentors Metabolic Pathway Metabolism Methylation Methylenetetrahydrofolate reductase (NADPH)Modeling Molecular National Institute of Mental Health Patients Pattern Performance Pharmaceutical Preparations Physiology Prefrontal Cortex Principal Investigator Reaction Research Retrospective Studies Risk Role Schizophrenia Serum Folate Level Short-Term Memory Signal Transduction Suggestion Task Performances Update Variant Work base clinical phenotype cognitive enhancement cohort drug discovery effective therapy falls frontal lobe genetic variant interest methionylmethionine neural model neurogenetics neuroimaging novel patient oriented research prospective public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): This is an application for an NIMH Patient Oriented Research Career Development Award (K23) entitled "Contributions of MTHFR Genotype to Frontal Lobe Dysfunction in Schizophrenia." Although schizophrenia (Sz) is a strongly heritable disorder, the search for risk-conferring genes has been hindered by their relatively small individual contributions to clinical phenotypes. In recent years, Sz neuroimagers have attempted to amplify the signal of risk alleles by measuring their effects on the level of brain physiology, rather than behavior. This approach has yielded results that are robust and internally consistent, but largely disconnected from cellular and molecular pathophysiology, and more importantly, to drug discovery. The candidate's interest is in the full translational potential of imaging-genetics, as a way station connecting basic mechanisms and novel treatments for cognitive impairment in Sz. Toward this end, the candidate's previous and proposed work concerns how functional genetic variants at the intersection of two biochemical pathways implicated in Sz - folate and dopamine metabolism - contribute to prefrontal and working memory function. In retrospective studies, the candidate has associated the MTHFR C677T polymorphism with working memory and prefrontal dysfunction in Sz patients. These effects were further magnified through a diagnostically specific interaction with COMT Val158Met genotype, suggesting that the MTHFR T allele may exacerbate prefrontal dopamine deficiencies in Sz. The planned study, a prospective functional magnetic resonance imaging (fMRI) investigation of genetically matched Sz patients and healthy controls, will attempt to validate and fine-tune the proposed mechanism of deleterious MTHFR effects on working memory in Sz. MTHFR and COMT genotype will be mapped to prefrontal function during maintenance and temporal updating components of working memory, using tasks that have been tied to prefrontal dopamine signaling. The proposed research plan, didactic courses, and individual instruction from mentors, advisors, and other consultants will foster the candidate's development into an independent clinical investigator in the functional neuroimaging of gene effects in Sz. PUBLIC HEALTH RELEVANCE: There remain few effective treatments for cognitive impairment in schizophrenia. It is hoped that these Studies will lay a foundation for the development of new and more efficient cognitive enhancement strategies, based on individual genetic variation and its downstream effects on brain function. The genes of interest, MTHFR and COMT, contribute to two related biochemical pathways that have been implicated in schizophrenia, and are that amenable to targeted interventions with drugs currently in development.

描述（由申请人提供）：这是针对NIMH患者面向研究职业发展奖（K23）的申请，题为“ MTHFR基因型对精神分裂症的额叶功能障碍的贡献”。尽管精神分裂症（SZ）是一种强烈的遗传障碍，但对风险支配基因的搜索受到其对临床表型的相对较小的贡献的阻碍。近年来，SZ Neuroimager试图通过测量其对脑生理水平而不是行为的影响来扩大风险等位基因的信号。这种方法产生了稳健且内部一致的结果，但在很大程度上与细胞和分子病理生理学脱节，更重要的是，与药物发现有关。候选人的兴趣是成像基因学的全部翻译潜力，这是连接基本机制和新型认知障碍的新方法的方式。为此，候选人的先前和提议的工作涉及两种与SZ-叶酸和多巴胺代谢有关的两种生化途径的功能遗传变异如何有助于前额叶和工作记忆功能。在回顾性研究中，候选人将MTHFR C677T多态性与SZ患者的工作记忆和前额外功能障碍相关联。通过与COMT Val158MET基因型的诊断特异性相互作用进一步放大了这些效果，这表明MTHFR T等位基因可能加剧SZ中的前额叶多巴胺缺陷。计划的研究是对遗传匹配的SZ患者和健康对照组的前瞻性功能磁共振成像（fMRI）研究，将试图验证和调整有害MTHFR对SZ工作记忆的有害MTHFR效应的拟议机制。 MTHFR和COMT基因型将在维护和时间更新工作记忆的组件期间映射到前额叶功能，使用与前额叶多巴胺信号相关的任务。拟议的研究计划，教学课程以及导师，顾问和其他顾问的个人指导将促进候选人的发展成独立的临床研究者，从而在SZ中基因效应的功能性神经影像学。公共卫生相关性：精神分裂症中的认知障碍有效治疗很少。希望这些研究将基于基于个体的遗传变异及其对大脑功能的下游影响，为新的，更有效的认知增强策略的发展奠定基础。感兴趣的基因MTHFR和COMT促成了与精神分裂症有关的两种相关的生化途径，并且可以适应目前正在开发的药物的有针对性干预措施。