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：
8247076
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 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8247076
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 research study

项目摘要

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. RELEVANCE (See instructions): 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.

这是NIMH以NIMH患者为导向的研究职业发展奖（K23）的申请。 “ MTHFR基因型对精神分裂症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，但寻找风险支配基因的疾病已有由于他们对临床表型的个人贡献相对较小而受到阻碍。近年来，SZ 神经模子试图通过测量其对水平的影响来扩大风险等位基因的信号大脑生理学，而不是行为。这种方法产生了稳健且内部的结果一致，但在很大程度上与细胞和分子病理生理学断开，更重要的是药物发现。候选人的兴趣是成像基因学的全部翻译潜力，连接SZ认知障碍的基本机制和新的治疗方法。为此，候选人的先前和提议的工作涉及功能性遗传变异与Sz叶酸和多巴胺代谢有关的两种生化途径的交集贡献前额叶和工作记忆功能。在回顾性研究中，候选人已将 SZ患者的MTHFR C677T多态性具有工作记忆和前额外功能障碍。这些影响通过与COMT Val158MET基因型的诊断特异性相互作用进一步放大表明MTHFR T等位基因可能加剧SZ中的前额叶多巴胺缺陷。计划研究，一种前瞻性功能磁共振成像（fMRI）研究遗传匹配的SZ患者和健康对照将尝试验证和微调所提出的有害MTHFR对SZ工作记忆的影响的机制。 MTHFR和COMT基因型将是在维护和时间更新工作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，教学导师，顾问和其他顾问的课程以及个人指导将促进候选人的开发在SZ中基因作用的功能性神经影像学方面发展成独立的临床研究者。相关性（请参阅说明）：在精神分裂症中，几乎没有有效的认知障碍治疗方法。希望这些研究将为发展新的，更有效的认知增强奠定基础基于个体遗传变异及其对大脑功能的下游影响的策略。基因 MTHFR和COMT的兴趣有助于两种相关的生化途径精神分裂症，是针对目前正在开发的药物的有针对性干预措施的。