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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：
8416438
负责人：
Joshua Lawrence Roffman
金额：
$ 16.42万
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 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8416438
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面向患者的研究职业发展奖（K23）的申请， “MTHFR基因型对精神分裂症额叶功能障碍的贡献。" 虽然精神分裂症（Sz）是一种强遗传性疾病，但对风险基因的研究已经取得了进展。由于其对临床表型的个体贡献相对较小而受到阻碍。近年来，神经成像学家试图通过测量风险等位基因对神经元水平的影响来放大风险等位基因的信号。大脑生理学，而不是行为。这一办法产生了强有力的结果，一致，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，药物发现候选人的兴趣在于成像遗传学的全部转化潜力，站连接的基本机制和新的治疗认知障碍的Sz。为此，候选人以前和拟议的工作涉及功能性遗传变异如何在 Sz中涉及的两种生化途径的交叉-叶酸和多巴胺代谢-有助于前额叶和工作记忆功能。在回顾性研究中，候选人将 Sz患者MTHFR C677 T多态性与工作记忆和前额叶功能障碍这些影响通过与COMT Val 158 Met基因型的诊断特异性相互作用进一步放大，提示MTHFR T等位基因可能加重Sz. 这项计划中的研究是一项前瞻性的功能性磁共振成像（fMRI）研究，基因匹配的Sz患者和健康对照，将试图验证和微调提出的 MTHFR对Sz. MTHFR和COMT基因型将是映射到工作记忆的维持和时间更新组件期间的前额叶功能，使用与前额多巴胺信号有关的任务。建议的研究计划，教学课程，以及导师，顾问和其他顾问的个人指导将培养候选人的发展成为一个独立的临床研究者在功能性神经成像的基因效应在Sz。相关性（参见说明）：精神分裂症认知障碍的有效治疗方法仍然很少。希望这些研究将为开发新的、更有效的认知增强技术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。的基因感兴趣的是MTHFR和COMT，它们参与了两种相关的生化途径，精神分裂症，并适合目前正在开发的药物的靶向干预。