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

• 批准号: 7864199
• 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
• 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/7864199
• 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

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）：这是一份申请NIMH面向患者的研究职业发展奖（K23），题为“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受到了其对临床表型相对较小的个体贡献的阻碍。近年来，Sz神经成像仪试图通过测量风险等位基因对大脑生理水平的影响来放大风险等位基因的信号，而不是行为。这种方法已经产生了强大的和内部一致的结果，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，药物发现。候选人的兴趣是成像遗传学的全部转化潜力，作为连接Sz认知障碍的基本机制和新型治疗方法的中转站。为此，候选人以前和拟议的工作涉及Sz中涉及的两个生化途径-叶酸和多巴胺代谢-的交叉点的功能性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 C677 T多态性与Sz患者的工作记忆和前额叶功能障碍相关联。通过与COMT Val 158 Met基因型的诊断特异性相互作用，这些效应被进一步放大，表明MTHFR T等位基因可能加剧Sz的前额多巴胺缺乏症。计划中的研究，一个前瞻性的功能磁共振成像（fMRI）调查的遗传匹配的Sz患者和健康对照，将试图验证和微调的MTHFR有害影响的工作记忆在Sz的拟议机制。MTHFR和COMT基因型将被映射到前额叶功能在维护和时间更新的工作记忆组件，使用任务，已绑定到前额叶多巴胺信号。拟议的研究计划，教学课程，并从导师，顾问和其他顾问的个人指导将促进候选人的发展成为一个独立的临床研究者在Sz的基因效应的功能性神经成像。公共卫生相关性：精神分裂症认知障碍的有效治疗方法仍然很少。希望这些研究将为基于个体遗传变异及其对大脑功能的下游影响开发新的更有效的认知增强策略奠定基础。感兴趣的基因，MTHFR和COMT，有助于两个相关的生化途径，已被牵连在精神分裂症，并适合与目前正在开发的药物有针对性的干预。