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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.

这是一份申请NIMH患者导向研究职业发展奖（K23）的申请