Contributions of MTHFR Genotype to Frontal Lobe Dysfunction in Schizophrenia

描述(申请人提供)：这是一份NIMH以患者为导向的研究职业发展奖(K23)的申请书，题为“MTHFR基因型别对精神分裂症患者额叶功能障碍的贡献”。虽然精神分裂症(Sz)是一种高度可遗传的疾病，但由于其相对较小的个体对临床表型的贡献，对危险相关基因的寻找一直受到阻碍。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，而不是对行为的影响，来放大风险等位基因的信号。这种方法已经产生了稳健和内部一致的结果，但在很大程度上与细胞和分子病理生理学无关，更重要的是，与药物发现无关。候选人感兴趣的是成像遗传学的全部翻译潜力，作为连接Sz认知障碍的基本机制和新疗法的中转站。为此，候选人之前和提议的工作涉及两条生化途径交叉处的功能性遗传变异-叶酸和多巴胺代谢-如何有助于前额叶和工作记忆功能。在回溯性研究中，候选人将亚甲基四氢叶酸还原酶C677T多态与Sz患者的工作记忆和前额叶功能障碍联系起来。通过与COMT Val158Met基因的诊断特异性相互作用，这些效应进一步放大，表明MTHFR T等位基因可能加剧了Sz的前额叶多巴胺缺乏。这项计划中的研究是对基因匹配的Sz患者和健康对照进行的前瞻性功能磁共振成像(FMRI)研究，将试图验证和微调提出的有害MTHFR对Sz工作记忆影响的机制。MTHFR和COMT基因型将被映射到前额叶功能，在工作记忆的维护和时间更新部分，使用与前额叶多巴胺信号相关的任务。拟议的研究计划、教学课程以及来自导师、顾问和其他顾问的个人指导将促进候选人发展为Sz基因效应功能神经成像领域的独立临床研究员。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的新的、更有效的认知增强策略的开发奠定基础。相关基因MTHFR和COMT有助于两个相关的生化途径，这两个途径与精神分裂症有关，并且可以通过目前正在开发的药物进行有针对性的干预。

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.