Contributions of MTHFR Genotype to Frontal Lobe Dysfunction in Schizophrenia

这是一份NIMH以患者为导向的研究职业发展奖(K23)的申请书，名为 “MTHFR基因型别在精神分裂症患者额叶功能障碍中的作用。” 尽管精神分裂症(Sz)是一种遗传性很强的疾病，但对危险基因的研究已经 由于他们对临床表型的个体贡献相对较小而受到阻碍。近年来，Sz 神经成像学家试图通过测量风险等位基因对脑血管紧张素转换酶水平的影响来放大其信号。 大脑生理，而不是行为。这种方法产生了稳健的、内部的结果 始终如一，但在很大程度上与细胞和分子病理生理无关，更重要的是， 药物发现。候选人感兴趣的是成像遗传学的全部翻译潜力，作为一种方式 深圳认知障碍的基本机制和新疗法的连结站。 为此，候选人之前和提议的工作涉及功能性基因变异如何 参与Sz-叶酸和多巴胺代谢的两条生化途径的交集--贡献 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基因多态性与工作记忆和前额叶功能障碍的关系这些影响 通过与COMT Val158Met基因型的诊断特异性相互作用进一步放大， 提示亚甲基四氢叶酸还原酶T等位基因可能加重Sz前额叶多巴胺缺乏。 这项计划中的研究是一项前瞻性的功能磁共振成像(FMRI)研究 基因匹配的SZ患者和健康对照将尝试验证和微调所提出的 亚甲基四氢叶酸还原酶对深圳地区工作记忆影响的机制。MTHFR和COMT基因将是 在工作记忆的维护和时间更新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，说教 课程，以及来自导师、顾问和其他顾问的个人指导，将培养候选人的 在深圳基因效应的功能神经成像方面发展成为独立的临床研究者。 相关性(请参阅说明)： 精神分裂症认知障碍的有效治疗方法仍然很少。希望这些都是 研究将为开发新的、更有效的认知增强奠定基础 策略，基于个体遗传变异及其对大脑功能的下游影响。人类的基因 兴趣，MTHFR和COMT，促成了两个相关的生化途径，这两个途径已被牵连到 精神分裂症，而且对目前正在开发的药物进行有针对性的干预。

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.