Transcriptional Regulation of Metabolism in Schizophrenia

描述（由申请人提供）：在她的大部分科研生涯中，Cowell博士研究了神经细胞死亡和损伤的细胞机制。然而，她最近在长期研究兴趣上有了重大改变，正在进入心理健康研究领域。该提案概述了一项教学和技术培训策略，以及在转化精神分裂症研究中接触新兴概念的策略，其目标是促进Cowell博士作为一名独立的、外部资助的精神卫生学术研究者取得成功。Cowell博士的发展计划包括完成课程，参加研究会议，职业发展和研究伦理行为研讨会，以及在技术和智力上为她走向独立做出贡献的研究项目。基于初步数据表明过氧化物酶体增殖物激活受体g （ppar）共激活因子1a （PGC-1a）参与抑制性神经元的代谢稳态，本实验旨在验证PGC-1a在体外和体内调节gaba能神经元代谢和突触可塑性的假设。2)围产期不良事件（缺氧）通过破坏发育过程中PGC-1a的正常表达和组蛋白乙酰化，对gaba能回路的成熟产生长期影响；3)精神分裂症患者皮层抑制性中间神经元中PGC-1a及相关代谢基因的表达水平发生改变。为了验证这些假设，Cowell博士选择了一个顾问小组，他们在细胞培养、围生期缺氧啮齿动物模型、染色质乙酰化/甲基化状态评估以及人类死后脑组织的激光显微解剖方面具有丰富的经验。该计划将为申请人提供知识和技术专长，以解决心理健康研究中的关键问题，同时阐明大脑发育障碍导致精神分裂症发病机制。精神分裂症是一个重大的健康问题；据估计，1%的普通人群和14%的无家可归者患有精神分裂症。仅在1990年，精神分裂症的医疗费用就占325亿美元。需要新的治疗方法来改善精神分裂症患者的生活，并防止高危人群出现精神分裂症。

DESCRIPTION (provided by applicant): For much of her scientific research career, Dr. Cowell has studied the cellular mechanisms underlying neuronal cell death and injury. However, she has recently made a significant change in long-term research interests and is in the process of entering the field of mental health research. This proposal outlines a strategy for didactic and technical training and exposure to emerging concepts in translational schizophrenia research, with the goal of promoting Dr. Cowell's success as an independent, extramurally funded, academic investigator in mental health. Dr. Cowell's development plan involves the completion of coursework and attendance at research conferences, workshops in career development and ethical conduct in research, and a program of research that will contribute technically and intellectually to her progress towards independence. Based on preliminary data suggesting that peroxisome proliferator activated receptor g (PPARg) coactivator 1a (PGC-1a) is involved in metabolic homeostasis in inhibitory neurons, experiments are designed to test the hypotheses that 1) PGC-1a regulates metabolism and synaptic plasticity in GABAergic neurons in vitro and in vivo, 2) adverse perinatal events (hypoxia) have a long-term effect on the maturation of GABAergic circuits by disrupting normal PGC-1a expression and histone acetylation in development, and 3) the expression levels of PGC-1a and related metabolic genes are altered in inhibitory interneurons in the cortex of schizophrenic patients. To test these hypotheses, Dr. Cowell has chosen a panel of consultants with extensive experience in cell culture, rodent models of perinatal hypoxia, assessment of chromatin acetylation/methylation status, and laser capture microdissection from human postmortem brain tissue. This plan will equip the applicant with the knowledge and technical expertise to address key issues in mental health research, while elucidating the mechanisms by which disturbances in brain development contribute to the pathogenesis of schizophrenia. Schizophrenia is a significant health concern; it has been estimated that 1% of the general population and 14% of the homeless population has schizophrenia. In 1990 alone, schizophrenia accounted for $32.5 billion in medical costs. New treatments are needed to improve the lives of those with schizophrenia and to prevent the emergence of schizophrenia in high-risk populations.