Transcriptional Regulation of Metabolism in Schizophrenia

描述(申请人提供)：在她的大部分科学研究生涯中，考威尔博士一直在研究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变化，正在进入心理健康研究领域。这项提案概述了传授和技术培训的战略，以及在翻译型精神分裂症研究中接触新兴概念的机会，目的是促进考威尔博士作为一名独立的、由校外资助的心理健康学术研究人员取得成功。考威尔博士的发展计划包括完成课程和参加研究会议、职业发展研讨会和研究中的道德行为，以及一个有助于她在技术和智力上取得独立进步的研究计划。根据初步数据提示PPARg共激活受体1a(PGC-1a)参与抑制性神经元的代谢动态平衡，本实验旨在验证如下假设：1)PGC-1a在体内外调节GABA能神经元的代谢和突触可塑性；2)围产期不良事件(低氧)通过干扰正常的PGC-1a表达和发育中的组蛋白乙酰化而影响GABA能回路的成熟；以及3)精神分裂症患者皮质抑制性中间神经元中PGC-1a和相关代谢基因的表达水平发生改变。为了验证这些假设，考威尔博士选择了一个顾问小组，他们在细胞培养、围产期缺氧的啮齿动物模型、染色质乙酰化/甲基化状态的评估以及激光捕获人类死后脑组织的显微解剖方面拥有丰富的经验。该计划将为申请者提供知识和技术专长，以解决精神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的发病机制。精神分裂症是一个重大的健康问题；据估计，1%的总人口和14%的无家可归人口患有精神分裂症。仅在1990年，精神分裂症就占了325亿美元的医疗费用。需要新的治疗方法来改善精神分裂症患者的生活，防止精神分裂症在高危人群中出现。

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.