Transcriptional Regulation of Metabolism in Schizophrenia

描述（由申请人提供）：在她的大部分科学研究生涯中，Cowell博士研究了神经元细胞死亡和损伤的细胞机制。然而，她最近在长期的研究兴趣方面做出了重大改变，正在进入心理健康研究领域。该提案概述了教学和技术培训以及接触转化型精神分裂症研究中新兴概念的策略，其目标是促进Cowell博士作为独立的，校外资助的，精神健康学术研究者的成功。Cowell的发展计划包括完成课程和参加研究会议，职业发展和研究道德行为研讨会，以及一项研究计划，该计划将在技术和智力上为她走向独立做出贡献。基于初步数据表明过氧化物酶体增殖物激活受体g（PPARg）辅激活剂1a（PGC-1a）参与抑制性神经元的代谢稳态，设计实验来验证以下假设：1）PGC-1a调节代谢和突触可塑性体外和体内GABA能神经元，2）围产期不良事件（缺氧）通过破坏发育中正常的PGC-1a表达和组蛋白乙酰化，对GABA能回路的成熟产生长期影响，精神分裂症患者皮层抑制性中间神经元PGC-1a及相关代谢基因表达水平改变。为了验证这些假设，Cowell博士选择了一组在细胞培养、围产期缺氧的啮齿动物模型、染色质乙酰化/甲基化状态评估和人类死后脑组织激光捕获显微切割方面具有丰富经验的顾问。该计划将使申请人具备解决精神健康研究中关键问题的知识和技术专长，同时阐明大脑发育障碍导致精神分裂症发病机制的机制。精神分裂症是一个重要的健康问题;据估计，1%的一般人口和14%的无家可归者患有精神分裂症。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，并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.