Neurosteroids and Schizophrenia

描述：(改编自应聘者摘要)我的职业目标是成为一名 学术精神病学家和独立调查员在以下领域 精神分裂症的神经生物学和治疗学，应用分子 从基于机理的研究到前瞻性临床研究。具体来说，我 建议研究神经类固醇在精神分裂症中的重要性。 神经类固醇在男性和女性中的差异表达，调节GABAA 而调节神经元细胞结构的NMDA受体则表明 神经保护作用，在神经发育中发挥作用，并拥有 增强记忆力的效果。因此，神经类固醇是符合逻辑的候选药物 调查精神分裂症的病理生理学，因为他们是 精神分裂症性别差异的潜在调节因子--GABA和 谷氨酸能失调，神经发育障碍与 死后精神分裂症风险增加，细胞结构异常 精神分裂症患者的样本和认知障碍 无序。实验室已经证明神经类固醇对胚胎有保护作用 大脑皮层神经元抵抗缺氧，这是一种神经发育损害 与精神分裂症风险增加有关。我们也证明了 奥氮平和氯氮平急性给药改变大脑皮层 啮齿动物体内的神经类固醇。研究人员假设神经类固醇是 精神分裂症病理生理学的重要调节因子(包括明显的 精神障碍的性别差异)和抗精神病药物的作用。我们也 提出影响神经类固醇表达或神经类固醇的化合物 它们本身可能被开发为治疗糖尿病的新的治疗剂 精神分裂症。为了验证这一假设，有三种调查策略 建议：1.)一项检测抗精神病药物对患者的影响的临床前研究 啮齿类动物的大脑皮层和血清神经类固醇水平，2。验尸报告 测定顶叶皮质及后部神经类固醇水平的研究 斯坦利基金会提供的患者的扣带细胞标本 精神分裂症与对照组比较，以及3)。一项临床研究检查 北卡罗来纳大学两项临床试验中精神分裂症患者的神经类固醇水平 (利伯曼博士，PI)确定血清或脑脊液神经类固醇改变是否 与抗精神病药物疗效、神经认知变化和/或 核磁共振的结构改变。这些初步调查的结果将 通知未来前瞻性临床研究的设计，以确认最初的 神经类固醇作为精神分裂症治疗药物的发现和靶向。至 达到这些目标，应聘者将接受正式的 神经药理学、临床试验设计、药物开发和 生物统计学。她还将学习高度敏感和特定的气体 色谱质谱(GC/MS)和其他最新技术 神经类固醇检测方法。杰弗里·利伯曼博士和 莱斯利·莫罗将对这项提案的总体目标至关重要， 令人兴奋的临床前神经类固醇研究成果成功转化为 精神分裂症患者神经类固醇的前瞻性临床研究 病理生理学和治疗学。

DESCRIPTION: (Adapted from applicant's abstract) My career goal is to become an academic psychiatrist and independent investigator in the areas of schizophrenia focusing on its neurobiology and therapeutics, applying molecular mechanism-based research to prospective clinical studies. Specifically, I propose to investigate the importance of neurosteroids in schizophrenia. Neurosteroids are differentially expressed in males and females, modulate GABAA and NMDA receptors, regulate neuronal cytoarchitecture, demonstrate neuroprotective effects, play a role in neurodevelopment, and possess memory-enhancing effects. Neurosteroids are therefore logical candidates of investigation to elucidate schizophrenia pathophysiology, since they are potential modulators of schizophrenia gender differences, GABAergic and glutamatergic dysregulation, neurodevelopmental insults associated with increased schizophrenia risk, cytoarchitectural abnormalities in postmortem specimens from patients with schizophrenia, and cognitive disturbances in the disorder. The laboratory has demonstrated that neurosteroids protect embryonic cerebral cortical neurons against anoxia, a neurodevelopmental insult associated with increased schizophrenia risk. We have also demonstrated that acute olanzapine and clozapine administration alters cerebral cortical neurosteroids in rodents. The investigators hypothesize that neurosteroids are important modulators of schizophrenia pathophysiology (including the pronounced gender differences of the disorder) and antipsychotic drug action. We also propose that compounds affecting neurosteroid expression or neurosteroids themselves may be developed as novel therapeutic agents in the treatment of schizophrenia. To test this hypothesis, three investigational strategies are proposed: 1.) A preclinical study examining the effects of antipsychotics on cerebral cortical and serum neurosteroid levels in rodents, 2.) A postmortem study determining neurosteroid levels in parietal cortex and posterior cingulate specimens provided by the Stanley Foundation from patients with schizophrenia compared to control subjects, and 3.) A clinical study examining neurosteroid levels in subjects with schizophrenia from two UNC clinical trials (Dr. Lieberman, PI) to determine if serum or CSF neurosteroid alterations are correlated with antipsychotic efficacy, neurocognitive changes, and/or structural changes on MRI. Results from these preliminary investigations will inform the design of future prospective clinical studies to confirm initial findings and target neurosteroids as therapeutic agents in schizophrenia. To achieve these goals, the candidate will receive training through formal coursework in neuropharmacology, clinical trials design, drug development, and biostatistics. She will also learn highly sensitive and specific gas chromatography mass spectrometry (GC/MS) and other state-of-the-art neurosteroid detection methods. The mentorship of Drs. Jeffrey Lieberman and Leslie Morrow will be critical to the overarching goal of this proposal, the successful translation of exciting preclinical neurosteroid findings to prospective clinical studies examining neurosteroids in schizophrenia pathophysiology and therapeutics.