Neurosteroids and Schizophrenia

描述：（改编自申请人的摘要）我的职业目标是成为一名 学术精神病学家和独立调查员， 精神分裂症，侧重于其神经生物学和治疗学，应用分子 从机制研究到前瞻性临床研究。我特别 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差异表达，调节GABAA 和NMDA受体，调节神经元细胞结构，证明 神经保护作用，在神经发育中发挥作用，并具有 增强记忆力的效果。因此，神经类固醇是 研究，以阐明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剂，GABA能和 神经元功能失调，神经发育损伤与 精神分裂症风险增加，死后细胞结构异常 精神分裂症患者的样本，以及 disorder.实验室已经证明神经类固醇可以保护胚胎 大脑皮层神经元对缺氧，神经发育损伤 与精神分裂症风险增加有关。我们还证明， 急性奥氮平和氯氮平给药改变大脑皮质 啮齿类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剂（包括显著的 障碍的性别差异）和抗精神病药物作用。我们也 提出影响神经类固醇表达或神经类固醇的化合物 它们本身可以被开发为治疗以下疾病的新型治疗剂： 精神分裂症为了验证这一假设，三种研究策略是 建议：1.）一项检查抗精神病药物对 啮齿类动物的大脑皮质和血清神经类固醇水平，2.）尸检 研究确定顶叶皮质和后部神经类固醇水平 由斯坦利基金会提供的患者的扣带回标本 精神分裂症与对照组相比，以及3.）一项临床研究， 精神分裂症患者神经甾体水平的两项临床研究 (Dr. Lieberman，PI），以确定血清或CSF神经类固醇的改变是否是 与抗精神病疗效、神经认知变化和/或 MRI上的结构变化这些初步调查的结果将 通知未来前瞻性临床研究的设计，以确认初始 发现和目标神经类固醇作为精神分裂症的治疗药物。到 为了实现这些目标，候选人将通过正式的培训， 神经药理学课程，临床试验设计，药物开发，以及 生物统计学她还将学习高度敏感和特定的气体 色谱质谱法（GC/MS）和其他最先进的 神经类固醇检测方法。杰弗里·利伯曼博士的指导， 莱斯利莫罗将是至关重要的总体目标，这一建议， 令人兴奋的临床前神经类固醇发现的成功转化， 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.