Basic to Clinical Molecular Neurobiology of Nicotinic Receptors in Schizophrenia

精神分裂症烟碱受体的临床分子神经生物学基础

• 批准号: 8120344
• 负责人: Robert Freedman
• 金额: $ 201.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120344
• 关键词: Basic; Clinical; Molecular; Neurobiology; Nicotinic

The aims of this Translational Conte Center are (1) to enhance the basic molecular and neurobiological characterization of the role of the alpha7 nicotinic acetylcholine receptor in the brain and its dysfunction in schizophrenia; (2) to use this biology to continue development of a new therapeutic strategy to improve the treatment of cognitive dysfunction and negative symptoms in persons who have schizophrenia (Project 1), and (3) to use emerging information about the developmental role of the receptor to initiate a perinatal intervention for pregnant women and their children to decrease the risk of schizophrenia (Project 2). The Center investigates the potential therapeutic effects of selective alpha 7 nicotinic agonists in animal models of neuronal dysfunction in schizophrenia and then in early human clinical trials in patients with schizophrenia. It examines CHRNA7, the gene for this receptor, to determine how its expression becomes aberrant in schizophrenia (Project 3) and in animal models where the gene is naturally or intentionally mutated (Project 4). It determines in humans and animal models how specific variants in the gene result in dysfunction in the development of inhibitory neuronal circuitry in the hippocampus and other forebrain regions. It then examines the effects of nicotinic agonists that can potentially alter these genetic effects on development. These agonists include selective alpha 7 nicotinic receptor agonists in animal models and nicotine itself in both humans and animal models because some pregnant women smoke cigarettes. Because the endogenous ligand during fetal brain development appears to be choline, the Center also examines the potential beneficial effects of choline supplementation on alpha 7 nicotinic receptor function and neuronal development in a clinical trial in pregnant women and their newborn infants and in related animal models. To support these investigations, the Center develops strategies to image inhibitory function hemodynamically and electrophysiologically, in both adults and infants, and it develops new animal models, including the transfer of human CHRNA7 into mice (Project 5) and models of developmental abnormalities induced by the immune response to infections (Project 6).

该翻译中心的目的是：(1)加强α - 7烟碱乙酰胆碱受体在大脑中的作用及其在精神分裂症中的功能障碍的基本分子和神经生物学特征；(2)利用这一生物学继续发展新的治疗策略，以改善精神分裂症患者的认知功能障碍和阴性症状的治疗（项目1）；(3)利用有关受体发育作用的新信息，启动孕妇及其子女的围产期干预，以降低精神分裂症的风险（项目2）。该中心研究了选择性α - 7尼古丁激动剂在精神分裂症神经元功能障碍动物模型中的潜在治疗效果，然后在精神分裂症患者的早期人类临床试验中进行了研究。该研究检测了该受体的基因CHRNA7，以确定其在精神分裂症（项目3）和该基因自然或故意突变的动物模型（项目4）中的表达如何变得异常。它在人类和动物模型中确定了该基因的特定变异如何导致海马和其他前脑区域抑制性神经元回路发育的功能障碍。然后，它检查了尼古丁激动剂的影响，这些激动剂可能会改变这些对发育的遗传影响。这些激动剂包括动物模型中的选择性- 7尼古丁受体激动剂以及人类和动物模型中的尼古丁本身因为一些孕妇吸烟。由于胎儿大脑发育过程中的内源性配体似乎是胆碱，该中心还在孕妇及其新生儿和相关动物模型的临床试验中研究了补充胆碱对α - 7烟碱受体功能和神经元发育的潜在有益影响。为了支持这些研究，该中心开发了成人和婴儿血液动力学和电生理成像抑制功能的策略，并开发了新的动物模型，包括将人类CHRNA7转移到小鼠（项目5）和由感染免疫反应引起的发育异常模型（项目6）。