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: 8063248
• 负责人: Robert Freedman
• 金额: $ 50万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063248
• 关键词: Adult; Agonist; Animal Model; Biology; Brain; Child; Choline; Clinical; Clinical Trials; Development; Functional disorder; Genes; Genetic; Hippocampus (Brain); Human; Image; Immune response; Impaired cognition; Infant; Infection; Investigation; Ligands; Modeling; Molecular; Molecular Neurobiology; Mus; Mutate; Neurobiology; Neuronal Dysfunction; Newborn Infant; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Patients; Persons; Pregnant Women; Prosencephalon; Receptor Gene; Risk; Role; Schizophrenia; Supplementation; Symptoms; Therapeutic Effect; Variant; alpha-bungarotoxin receptor; cigarette smoking; fetal; improved; neuron development; neuronal circuitry; novel therapeutics; perinatal intervention; receptor; receptor function

DESCRIPTION (provided by applicant): 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).

描述（由申请人提供）：该Conte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表征;（二）利用这种生物学继续开发一种新的治疗策略，以改善对患有认知功能障碍和阴性症状的人的治疗，精神分裂症（项目1），和（3）使用新出现的信息受体的发育作用，开始围产期干预孕妇及其子女，以减少精神分裂症的风险（项目2）。该中心研究了选择性α 7烟碱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作用，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。 它检查了CHRNA 7，这种受体的基因，以确定其表达如何变得异常， 精神分裂症（项目3）和动物模型中的基因是自然或故意突变（项目4）。它决定了在人类和动物模型中，基因中的特定变体如何导致海马和其他前脑区域中抑制性神经元回路发育的功能障碍。然后，它检查了可能改变这些遗传效应对发育的烟碱激动剂的影响。这些激动剂包括动物模型中的选择性α 7烟碱受体激动剂和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的临床试验和相关动物模型中研究了胆碱补充对α 7烟碱受体功能和神经元发育的潜在有益作用。为了支持这些研究，该中心制定了在成人和婴儿中对血流动力学和电生理学抑制功能进行成像的策略，并开发了新的动物模型，包括将人CHRNA 7转移到小鼠中（项目5）和由感染免疫反应诱导的发育异常模型（项目6）。