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: 8310139
• 负责人: Robert Freedman
• 金额: $ 195.16万
• 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/8310139
• 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; Infant Development; Infection; Intervention; Investigation; Ligands; Modeling; Molecular; Molecular Neurobiology; Mus; Mutate; Neurobiology; Neuronal Dysfunction; Newborn Infant; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Nutrient; Patients; Persons; Pharmaceutical Preparations; Pregnant Women; Prosencephalon; Psychotic Disorders; Receptor Gene; Risk; Role; Schizophrenia; Supplementation; Symptoms; Therapeutic Effect; Variant; alpha-bungarotoxin receptor; cigarette smoking; design; fetal; improved; neuron development; neuronal circuitry; new therapeutic target; novel therapeutics; perinatal intervention; prevent; receptor; receptor function

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Conte转化中心的目标是（1）增强大脑中α7烟碱乙酰胆碱受体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) 利用这种生物学继续开发新的治疗策略，以改善精神分裂症患者认知功能障碍和阴性症状的治疗（项目 1），以及 (3) 利用有关受体发育作用的新信息对孕妇及其子女启动围产期干预，以降低精神分裂症的风险（项目 2）。该中心研究选择性α7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效果，然后在精神分裂症患者的早期人体临床试验中进行研究。 它检查 CHRNA7（该受体的基因），以确定其表达如何在精神分裂症（项目 3）以及该基因自然或有意突变的动物模型（项目 4）中变得异常。它在人类和动物模型中确定基因中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功能障碍。然后，它检查了烟碱激动剂的影响，这些激动剂可能会改变这些遗传对发育的影响。这些激动剂包括动物模型中的选择性 α7 烟碱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，因此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 α7 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，该中心制定了对成人和婴儿的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，包括将人类 CHRNA7 转移到小鼠体内（项目 5）和由感染免疫反应诱导的发育异常模型（项目 6）。